OA20008A - Pharmaceutical composition in the form of a chewable tablet of Diosmin or of a flavonoid moiety. - Google Patents
Pharmaceutical composition in the form of a chewable tablet of Diosmin or of a flavonoid moiety. Download PDFInfo
- Publication number
- OA20008A OA20008A OA1202100022 OA20008A OA 20008 A OA20008 A OA 20008A OA 1202100022 OA1202100022 OA 1202100022 OA 20008 A OA20008 A OA 20008A
- Authority
- OA
- OAPI
- Prior art keywords
- micronised
- pharmaceutical composition
- diosmin
- active ingrédient
- polyol
- Prior art date
Links
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 46
- GZSOSUNBTXMUFQ-NJGQXECBSA-N 5,7,3'-Trihydroxy-4'-methoxyflavone 7-O-rutinoside Natural products O(C[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@H](Oc2cc(O)c3C(=O)C=C(c4cc(O)c(OC)cc4)Oc3c2)O1)[C@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@H](C)O1 GZSOSUNBTXMUFQ-NJGQXECBSA-N 0.000 title claims abstract description 35
- 229960004352 diosmin Drugs 0.000 title claims abstract description 35
- GZSOSUNBTXMUFQ-YFAPSIMESA-N diosmin Chemical compound C1=C(O)C(OC)=CC=C1C(OC1=C2)=CC(=O)C1=C(O)C=C2O[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO[C@H]2[C@@H]([C@H](O)[C@@H](O)[C@H](C)O2)O)O1 GZSOSUNBTXMUFQ-YFAPSIMESA-N 0.000 title claims abstract description 34
- 239000007910 chewable tablet Substances 0.000 title claims abstract description 28
- 229940068682 Chewable Tablet Drugs 0.000 title claims abstract description 20
- 150000002215 flavonoids Chemical group 0.000 title claims description 36
- 201000002282 venous insufficiency Diseases 0.000 claims abstract description 5
- 229930003935 flavonoids Natural products 0.000 claims description 36
- 235000021285 flavonoid Nutrition 0.000 claims description 31
- 239000000203 mixture Substances 0.000 claims description 26
- 229920005862 polyol Polymers 0.000 claims description 25
- 150000003077 polyols Chemical class 0.000 claims description 25
- 238000000034 method Methods 0.000 claims description 11
- 238000004519 manufacturing process Methods 0.000 claims description 10
- 239000011230 binding agent Substances 0.000 claims description 9
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 7
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 7
- 239000000600 sorbitol Substances 0.000 claims description 7
- MBNGWHIJMBWFHU-UHFFFAOYSA-N Diosmetin Chemical compound C1=C(O)C(OC)=CC=C1C1=CC(=O)C2=C(O)C=C(O)C=C2O1 MBNGWHIJMBWFHU-UHFFFAOYSA-N 0.000 claims description 6
- YFVGIJBUXMQFOF-SAXLCNSLSA-N Linarin Natural products O(C[C@H]1[C@@H](O)[C@H](O)[C@H](O)[C@H](Oc2cc(O)c3C(=O)C=C(c4ccc(OC)cc4)Oc3c2)O1)[C@H]1[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O1 YFVGIJBUXMQFOF-SAXLCNSLSA-N 0.000 claims description 6
- 238000007907 direct compression Methods 0.000 claims description 4
- 239000000314 lubricant Substances 0.000 claims description 4
- 239000001100 (2S)-5,7-dihydroxy-2-(3-hydroxy-4-methoxyphenyl)chroman-4-one Substances 0.000 claims description 3
- 229940025878 Hesperidin Drugs 0.000 claims description 3
- QUQPHWDTPGMPEX-YEDPJISVSA-N Hesperidin Natural products O(C[C@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@H](Oc2cc(O)c3C(=O)C[C@@H](c4cc(O)c(OC)cc4)Oc3c2)O1)[C@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@H](C)O1 QUQPHWDTPGMPEX-YEDPJISVSA-N 0.000 claims description 3
- FKIYLTVJPDLUDL-SLNHTJRHSA-N Isorhoifolin Chemical compound O[C@@H]1[C@H](O)[C@@H](O)[C@H](C)O[C@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@H](OC=2C=C3C(C(C=C(O3)C=3C=CC(O)=CC=3)=O)=C(O)C=2)O1 FKIYLTVJPDLUDL-SLNHTJRHSA-N 0.000 claims description 3
- 235000015428 diosmetin Nutrition 0.000 claims description 3
- 229960001876 diosmetin Drugs 0.000 claims description 3
