AU2019306315B2 - 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
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- AU2019306315B2 AU2019306315B2 AU2019306315A AU2019306315A AU2019306315B2 AU 2019306315 B2 AU2019306315 B2 AU 2019306315B2 AU 2019306315 A AU2019306315 A AU 2019306315A AU 2019306315 A AU2019306315 A AU 2019306315A AU 2019306315 B2 AU2019306315 B2 AU 2019306315B2
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- pharmaceutical composition
- micronised
- diosmin
- composition according
- polyol
- Prior art date
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- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 50
- VUYDGVRIQRPHFX-UHFFFAOYSA-N hesperidin Natural products COc1cc(ccc1O)C2CC(=O)c3c(O)cc(OC4OC(COC5OC(O)C(O)C(O)C5O)C(O)C(O)C4O)cc3O2 VUYDGVRIQRPHFX-UHFFFAOYSA-N 0.000 title claims abstract description 41
- 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 37
- 229960004352 diosmin Drugs 0.000 title claims abstract description 37
- IGBKNLGEMMEWKD-UHFFFAOYSA-N diosmin Natural products COc1ccc(cc1)C2=C(O)C(=O)c3c(O)cc(OC4OC(COC5OC(C)C(O)C(O)C5O)C(O)C(O)C4O)cc3O2 IGBKNLGEMMEWKD-UHFFFAOYSA-N 0.000 title claims abstract description 37
- 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 35
- 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 39
- 201000002282 venous insufficiency Diseases 0.000 claims abstract description 9
- 238000011282 treatment Methods 0.000 claims abstract description 8
- 229930003935 flavonoid Natural products 0.000 claims description 39
- 235000017173 flavonoids Nutrition 0.000 claims description 39
- 239000000203 mixture Substances 0.000 claims description 32
- 229920005862 polyol Polymers 0.000 claims description 26
- 150000003077 polyols Chemical class 0.000 claims description 26
- 239000004480 active ingredient Substances 0.000 claims description 25
- 238000000034 method Methods 0.000 claims description 17
- 238000004519 manufacturing process Methods 0.000 claims description 12
- 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
- 239000000600 sorbitol Substances 0.000 claims description 7
- 238000007907 direct compression Methods 0.000 claims description 5
- 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 5
- 239000001100 (2S)-5,7-dihydroxy-2-(3-hydroxy-4-methoxyphenyl)chroman-4-one Substances 0.000 claims description 4
- YFVGIJBUXMQFOF-PJOVQGMDSA-N 5-hydroxy-2-(4-methoxyphenyl)-7-[(2s,3r,4s,5s,6r)-3,4,5-trihydroxy-6-[[(2r,3r,4r,5r,6s)-3,4,5-trihydroxy-6-methyloxan-2-yl]oxymethyl]oxan-2-yl]oxychromen-4-one Chemical compound C1=CC(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 YFVGIJBUXMQFOF-PJOVQGMDSA-N 0.000 claims description 4
- QAGGICSUEVNSGH-UHFFFAOYSA-N Diosmetin Natural products C1=C(O)C(OC)=CC=C1C1=CC(=O)C2=CC=C(O)C=C2O1 QAGGICSUEVNSGH-UHFFFAOYSA-N 0.000 claims description 4
- QUQPHWDTPGMPEX-UHFFFAOYSA-N Hesperidine Natural products C1=C(O)C(OC)=CC=C1C1OC2=CC(OC3C(C(O)C(O)C(COC4C(C(O)C(O)C(C)O4)O)O3)O)=CC(O)=C2C(=O)C1 QUQPHWDTPGMPEX-UHFFFAOYSA-N 0.000 claims description 4
- FKIYLTVJPDLUDL-FLPYCHHVSA-N Isorhoifolin Natural products C[C@H]1O[C@@H](OC[C@H]2O[C@@H](Oc3cc(O)c4C(=O)C=C(Oc4c3)c5ccc(O)cc5)[C@H](O)[C@@H](O)[C@@H]2O)[C@@H](O)[C@@H](O)[C@@H]1O FKIYLTVJPDLUDL-FLPYCHHVSA-N 0.000 claims description 4
- 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 4
- 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 4
- QUQPHWDTPGMPEX-UTWYECKDSA-N aurantiamarin Natural products COc1ccc(cc1O)[C@H]1CC(=O)c2c(O)cc(O[C@@H]3O[C@H](CO[C@@H]4O[C@@H](C)[C@H](O)[C@@H](O)[C@H]4O)[C@@H](O)[C@H](O)[C@H]3O)cc2O1 QUQPHWDTPGMPEX-UTWYECKDSA-N 0.000 claims description 4
- APSNPMVGBGZYAJ-GLOOOPAXSA-N clematine Natural products COc1cc(ccc1O)[C@@H]2CC(=O)c3c(O)cc(O[C@@H]4O[C@H](CO[C@H]5O[C@@H](C)[C@H](O)[C@@H](O)[C@H]5O)[C@@H](O)[C@H](O)[C@H]4O)cc3O2 APSNPMVGBGZYAJ-GLOOOPAXSA-N 0.000 claims description 4
- 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 4
- 229960001876 diosmetin Drugs 0.000 claims description 4
- 235000015428 diosmetin Nutrition 0.000 claims description 4
- 229940025878 hesperidin Drugs 0.000 claims description 4
- 239000000314 lubricant Substances 0.000 claims description 4
- ARGKVCXINMKCAZ-UHFFFAOYSA-N neohesperidine Natural products C1=C(O)C(OC)=CC=C1C1OC2=CC(OC3C(C(O)C(O)C(CO)O3)OC3C(C(O)C(O)C(C)O3)O)=CC(O)=C2C(=O)C1 ARGKVCXINMKCAZ-UHFFFAOYSA-N 0.000 claims description 4
