EP4041197A1 - Masquage du goût de l'isosorbide - Google Patents
Masquage du goût de l'isosorbideInfo
- Publication number
- EP4041197A1 EP4041197A1 EP20796640.9A EP20796640A EP4041197A1 EP 4041197 A1 EP4041197 A1 EP 4041197A1 EP 20796640 A EP20796640 A EP 20796640A EP 4041197 A1 EP4041197 A1 EP 4041197A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- isosorbide
- equal
- beads
- gelled
- gelled beads
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- KLDXJTOLSGUMSJ-JGWLITMVSA-N Isosorbide Chemical compound O[C@@H]1CO[C@@H]2[C@@H](O)CO[C@@H]21 KLDXJTOLSGUMSJ-JGWLITMVSA-N 0.000 title claims abstract description 114
- 229960002479 isosorbide Drugs 0.000 title claims abstract description 114
- 235000019640 taste Nutrition 0.000 title claims abstract description 39
- 230000000873 masking effect Effects 0.000 title claims abstract description 21
- 238000004519 manufacturing process Methods 0.000 claims abstract description 13
- 239000011324 bead Substances 0.000 claims description 106
- 239000000203 mixture Substances 0.000 claims description 37
- 239000003349 gelling agent Substances 0.000 claims description 32
- 235000010443 alginic acid Nutrition 0.000 claims description 28
- 229920000615 alginic acid Polymers 0.000 claims description 28
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 claims description 26
- 229940072056 alginate Drugs 0.000 claims description 26
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 26
- 238000000034 method Methods 0.000 claims description 25
- 239000008194 pharmaceutical composition Substances 0.000 claims description 15
- 238000002360 preparation method Methods 0.000 claims description 12
- 238000001035 drying Methods 0.000 claims description 11
- 229910021645 metal ion Inorganic materials 0.000 claims description 10
- 238000001879 gelation Methods 0.000 claims description 9
- 239000003814 drug Substances 0.000 claims description 5
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 4
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 4
- 239000011575 calcium Substances 0.000 claims description 4
- 229910052791 calcium Inorganic materials 0.000 claims description 4
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 2
- PTFCDOFLOPIGGS-UHFFFAOYSA-N Zinc dication Chemical compound [Zn+2] PTFCDOFLOPIGGS-UHFFFAOYSA-N 0.000 claims description 2
- 229910052782 aluminium Inorganic materials 0.000 claims description 2
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 claims description 2
- 229910052802 copper Inorganic materials 0.000 claims description 2
- 239000010949 copper Substances 0.000 claims description 2
- 229910052742 iron Inorganic materials 0.000 claims description 2
- 235000019658 bitter taste Nutrition 0.000 abstract description 22
- 239000002552 dosage form Substances 0.000 abstract description 7
- 239000000243 solution Substances 0.000 description 48
- 238000009472 formulation Methods 0.000 description 27
- 239000000499 gel Substances 0.000 description 17
- 235000010413 sodium alginate Nutrition 0.000 description 11
- 239000000126 substance Substances 0.000 description 11
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 10
- 239000000661 sodium alginate Substances 0.000 description 10
- 229940005550 sodium alginate Drugs 0.000 description 10
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 8
- 239000001110 calcium chloride Substances 0.000 description 8
- 229910001628 calcium chloride Inorganic materials 0.000 description 8
- 150000003839 salts Chemical class 0.000 description 8
- 150000001875 compounds Chemical class 0.000 description 7
- 201000010099 disease Diseases 0.000 description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 7
- 244000024675 Eruca sativa Species 0.000 description 6
- 235000014755 Eruca sativa Nutrition 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 239000000796 flavoring agent Substances 0.000 description 6
- 235000019634 flavors Nutrition 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 239000007787 solid Substances 0.000 description 5
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 4
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 229940016286 microcrystalline cellulose Drugs 0.000 description 4
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 4
- 239000008108 microcrystalline cellulose Substances 0.000 description 4
- MIDXCONKKJTLDX-UHFFFAOYSA-N 3,5-dimethylcyclopentane-1,2-dione Chemical compound CC1CC(C)C(=O)C1=O MIDXCONKKJTLDX-UHFFFAOYSA-N 0.000 description 3