- QUQPHWDTPGMPEX-QJBIFVCTSA-N hesperidin Chemical compound C1=C(O)C(OC)=CC=C1[C@H]1OC2=CC(O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@@H](CO[C@H]4[C@@H]([C@H](O)[C@@H](O)[C@H](C)O4)O)O3)O)=CC(O)=C2C(=O)C1 QUQPHWDTPGMPEX-QJBIFVCTSA-N 0.000 claims description 3
- 238000007908 dry granulation Methods 0.000 claims description 2
- 238000005550 wet granulation Methods 0.000 claims description 2
- 239000000843 powder Substances 0.000 description 16
- 239000002245 particle Substances 0.000 description 14
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 12
- 239000008187 granular material Substances 0.000 description 10
- 239000000796 flavoring agent Substances 0.000 description 9
- 235000019634 flavors Nutrition 0.000 description 8
- 239000000377 silicon dioxide Substances 0.000 description 6
- FBPFZTCFMRRESA-KAZBKCHUSA-N D-Mannitol Natural products OC[C@@H](O)[C@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KAZBKCHUSA-N 0.000 description 5
- FBPFZTCFMRRESA-KVTDHHQDSA-N Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 5
- 235000017173 flavonoids Nutrition 0.000 description 5
- 235000003599 food sweetener Nutrition 0.000 description 5
- 239000000594 mannitol Substances 0.000 description 5
- 235000010355 mannitol Nutrition 0.000 description 5
- 239000003765 sweetening agent Substances 0.000 description 5
- 239000003826 tablet Substances 0.000 description 5
- 229960004998 Acesulfame potassium Drugs 0.000 description 4
- WBZFUFAFFUEMEI-UHFFFAOYSA-N Acesulfame potassium Chemical compound [K+].CC1=CC(=O)NS(=O)(=O)O1 WBZFUFAFFUEMEI-UHFFFAOYSA-N 0.000 description 4
- 235000010358 acesulfame potassium Nutrition 0.000 description 4
- 239000000619 acesulfame-K Substances 0.000 description 4
- 239000003085 diluting agent Substances 0.000 description 4
- 239000007968 orange flavor Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 239000005913 Maltodextrin Substances 0.000 description 3
- 229920002774 Maltodextrin Polymers 0.000 description 3
- 238000005461 lubrication Methods 0.000 description 3
- 229940035034 maltodextrin Drugs 0.000 description 3
- 230000036912 Bioavailability Effects 0.000 description 2
- 235000005979 Citrus limon Nutrition 0.000 description 2
- 240000002268 Citrus limon Species 0.000 description 2
- 241001093501 Rutaceae Species 0.000 description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N Stearic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
- 230000035514 bioavailability Effects 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 230000001055 chewing Effects 0.000 description 2
- 238000005056 compaction Methods 0.000 description 2
- 238000007906 compression Methods 0.000 description 2
- 230000001079 digestive Effects 0.000 description 2
- 238000009826 distribution Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 230000002708 enhancing Effects 0.000 description 2
- 238000001033 granulometry Methods 0.000 description 2
- 230000018984 mastication Effects 0.000 description 2
- 239000000546 pharmaceutic aid Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 235000019605 sweet taste sensations Nutrition 0.000 description 2
- 230000001225 therapeutic Effects 0.000 description 2
- IAOZJIPTCAWIRG-QWRGUYRKSA-N Aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 description 1
- 229960003438 Aspartame Drugs 0.000 description 1
- 108010011485 Aspartame Proteins 0.000 description 1
- 206010007191 Capillary fragility Diseases 0.000 description 1
- 229940109275 Cyclamate Drugs 0.000 description 1
- 210000003141 Lower Extremity Anatomy 0.000 description 1
- VQHSOMBJVWLPSR-WUJBLJFYSA-N Maltitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O VQHSOMBJVWLPSR-WUJBLJFYSA-N 0.000 description 1
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinylpyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 229960003975 Potassium Drugs 0.000 description 1