- 238000007908 dry granulation Methods 0.000 claims description 3
- 238000005550 wet granulation Methods 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims description 2
- 239000000843 powder Substances 0.000 description 16
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 14
- 239000002245 particle Substances 0.000 description 14
- 239000008187 granular material Substances 0.000 description 10
- 239000000796 flavoring agent Substances 0.000 description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
- 235000019634 flavors Nutrition 0.000 description 8
- 235000019359 magnesium stearate Nutrition 0.000 description 7
- 239000000546 pharmaceutical excipient Substances 0.000 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 description 6
- 239000003826 tablet Substances 0.000 description 6
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 5
- 229930195725 Mannitol Natural products 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
- WBZFUFAFFUEMEI-UHFFFAOYSA-M Acesulfame k Chemical compound [K+].CC1=CC(=O)[N-]S(=O)(=O)O1 WBZFUFAFFUEMEI-UHFFFAOYSA-M 0.000 description 4
- 239000005913 Maltodextrin Substances 0.000 description 4
- 229920002774 Maltodextrin Polymers 0.000 description 4
- 235000010358 acesulfame potassium Nutrition 0.000 description 4
- 229960004998 acesulfame potassium Drugs 0.000 description 4
- 239000000619 acesulfame-K Substances 0.000 description 4
- 239000008119 colloidal silica Substances 0.000 description 4
- 239000003085 diluting agent Substances 0.000 description 4
- 229940035034 maltodextrin Drugs 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
- 238000005461 lubrication Methods 0.000 description 3
- 235000005979 Citrus limon Nutrition 0.000 description 2
- 244000131522 Citrus pyriformis Species 0.000 description 2
- 241001093501 Rutaceae Species 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 230000001055 chewing effect Effects 0.000 description 2
- 238000005056 compaction Methods 0.000 description 2
- 238000007906 compression Methods 0.000 description 2
- 230000006835 compression Effects 0.000 description 2
- 230000001079 digestive effect Effects 0.000 description 2
- 238000009826 distribution Methods 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 238000001033 granulometry Methods 0.000 description 2
- 239000012729 immediate-release (IR) formulation Substances 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 235000019605 sweet taste sensations Nutrition 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- FTLYMKDSHNWQKD-UHFFFAOYSA-N (2,4,5-trichlorophenyl)boronic acid Chemical compound OB(O)C1=CC(Cl)=C(Cl)C=C1Cl FTLYMKDSHNWQKD-UHFFFAOYSA-N 0.000 description 1
- MIDXCONKKJTLDX-UHFFFAOYSA-N 3,5-dimethylcyclopentane-1,2-dione Chemical compound CC1CC(C)C(=O)C1=O MIDXCONKKJTLDX-UHFFFAOYSA-N 0.000 description 1
- 108010011485 Aspartame Proteins 0.000 description 1
- 206010007191 Capillary fragility Diseases 0.000 description 1
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 208000005793 Restless legs syndrome Diseases 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 235000009499 Vanilla fragrans Nutrition 0.000 description 1
- 244000263375 Vanilla tahitensis Species 0.000 description 1
- 235000012036 Vanilla tahitensis Nutrition 0.000 description 1
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 239000000605 aspartame Substances 0.000 description 1
- 235000010357 aspartame Nutrition 0.000 description 1
- 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
- 238000010296 bead milling Methods 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 235000013736 caramel Nutrition 0.000 description 1
- 238000012512 characterization method Methods 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 effect Effects 0.000 description 1
- 230000001627 detrimental effect Effects 0.000 description 1
- -1 diosmin Chemical class 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 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
- 238000011866 long-term treatment Methods 0.000 description 1
- 210000003141 lower extremity Anatomy 0.000 description 1
- 239000000845 maltitol Substances 0.000 description 1
- 235000010449 maltitol Nutrition 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