- 108010011485 Aspartame Proteins 0.000 description 3
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 3
- 229920000858 Cyclodextrin Polymers 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- 239000004376 Sucralose Substances 0.000 description 3
- 244000299461 Theobroma cacao Species 0.000 description 3
- 239000000605 aspartame Substances 0.000 description 3
- 235000010357 aspartame Nutrition 0.000 description 3
- 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 3
- 229960003438 aspartame Drugs 0.000 description 3
- 229960005069 calcium Drugs 0.000 description 3
- 235000013736 caramel Nutrition 0.000 description 3
- 229940097362 cyclodextrins Drugs 0.000 description 3
- 235000003599 food sweetener Nutrition 0.000 description 3
- 235000013615 non-nutritive sweetener Nutrition 0.000 description 3
- 239000002245 particle Substances 0.000 description 3
- 239000001814 pectin Substances 0.000 description 3
- 235000010987 pectin Nutrition 0.000 description 3
- 229920001277 pectin Polymers 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 3
- 238000005063 solubilization Methods 0.000 description 3
- 230000007928 solubilization Effects 0.000 description 3
- 239000008107 starch Substances 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 235000019408 sucralose Nutrition 0.000 description 3
- BAQAVOSOZGMPRM-QBMZZYIRSA-N sucralose Chemical compound O[C@@H]1[C@@H](O)[C@@H](Cl)[C@@H](CO)O[C@@H]1O[C@@]1(CCl)[C@@H](O)[C@H](O)[C@@H](CCl)O1 BAQAVOSOZGMPRM-QBMZZYIRSA-N 0.000 description 3
- 239000003765 sweetening agent Substances 0.000 description 3
- 244000144730 Amygdalus persica Species 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 241000167854 Bourreria succulenta Species 0.000 description 2
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 2
- 235000005979 Citrus limon Nutrition 0.000 description 2
- 244000131522 Citrus pyriformis Species 0.000 description 2
- 244000307700 Fragaria vesca Species 0.000 description 2
- 235000016623 Fragaria vesca Nutrition 0.000 description 2
- 235000011363 Fragaria x ananassa Nutrition 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- 229920002774 Maltodextrin Polymers 0.000 description 2
- 239000005913 Maltodextrin Substances 0.000 description 2
- 235000006679 Mentha X verticillata Nutrition 0.000 description 2
- 235000002899 Mentha suaveolens Nutrition 0.000 description 2
- 235000001636 Mentha x rotundifolia Nutrition 0.000 description 2
- 240000008790 Musa x paradisiaca Species 0.000 description 2
- 235000018290 Musa x paradisiaca Nutrition 0.000 description 2
- 235000006040 Prunus persica var persica Nutrition 0.000 description 2
- 240000001890 Ribes hudsonianum Species 0.000 description 2
- 235000016954 Ribes hudsonianum Nutrition 0.000 description 2
- 235000001466 Ribes nigrum Nutrition 0.000 description 2
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- WNLRTRBMVRJNCN-UHFFFAOYSA-N adipic acid Chemical compound OC(=O)CCCCC(O)=O WNLRTRBMVRJNCN-UHFFFAOYSA-N 0.000 description 2
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 description 2
- 230000000595 bitter masking effect Effects 0.000 description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 description 2
- 229910001424 calcium ion Inorganic materials 0.000 description 2
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 2
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 2
- 125000002091 cationic group Chemical group 0.000 description 2
- 235000019693 cherries Nutrition 0.000 description 2
- 235000019219 chocolate Nutrition 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 238000004132 cross linking Methods 0.000 description 2
- 239000008367 deionised water Substances 0.000 description 2
- 229910021641 deionized water Inorganic materials 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000005538 encapsulation Methods 0.000 description 2
- 238000004817 gas chromatography Methods 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- -1 hydroxypropyl Chemical group 0.000 description 2
- 239000012669 liquid formulation Substances 0.000 description 2
- 239000000845 maltitol Substances 0.000 description 2
- 235000010449 maltitol Nutrition 0.000 description 2
- 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 2
- 229940035436 maltitol Drugs 0.000 description 2
- 229940035034 maltodextrin Drugs 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- ODLHGICHYURWBS-LKONHMLTSA-N trappsol cyclo Chemical compound CC(O)COC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)COCC(O)C)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1COCC(C)O ODLHGICHYURWBS-LKONHMLTSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 239000000811 xylitol Substances 0.000 description 2