- 229940069328 Povidone Drugs 0.000 description 1
- 208000005793 Restless Legs Syndrome Diseases 0.000 description 1
- 229940085605 Saccharin Sodium Drugs 0.000 description 1
- WINXNKPZLFISPD-UHFFFAOYSA-M Saccharin sodium Chemical compound [Na+].C1=CC=C2C(=O)[N-]S(=O)(=O)C2=C1 WINXNKPZLFISPD-UHFFFAOYSA-M 0.000 description 1
- UDIPTWFVPPPURJ-UHFFFAOYSA-M Sodium cyclamate Chemical compound [Na+].[O-]S(=O)(=O)NC1CCCCC1 UDIPTWFVPPPURJ-UHFFFAOYSA-M 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 235000009499 Vanilla fragrans Nutrition 0.000 description 1
- 240000006722 Vanilla planifolia Species 0.000 description 1
- 235000012036 Vanilla tahitensis Nutrition 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N Xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 229960002675 Xylitol Drugs 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000000605 aspartame Substances 0.000 description 1
- 235000010357 aspartame Nutrition 0.000 description 1
- 238000010296 bead milling Methods 0.000 description 1
- 235000013736 caramel Nutrition 0.000 description 1
- 201000002816 chronic venous insufficiency Diseases 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000003111 delayed Effects 0.000 description 1
- 230000001627 detrimental Effects 0.000 description 1
- -1 diosmin Chemical class 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 230000001788 irregular Effects 0.000 description 1
- 239000000845 maltitol Substances 0.000 description 1
- 235000010449 maltitol Nutrition 0.000 description 1
- 229940035436 maltitol Drugs 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 230000002035 prolonged Effects 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 230000001105 regulatory Effects 0.000 description 1
- 230000014860 sensory perception of taste Effects 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000019640 taste Nutrition 0.000 description 1
- 230000035917 taste Effects 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 230000001643 venotonic Effects 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
Abstract
A pharmaceutical composition in the form of a chewable tablet containing a high dose of micronised diosmin. This pharmaceutical composition comprises a percentage of micronised diosmin of from 20% to 80% of the total mass of the pharmaceutical composition. This pharmaceutical composition is used in the treatment of venous insufficiency and haemorrhoidal attack
Description
PHARMACEUTICAL COMPOSITION IN THE FORM OF A CHEWABLE TABLET OF DIOSMIN OR OF A FLAVONOID MOIETY
The present invention relates to a pharmaceutical composition in the form of 5 a chewable tablet containing a high dose of micronised diosmin.
The present invention relates also to a pharmaceutical composition in the form of a chewable tablet containing a high dose of micronised purified flavonoid fraction (MPFF).
The flavonoid fraction is derived from a Rutaceae extract. The micronised 10 purified flavonoid fraction used in the invention contains from 87% to 93% of diosmin and other flavonoids concomitantly. These other flavonoids in an amount of approximately 10% comprise 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.
The diosmin and the flavonoid fraction according to the invention are micronised. Micronisation of the active ingrédient significantly increases its bioavailability. The micronisation of flavonoids, including diosmin, is particularly valuable for enhancing the digestive absorption of these substances, which are poorly soluble in water and therefore poorly absorbed by the digestive mucosa. Consequently, it is préférable to develop galenic forms comprising micronised diosmin or a micronised flavonoid fraction in order to improve the bioavailability.