- 229940035436 maltitol Drugs 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- PALPTWOXTUVPKA-UHFFFAOYSA-M potassium;n-cyclohexylsulfamate Chemical compound [K+].[O-]S(=O)(=O)NC1CCCCC1 PALPTWOXTUVPKA-UHFFFAOYSA-M 0.000 description 1
- 229940069328 povidone Drugs 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000001012 protector Effects 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 229940085605 saccharin sodium Drugs 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 235000019640 taste Nutrition 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 230000001643 venotonic effect Effects 0.000 description 1
- 208000037997 venous disease Diseases 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
- 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
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Zoology (AREA)
- Cardiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Heart & Thoracic Surgery (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Organic Chemistry (AREA)
- Vascular Medicine (AREA)
- Nutrition Science (AREA)
- Physiology (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines Containing Plant Substances (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Disclosed is a pharmaceutical composition in the form of a chewable tablet containing a high dose of micronized diosmin. Said pharmaceutical composition comprises micronized diosmin amounting to 20% to 80% of the total weight of the pharmaceutical composition. The disclosed pharmaceutical composition is used in the treatment of venous insufficiency and hemorrhoidal crises.
Description
The present invention relates to a pharmaceutical composition in the form of 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 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 ingredient 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 preferable 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 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 ingredients 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 order to encourage compliance with the treatment on the part of patients. Consequently, it is preferable 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 specification EP 0 711 560. That patent specification 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 have 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 ingredient in micronised form.
Any reference to or discussion of any document, act or item of knowledge in this specification is included solely for the purpose of providing a context for the present invention. It is not suggested or represented that any of these matters or any combination thereof formed at the priority date part of the common general knowledge, or was known to be relevant to an attempt to solve any problem with which this specification is concerned.
Accordingly, the present 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 have specific functional properties in order to address the technological difficulties relating to chewable tablets containing a high dose of micronised active ingredient.
Indeed, it is necessary that the pharmaceutical composition is sufficiently compressible while avoiding phenomena of splitting and friability. The very high proportion of active ingredient and the 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.
Moreover, the effect of micronising the active ingredient 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 present 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.
In one aspect, the present invention provides a pharmaceutical composition in the form of a chewable tablet comprising 1000 mg of micronised diosmin as active ingredient, wherein: - the d5o 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.
In another aspect, the present invention provides a pharmaceutical composition in the form of a chewable tablet comprising 1000 mg of a micronised purified flavonoid fraction as active ingredient, wherein: - the d5o of the micronised purified flavonoid fraction is below 5 pm, - the composition comprises at least one polyol, the composition comprises from 30% to 60% by weight of micronised purified flavonoid fraction, based on the total mass of the composition,
3a
- the micronized purified flavonoid fraction comprises from 87% to 93% of diosmin, 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.