- 235000010447 xylitol Nutrition 0.000 description 2
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 2
- 229960002675 xylitol Drugs 0.000 description 2
- 229920000856 Amylose Polymers 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- PHOQVHQSTUBQQK-SQOUGZDYSA-N D-glucono-1,5-lactone Chemical compound OC[C@H]1OC(=O)[C@H](O)[C@@H](O)[C@@H]1O PHOQVHQSTUBQQK-SQOUGZDYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- XCOBLONWWXQEBS-KPKJPENVSA-N N,O-bis(trimethylsilyl)trifluoroacetamide Chemical compound C[Si](C)(C)O\C(C(F)(F)F)=N\[Si](C)(C)C XCOBLONWWXQEBS-KPKJPENVSA-N 0.000 description 1
- 229940079172 Osmotic diuretic Drugs 0.000 description 1
- 229920002230 Pectic acid Polymers 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 235000009470 Theobroma cacao Nutrition 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000001361 adipic acid Substances 0.000 description 1
- 235000011037 adipic acid Nutrition 0.000 description 1
- 125000000129 anionic group Chemical group 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 235000019568 aromas Nutrition 0.000 description 1
- 239000001045 blue dye Substances 0.000 description 1
- FNAQSUUGMSOBHW-UHFFFAOYSA-H calcium citrate Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O FNAQSUUGMSOBHW-UHFFFAOYSA-H 0.000 description 1
- 239000001354 calcium citrate Substances 0.000 description 1
- 229960004256 calcium citrate Drugs 0.000 description 1
- 239000004227 calcium gluconate Substances 0.000 description 1
- 229960004494 calcium gluconate Drugs 0.000 description 1
- 235000013927 calcium gluconate Nutrition 0.000 description 1
- MKJXYGKVIBWPFZ-UHFFFAOYSA-L calcium lactate Chemical compound [Ca+2].CC(O)C([O-])=O.CC(O)C([O-])=O MKJXYGKVIBWPFZ-UHFFFAOYSA-L 0.000 description 1
- 239000001527 calcium lactate Substances 0.000 description 1
- 229960002401 calcium lactate Drugs 0.000 description 1
- 235000011086 calcium lactate Nutrition 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- NEEHYRZPVYRGPP-UHFFFAOYSA-L calcium;2,3,4,5,6-pentahydroxyhexanoate Chemical compound [Ca+2].OCC(O)C(O)C(O)C(O)C([O-])=O.OCC(O)C(O)C(O)C(O)C([O-])=O NEEHYRZPVYRGPP-UHFFFAOYSA-L 0.000 description 1
- 235000010418 carrageenan Nutrition 0.000 description 1
- 229920001525 carrageenan Polymers 0.000 description 1
- 239000012159 carrier gas Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 238000010668 complexation reaction Methods 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- HEBKCHPVOIAQTA-NGQZWQHPSA-N d-xylitol Chemical compound OC[C@H](O)C(O)[C@H](O)CO HEBKCHPVOIAQTA-NGQZWQHPSA-N 0.000 description 1
- 239000008393 encapsulating agent Substances 0.000 description 1
- 235000012209 glucono delta-lactone Nutrition 0.000 description 1
- 239000000182 glucono-delta-lactone Substances 0.000 description 1
- 229960003681 gluconolactone Drugs 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000001307 helium Substances 0.000 description 1
- 229910052734 helium Inorganic materials 0.000 description 1
- SWQJXJOGLNCZEY-UHFFFAOYSA-N helium atom Chemical compound [He] SWQJXJOGLNCZEY-UHFFFAOYSA-N 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- HOVAGTYPODGVJG-ZFYZTMLRSA-N methyl alpha-D-glucopyranoside Chemical compound CO[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O HOVAGTYPODGVJG-ZFYZTMLRSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 210000000214 mouth Anatomy 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000002337 osmotic diuretic agent Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 238000007430 reference method Methods 0.000 description 1
- 238000001223 reverse osmosis Methods 0.000 description 1
- 210000003296 saliva Anatomy 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 238000000527 sonication Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 210000001779 taste bud Anatomy 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 235000013337 tricalcium citrate Nutrition 0.000 description 1
Classifications
-
- 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
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
-
- 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
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1682—Processes
Definitions
- the present technology relates to masking the taste of isosorbide, in particular its bitterness.