Moreover, the flavonoid fraction according to the invention is administered in daily doses ranging from 1000 mg to 3000 mg in order to treat the symptoms 25 of chronic venous insufficiency of the lower limbs. Owing to an increase in the daily dosages in the treatment of the main therapeutic indications of the flavonoid fraction and diosmin, these active ingrédients must be given in high doses each time they are administered. Moreover, treatments based on flavonoid fraction are long-term treatments which must be easy to take in 30 order to encourage compliance with the treatment on the part of patients.
Consequently, it is préférable to develop galenic forms which can be taken easily by elderly persons and without the addition of water for patients who consume them out of the home.
The therapeutic use of the flavonoid fraction extracted from Rutaceae according to the invention has been described in patent spécification EP 0 711 560. That patent spécification describes a composition of effervescent granules containing a high dose of 1000 mg of flavonoid fraction. The effervescent granules are to be dispersed in water prior to consumption.
Pharmaceutical forms of a chewable tablet, suckable tablet or tablet for chewing containing diosmin hâve been described in international patent application WO 2004/032942. The pharmaceutical forms according to application WO 2004/032842 do not contain a high dose of diosmin and do not employ the active ingrédient in micronised form.
Accordingly, the présent invention relates to pharmaceutical compositions in the form of a chewable tablet containing a high dose of micronised diosmin or micronised purified flavonoid fraction (MPFF).
The pharmaceutical composition of the chewable tablet according to the invention must hâve spécifie functional properties in order to address the technological difficulties relating to chewable tablets containing a high dose of micronised active ingrédient.
Indeed, it is necessary that the pharmaceutical composition is sufficiently compressible while avoiding phenomena of splitting and friability. The very high proportion of active ingrédient and the small proportion of excipients, so as not to increase the final mass of the chewable tablet, hâve a négative impact on the desired mechanical properties of the chewable tablet.
Moreover, the effect of micronising the active ingrédient powders is to reduce the flowability of said powders given the increase in the forces between the particles. The size of the particles is an essential factor in the pourability of the powders, which can likewise be influenced by the shape of the particles and/or humidity.
The présent invention provides a pharmaceutical composition in the form of a chewable tablet containing a high dose of micronised purified flavonoid fraction comprising diosmin, hesperidin, isorhoifolin, linarin and diosmetin.
The French term comprimé à croquer is understood according to the invention as meaning a pharmaceutical form known in English by the term chewable tablet. A chewable tablet or a tablet for chewing here dénoté équivalent pharmaceutical forms.
Chewable pharmaceutical forms are very 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.
The diosmin and the flavonoid fraction are micronised in the pharmaceutical compositions according to the invention. Micronisation is a process by which the size of the particles of a powder can be reduced. Micronisation of the active ingrédient such as diosmin or a flavonoid fraction can be carried out by means of different micronisation Systems. These micronisation Systems may be a grinder, an air jet mill or a bead milling microniser, in which the pressure of the air jets or the rate of supply of powder vary according to the expected particle size of the micronised active ingrédient.
The grain size is a particularly important characteristic of pulvérulent materials such as powders. Characterisation of the size of a particle is made according to its diameter or the diameter of the équivalent spheres if the particle is of irregular shape. The grain diameters determined by a laser diffraction granulometer allow a particle size distribution or granulometry dso, dæ (distribution ofthe size ofthe particles) to be characterised.
In the présent invention, a dso below X pm means that at least 50% of the particles of the micronised product hâve a size below X pm. In the présent 5 invention, a dæ below X pm means that at least 90% of the particles of the micronised product hâve a size below X pm.
In one embodiment, the dæ ofthe micronised active ingrédient is below 5 pm.
A dæ below 5 pm includes a dso below 4 pm, 3 pm, 2 pm, 1.8 pm, 1.6 pm, io 1.5 pm.
In one embodiment, the dso ofthe micronised active ingrédient is below 5 pm.
A dso below 5 pm includes a dso below 4 pm, 3 pm, 2 pm, 1.8 pm, 1.6 pm, 1.5 pm.
In some embodiments, the micronised diosmin or the micronised purified 15 flavonoid fraction are characterised by the following granulometry:
- a dso below 2 pm, preferably below 1.6 pm, and/or
- a dæ below 5 pm, preferably below 2 pm, yet more preferably below 1.6 pm.