In another aspect, the present invention provides a process for the manufacture of a pharmaceutical composition according to the invention, wherein the process comprises wet granulation, dry granulation or direct compression
In another aspect, the present invention provides a pharmaceutical composition according to the invention for use in the treatment of venous insufficiency and haemorrhoidal attack
In another aspect, the present invention provides a method of treating venous insufficiency and haemorrhoidal attack in a subject comprising administering to the subject the pharmaceutical composition according to the invention.
In another aspect, the present invention provides use of the pharmaceutical composition according to the invention in the manufacture of a medicament for treating venous insufficiency and haemorrhoidal attack.
For the avoidance of doubt, in this specification, the terms 'comprises', 'comprising', 'includes', 'including', or similar terms are intended to mean a non-exclusive inclusion, such that a method, use, composition, system or apparatus that comprises a list of elements does not include those elements solely, but may well include other elements not listed.
The French term "comprime a 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 denote equivalent pharmaceutical forms.
3b
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 ingredient 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 ingredient.
The grain size is a particularly important characteristic of pulverulent materials such as powders. Characterisation of the size of a particle is made according to its diameter or the diameter of the equivalent spheres if the particle is of irregular shape. The grain diameters determined by a laser diffraction granulometer allow a particle size distribution or granulometry d5o, deo (distribution of the size of the particles) to be characterised. In the present invention, a "do below X pm" means that at least 50% of the particles of the micronised product have a size below X pm. In the present invention, a "do below X pm" means that at least 90% of the particles of the micronised product have a size below X pm.
In one embodiment, the deo of the micronised active ingredient is below 5 pm. A deo below 5 pm includes a do below 4 pm, 3 pm, 2 pm, 1.8 pm, 1.6 pm, 1.5 pm. In one embodiment, the d5o of the micronised active ingredient is below 5 pm. A d5o below 5 pm includes a do 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 flavonoid fraction are characterised by the following granulometry: - a d5o below 2 pm, preferably below 1.6 pm, and/or - a deo below 5 pm, preferably below 2 pm, yet more preferably below 1.6 pm. The mean diameter of the particles of micronised active ingredient in the 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 mass of the composition. Preferably, the percentage of micronised active ingredient 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 formulations containing at least 20% active ingredient. The quantity of diosmin or flavonoid 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 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 inherent in the manufacture of the chewable tablet containing a micronised active ingredient 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 have 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 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 have the advantage of providing a sweet taste and have excellent properties of binding and compressibility. It is possible to replace the mannitol or the sorbitol with a different polyol, especially xylitol or maltitol.
In the pharmaceutical composition according to the invention, the ratio of the mass of the polyol or polyols to the mass of active ingredient is strictly less than 2, preferably the ratio is less than 1.6.
In addition to the micronised active ingredient 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 ingredient, (a) polyol(s) and a binder, or a pharmaceutical composition comprising the micronised active ingredient, (a) polyol(s), a binder and a lubricant. Binders or agglutinants are agents whose role is to bind the different particles of the pharmaceutical composition together. Among the binders there may be mentioned maltodextrin and povidone. The purpose of the lubricants is to avoid phenomena of jamming, adhesion and cohesion during the different industrial processes. The lubricant is chosen inter alia from stearic acid, magnesium stearate 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 colloidal 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 preparation 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 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 colloidal silica and magnesium stearate; 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 colloidal silica and magnesium stearate; 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 colloidal silica and magnesium stearate; d) compression of the lubricated mixture.
Preferably, there are obtained at the end of the process chewable tablets whose hardness, measured by diametral crushing, is from 180 N to 220 N (N = newtons). Preferably, the chewable tablets have a hardness of from 180 N to 200 N.
The present 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 protector.
The examples below illustrate the invention without limiting it.
Example 1: Pharmaceutical compositions of chewable tablets
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 flavour 33 1.1 Acesulfame potassium 2 0.06 Magnesium stearate 22.5 0.75 Anhydrous colloidal 6 0.2 silica Final mass 3000.0
Ingredients 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 Magnesium stearate 22.5 0.75 Anhydrous colloidal 6 0.2 silica Final mass 3000.0
Manufacture of the chewable tablets of Example 1:
The micronised diosmin or the micronised purified flavonoid fraction is carefully mixed with the excipients of the internal 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 complies with specifications, that is to say approximately 2% residual humidity. The granules are subsequently graded, homogenised and then lubricated with the magnesium stearate. 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 have 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 manner in the form of individual particles. The flowability of powders therefore determines the performance and correct operation of the production processes and plays a role 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 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 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 micronisation of the active ingredient and/or a high dose of an active ingredient, the pourability of the pharmaceutical compositions according to the invention meets the industrial and regulatory requirements.
The Carr index (Ic) describes the flow of a powder bed as a function of the density. It is determined by the equation below:
Ic = (ptapped - bulk) / Ptapped
where p is the density and Ic is a dimensionless physical quantity. The Carr index values are interpreted as follows: Ic < 0.15 good pourability
0.15 < Ic < 0.25 moderate pourability Ic > 0.25 poor pourability
The Hausner ratio (Hr) describes the compressibility and the flow of a power on the basis of density (p) measurements. It is calculated by the ratio of the tapped density (ptapped) to the bulk density (pbulk) according to the equation:
Hr = Ptapped / Pbulk
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 Ic 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 (11)
1. A pharmaceutical composition in the form of a chewable tablet comprising 1000 mg of micronised diosmin as active ingredient, wherein: - the d5o 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.
2. A pharmaceutical composition in the form of a chewable tablet comprising 1000 mg of a micronised purified flavonoid fraction as active ingredient, wherein: - the d5o of the micronised purified flavonoid fraction is below 5 pm, - the composition comprises at least one polyol, - the composition comprises from 30% to 60% by weight of micronised purified flavonoid fraction, based on the total mass of the composition, - the micronized purified flavonoid fraction comprises from 87% to 93% of diosmin, 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.
3. The pharmaceutical composition according to claim 1 or 2, wherein the composition comprises from 40% to 70% by weight of polyols, based on the total mass of the composition.
4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the ratio of the mass of the polyol or polyols to the mass of active ingredient is strictly less than 2.
5. The pharmaceutical composition according to any one of claims 1 to 4, wherein the polyol is sorbitol.
6. The pharmaceutical composition according to any one of claims 1 to 5, comprising a polyol and a binder.
7. The pharmaceutical composition according to any one of claims 1 to 6, comprising a polyol, a binder and a lubricant.
8. A process for the manufacture of a pharmaceutical composition according to any one of claims 1 to 7, wherein the process comprises wet granulation, dry granulation or direct compression.
9. A pharmaceutical composition according to any one of claims 1 to 7 for use in the treatment of venous insufficiency and haemorrhoidal attack.
10. A method of treating venous insufficiency and haemorrhoidal attack in a subject comprising administering to the subject the pharmaceutical composition according to any one of claims 1 to 7.
11. Use of the pharmaceutical composition according to any one of claims 1 to 7 in the manufacture of a medicament for treating venous insufficiency and haemorrhoidal attack.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR1856769A FR3083980B1 (en) | 2018-07-20 | 2018-07-20 | PHARMACEUTICAL COMPOSITION IN THE FORM OF A CHEWABLE TABLET OF DIOSMINE OR A FLAVONOIC FRACTION |
| FR18/56769 | 2018-07-20 | ||
| PCT/EP2019/069498 WO2020016408A1 (en) | 2018-07-20 | 2019-07-19 | Pharmaceutical composition in the form of a chewable tablet of diosmin or of a flavonoid moiety |
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| AU2019306315A1 AU2019306315A1 (en) | 2021-02-11 |
| AU2019306315B2 true AU2019306315B2 (en) | 2023-03-09 |
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| AU2019306315A Active AU2019306315B2 (en) | 2018-07-20 | 2019-07-19 | Pharmaceutical composition in the form of a chewable tablet of diosmin or of a flavonoid moiety |
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| EP (1) | EP3823588B1 (en) |
| KR (1) | KR20210034036A (en) |