The mean diameter of the particles of micronised active ingrédient in the 20 pharmaceutical composition according to the invention is strictly below 5 pm, preferably strictly below 1.6 pm.
The percentage of micronised diosmin or micronised purified flavonoid fraction in the pharmaceutical composition is from 20% to 80% of the total 25 mass of the composition. Preferably, the percentage of micronised active ingrédient is from 30% to 60% of the total mass of the composition. The pharmaceutical compositions according to the invention make it possible to administer a large quantity of flavonoids by the oral route for each unit dose. High dose pharmaceutical compositions are understood as meaning 30 formulations containing at least 20% active ingrédient. The quantity of diosmin orflavonoid fraction in the pharmaceutical composition is from 1000 mg to 3000 mg, including 2000 mg, 1500 mg, 2500 mg.
The pharmaceutical compositions in the form of high dose chewable tablets 5 comprise from 30% to 60% by weight of micronised diosmin or micronised purified flavonoid fraction, based on the total mass of the composition, and from 40% to 70% by weight of polyols, based on the total mass of the composition.
In order to address the industrial constraints inhérent in the manufacture of 10 the chewable tablet containing a micronised active ingrédient in a high dose, it is necessary to select excipients which assist in overcoming said industrial constraints. An excipient must be understood as being any compound forming part of the formulation which is intended to act simply as a support, that is to say which is not intended to hâve biological activity.
The pharmaceutical compositions according to the invention comprise at least one polyol serving as diluent.
A diluent serves to obtain a volume of powder sufficient to manufacture a tablet of the desired size and the physical characteristics of which are compatible with processes of manufacture by direct compression, for 20 example. One or more polyols are used as diluent. The polyol used is preferably sorbitol. There can advantageously be used two different polyols, and preferably a mixture of mannitol and sorbitol. Polyols as diluent hâve the advantage of providing a sweet taste and hâve excellent properties of binding and compressibility. It is possible to replace the mannitol or the sorbitol with 25 a different polyol, especially xylitol or maltitol.
In the pharmaceutical composition according to the invention, the ratio ofthe mass of the polyol or polyols to the mass of active ingrédient is strictly less than 2, preferably the ratio is less than 1.6.
In addition to the micronised active ingrédient and the polyol or polyols, the pharmaceutical composition according to the invention contains one or more pharmaceutically acceptable excipients. For example, the invention can provide a pharmaceutical composition comprising the micronised active ingrédient, (a) polyol(s) and a binder, or a pharmaceutical composition comprising the micronised active ingrédient, (a) polyol(s), a binder and a lubricant.
Binders or agglutinants are agents whose rôle is to bind the different particles of the pharmaceutical composition together. Among the binders there may be mentioned maltodextrin and povidone. The purpose ofthe lubricants is to avoid phenomena of jamming, adhesion and cohésion during the different industrial processes. The lubricant is chosen inter aiia from stearic acid, magnésium stéarate or talc.
Other pharmaceutically acceptable excipients may be added to the pharmaceutical composition according to the invention, such as flavours or sweeteners.
There may be mentioned as examples of excipients:
flavouring agents or flavours, the purpose of which is to mask unpleasant tastes and reduce earthy consistencies: orange flavour, lemon flavour, soft caramel flavour, vanilla/lemon flavour;
sweeteners enhance the sweet taste of the composition: aspartame, acesulfame potassium, saccharin sodium, potassium cyclamate; and flow agents such as anhydrous colloïdal silica.
The composition according to the invention can be an immediate-release, prolonged-release or delayed-release pharmaceutical composition. The composition according to the invention is preferably an immediate-release composition.
The invention relates also to a process for the préparation by wet granulation of a chewable tablet as described above, which process comprises at least the following steps:
a) mixing of micronised diosmin or micronised purified flavonoid 5 fraction, polyols, binders, flavours and sweeteners;
b) after mixing, carry out wetting. The wet mass so obtained subsequently being granulated, dried and then graded;
c) lubrication of the granules obtained in step b) by means of colloïdal silica and magnésium stéarate;
d) compression of the lubricated mixture.