| CN (1) | CN112423735A (en) |
| AR (1) | AR117612A1 (en) |
| AU (1) | AU2019306315B2 (en) |
| BR (1) | BR112021000440A2 (en) |
| CA (1) | CA3106495C (en) |
| CL (1) | CL2021000083A1 (en) |
| CO (1) | CO2021000115A2 (en) |
| CR (1) | CR20210023A (en) |
| EA (1) | EA202190269A1 (en) |
| EC (1) | ECSP21001232A (en) |
| FR (1) | FR3083980B1 (en) |
| JO (1) | JOP20210003A1 (en) |
| MA (1) | MA53159A (en) |
| MX (1) | MX2021000763A (en) |
| NI (1) | NI202100002A (en) |
| PE (1) | PE20210929A1 (en) |
| PH (1) | PH12021550037A1 (en) |
| SG (1) | SG11202100181YA (en) |
| TW (1) | TWI831808B (en) |
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| WO (1) | WO2020016408A1 (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0711560A1 (en) * | 1994-11-08 | 1996-05-15 | Adir Et Compagnie | Pharmaceutical composition for the oral administration of flavonoids |
| FR2845597A1 (en) * | 2002-10-11 | 2004-04-16 | Innothera Lab Sa | Dry formulation for easy oral administration of diosmin for use as venotopic agent e.g. in treatment of hemorrhoids, comprising suckable or chewable tablet |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2661610B1 (en) * | 1990-05-02 | 1994-09-30 | Rhone Poulenc Sante | NOVEL LYOPHILIZED FORM OF DIOSMINE AND ITS PREPARATION. |
| FR2661830B1 (en) * | 1990-05-11 | 1992-09-04 | Corbiere Jerome | NOVEL PHARMACEUTICAL COMPOSITIONS BASED ON FLAVONOSIDE. |
| ITMI20050517A1 (en) | 2005-03-30 | 2006-09-30 | Therapicon Srl | PHARMACEUTICAL COMPOSITION OF A TYPICAL MICROCRYSTALLINE FRACTION OF FLAVONOIDS |
| FR2999934B1 (en) * | 2012-12-21 | 2015-02-20 | Servier Lab | PHARMACEUTICAL COMPOSITION IN THE FORM OF AN ORAL SUSPENSION COMPRISING A FLAVONOIC FRACTION AND XANTHAN GUM |
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2018
- 2018-07-20 FR FR1856769A patent/FR3083980B1/en active Active
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- 2019-07-19 EP EP19742363.5A patent/EP3823588B1/en active Active
- 2019-07-19 AR ARP190102031A patent/AR117612A1/en unknown
- 2019-07-19 KR KR1020217004706A patent/KR20210034036A/en active Search and Examination
- 2019-07-19 WO PCT/EP2019/069498 patent/WO2020016408A1/en active Application Filing
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- 2019-07-19 CN CN201980047436.7A patent/CN112423735A/en active Pending
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- 2021-01-08 CO CONC2021/0000115A patent/CO2021000115A2/en unknown
- 2021-01-12 CL CL2021000083A patent/CL2021000083A1/en unknown
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0711560A1 (en) * | 1994-11-08 | 1996-05-15 | Adir Et Compagnie | Pharmaceutical composition for the oral administration of flavonoids |
| FR2845597A1 (en) * | 2002-10-11 | 2004-04-16 | Innothera Lab Sa | Dry formulation for easy oral administration of diosmin for use as venotopic agent e.g. in treatment of hemorrhoids, comprising suckable or chewable tablet |
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| EP3823588A1 (en) | 2021-05-26 |
| CL2021000083A1 (en) | 2021-07-30 |
| ECSP21001232A (en) | 2021-02-26 |
| JOP20210003A1 (en) | 2021-01-10 |
| CO2021000115A2 (en) | 2021-01-29 |
| AR117612A1 (en) | 2021-08-18 |
| MX2021000763A (en) | 2021-03-29 |
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| SG11202100181YA (en) | 2021-02-25 |
| FR3083980B1 (en) | 2021-04-16 |
| EP3823588B1 (en) | 2024-10-23 |
| CA3106495A1 (en) | 2020-01-23 |
| PH12021550037A1 (en) | 2021-09-27 |
| FR3083980A1 (en) | 2020-01-24 |
| AU2019306315A1 (en) | 2021-02-11 |
| CN112423735A (en) | 2021-02-26 |
| EA202190269A1 (en) | 2021-06-15 |
| CA3106495C (en) | 2023-08-08 |
| WO2020016408A1 (en) | 2020-01-23 |
| NI202100002A (en) | 2021-06-22 |
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