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) mixing of micronised diosmin or micronised purified flavonoid fraction, polyols, binders, flavours and sweeteners;
b) lubrication of the mixture obtained in step a) by means of colloïdal silica and magnésium stéarate;
c) direct compression of the lubricated mixture.
In an embodiment which is likewise preferred, the chewable tablet according to the invention is prepared by a process of compaction granulation or dry granulation comprising at least the following steps:
a) mixing of micronised diosmin or micronised purified flavonoid fraction, polyols, binders, flavours and sweeteners;
b) after mixing, carry out compaction to form granules;
c) lubrication of the granules obtained in step b) by means of colloïdal silica and magnésium stéarate;
d) compression of the lubricated mixture.
Preferably, there are obtained at the end of the process chewable tablets whose hardness, measured by diamétral crushing, is from 180 N to 220 N (N = newtons). Preferably, the chewable tablets hâve a hardness of from 180 N to 200 N.
The présent invention relates also to the use of the pharmaceutical compositions according to the invention in the treatment of venous disease, more particularly of venous insufficiency such as heavy legs, pain, restless legs syndrome, capillary fragility, and the treatment of haemorrhoidal attack.
These pharmaceutical compositions are used as a venotonic and vascular p rote cto r.
The examples below illustrate the invention without limiting it.
Example 1 : Pharmaceutical compositions of chewable tablets
| Ingrédients | 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 |
| Maltod extri n | 300 | 10 |
| Orange flavour | 33 | 1.1 |
| Acesulfame potassium | 2 | 0.06 |
| Magnésium stéarate | 22.5 | 0.75 |
| Anhydrous colloïdal silica | 6 | 0.2 |
| Final mass | 3000.0 |
| Ingrédients | Quantity (mg) | Content (%) |
| Micronised diosmin | 1000.0 | 33.3 |
| Mannitol | 409.13 | 13.6 |
| Sorbitol | 1227.37 | 40.9 |
| Maltodextrin | 300 | 10 |
| Orange flavour | 33 | 1.1 |
| Acesulfame potassium | 2 | 0.06 |
| Magnésium stéarate | 22.5 | 0.75 |
| Anhydrous colloïdal silica | 6 | 0.2 |
| Final mass | 3000.0 |
Manufacture of the chewable tablets of Example 1 :
The micronised diosmin or the micronised purified flavonoid fraction is 5 carefully mixed with the excipients of the internai phase, i.e. mannitol, sorbitol, maltodextrin, orange flavour, acesulfame potassium. The mixture is wetted with purified water by means of a pressurised vessel and then granulated.
The granules are dried to obtain a residual humidity which compiles with 10 spécifications, that is to say approximately 2% residual humidity. The granules are subsequently graded, homogenised and then lubricated with the magnésium stéarate. The granules are finally sieved through a sieve of mesh size 0.8 mm and then compressed by means of punches.
The chewable tablets of micronised diosmin and micronised purified flavonoid fraction according to Example 1 hâve a hardness of 196 N and 192 N (N = newtons), respectively.
Example 2: Flow properties of the pharmaceutical compositions according to the invention
The pourability of a powder is its ability to flow freely in a regular and constant 5 manner in the form of individual particles. The flowability of powders therefore détermines the performance and correct operation of the production processes and plays a rôle in the quality of the final product. Thus, a powder having good pourability flows without assistance. By contrast, a cohesive powder has poor pourability and a mechanical (agitation, vibration) or 10 Chemical (coating) device must be provided in order to facilitate its movement.
The pourability of the powders and granules containing a high dose of micronised diosmin and a high dose of micronised purified flavonoid fraction 15 according to the invention measured by different methods (Carr index, Hausner ratio and Schultze flow function) shows that the pharmaceutical compositions according to the invention are very effective in the processes for manufacturing the chewable tablets. Despite factors which are very detrimental to the yield of the manufacturing processes, such as 20 micronisation of the active ingrédient and/or a high dose of an active ingrédient, the pourability of the pharmaceutical compositions according to the invention meets the industrial and regulatory requirements.
The Carr index (le) describes the flow of a powder bed as a function of the 25 density. It is determined by the équation below:
le = (ptapped — Pbulk) / ptapped where p is the density and le is a dimensionless physical quantity.
The Carr index values are interpreted as follows:
le < 0.15 good pourability
0.15 < le < 0.25 moderate pourability le > 0.25 poor pourability
The Hausner ratio (Hr) describes the compressibility and the flow of a power 5 on the basis of density (p) measurements. It is calculated by the ratio of the tapped density (ptapped) to the bulk density (pbuik) according to the équation:
Hr — ptapped / pbuik
Hr is a dimensionless physical quantity. If Hr is between 1.0 and 1.2, the powder has little compressibility, is loosely cohesive and has good flowability; if Hr is between 1.2 and 1.4, the powder is compressible, cohesive and has poor flowability.
Finally, the Schultze apparatus is a shear cell for measuring the flow function (FFC). Good flow is characterised by an FFC between 4 and 10 and free flow is characterised by an FFC above 10.
| Methods | Powders or granules |
| micronised diosmin | micronised purified flavonoid fraction |
| le | 0.12-0.25 (moderate to good pourability) |
| Hr | 1.1-1.3 (good to fairly good pourability) |
| FFC | 7-13 (easy to free flow) |
Claims
Claims (11)
- Claims1. Pharmaceutical composition in the form of a chewable tablet comprising 1000 mg micronised diosmin as active ingrédient, characterised in that:5 - the dso of the micronised diosmin is below 5 pm,- the composition comprises at least one polyol,- the composition comprises from 30% to 60% by weight of micronised diosmin, based on the total mass of the composition.10
- 2. Pharmaceutical composition in the form of a chewable tablet comprising1000 mg micronised purified flavonoid fraction as active ingrédient, characterized in that:- the dso of the micronised purified flavonoid fraction is below 5 pm,- the composition comprises at least one polyol,15 - the composition comprises from 30% to 60% by weight of micronised purified flavonoid fraction, based on the total mass of the composition.
- 3. Pharmaceutical composition according to claim 2, characterised in that 20 the flavonoid fraction comprises diosmin, hesperidin, isorhoifolin, linarin and diosmetin.
- 4. Pharmaceutical composition according to any one of claims 1 to 3, characterised in that it comprises from 40% to 70% by weight of25 polyols, based on the total mass of the composition.
- 5. Pharmaceutical composition according to any one of claims 1 to 4, characterised in that the ratio of the mass of the polyol or polyols to the mass of active ingrédient is strictly less than 2.
- 6. Pharmaceutical composition according to any one of claims 1 to 5, wherein a polyol is sorbitol.
- 7. Pharmaceutical composition according to any one of claims 1 to 6, 5 comprising a polyol and a binder.
- 8. Pharmaceutical composition according to any one of claims 1 to 7, comprising a polyol, a binder and a lubricant.10
- 9. Process for the manufacture of a pharmaceutical composition according to any one of claims 1 to 8, characterised in that it is a process of wet granulation, dry granulation or direct compression.
- 10. Pharmaceutical composition according to any one of claims 1 to 8 for 15 use in the treatment of venous insufficiency and haemorrhoidal attack.
- 11. Use of micronised diosmin or micronised purified flavonoid fraction in the manufacture of a pharmaceutical composition in the form of a chewable tablet for the treatment of venous insufficiency and haemorrhoidal attack, 20 wherein the micronised diosmin or micronised purified flavonoid fraction is the active ingrédient in the pharmaceutical composition, wherein the pharmaceutical composition comprises 1000 mg of active ingrédient, the dso of the active ingrédient is below 5 pm, the percentage of active ingrédient is from 30% to 60% of the total mass of the pharmaceutical 25 composition, and the composition comprises at least one polyol.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR18/56769 | 2018-07-20 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| OA20008A true OA20008A (en) | 2021-08-31 |
Family
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