- the technology developed here thus provides a new dosage form to improve the taste of isosorbide, as well as a process for preparing this dosage form.
- Isosorbide is an osmotic diuretic used in the treatment of Méimba's disease in several countries. This active principle, which needs to be ingested in large quantities, is known for its extremely unpleasant taste, in particular its strong bitterness.
- a dose of isosorbide consists of the oral absorption of sticks of 40 mL at 70% isosorbide (ie 28 g of isosorbide administered per dose).
- no method has until now been found which effectively masks the taste of isosorbide, in particular considering the concentrations and quantities ingested.
- the present invention thus aims to provide an effective means for masking the taste of isosorbide, in particular when this active principle is administered in large quantities, and / or at high concentrations.
- This oral dosage form is in the form of gelled isosorbide beads, preferably using alginate as a gelling agent.
- the dosage form proposed by the present invention is simple to implement, in that it does not require the use of a large number of materials.
- isosorbide is a small, highly soluble molecule, it is surprising that bitterness is not felt, especially considering the amounts and concentrations administered. Indeed, one would have expected that isosorbide would diffuse beads very quickly into the saliva of the oral cavity, where its bitterness would have been detected by the taste buds, and therefore felt by the panel of tasters.
- document WO2006 / 001344 relates to a gelled mass based on alginate isosorbide and other gelling constituents. Such a composition is not suitable for making beads.
- this document teaches that taste masking is optimized by adding cocoa powder.
- Document US2010 / 120712 relates to a composition comprising these two ingredients, said composition being in the form of extruded granules or powders. Compositions in the form of beads are not described.
- document WO 00/06122 describes pharmaceutical compositions for oral administration comprising particles of active principle and a gelling agent.
- the particles of active principle can optionally be in the form of alginate beads (Example 12).
- the particles of active ingredient obtained are mixed with a gelling agent and other substances, in order to obtain the final dosage form.
- this solid form is added with water to obtain a gelled composition and the undesirable taste of the active ingredient is masked.
- This document does not mention isosorbide, and the pharmaceutical compositions finally ingested contain very small amounts of the active ingredient.
- the invention relates firstly to gelled beads, in particular for oral administration, comprising isosorbide, the isosorbide content being at least 50% by dry weight of isosorbide relative to the weight. total of said gelled beads.
- the invention relates secondly to a pharmaceutical composition comprising or consisting of the gel beads of the invention.
- the invention relates thirdly to a process for preparing the gelled beads of the invention, said process comprising the following steps:
- step (b) preparation of a gelation solution
- step (c) dropwise addition of the solution prepared in step (a), to the gelling solution prepared in step (b);
- the invention relates to a method of masking the unwanted taste of isosorbide, comprising putting said isosorbide in the form of gel beads.
- the invention relates firstly to gelled beads, in particular for oral administration, comprising isosorbide, the isosorbide content being at least 50% by dry weight of isosorbide relative to the total weight of said. gel beads.
- this dry weight content of isosorbide is at least 60%, preferably at least 70%, preferably at least 75%, more preferably at least 80%.
- This isosorbide dry weight content is generally less than or equal to 95%, or even less than or equal to 90%, or even less than or equal to 85%.
- This content by dry weight of isosorbide relative to the total weight of said gelled beads can be determined by a person skilled in the art, for example by gas chromatography with flame ionization detection and internal calibration, preferably using the methyl aD-glucopyranoside as internal standard, for example according to a protocol described in the examples below.
- the gelled beads of the invention typically comprise one or more gelling agent (s).
- Gelling agents capable of rapidly gelling at room temperature in the presence of water are particularly useful herein. They are preferably polymers capable of undergoing crosslinking gelation in the presence of polyvalent metal ions.
- Gelling agents include among others those agents which are capable of gelling when used in combination. Examples of gelling agents are alginates, pectates, carrageenans and gelatin. Preferably, gelatin will not be used, in particular due to the fact that it is a product of animal origin. Preferably, as gelling agent, at least the alginate will be used. When several gelling agents are present, the proportion by dry weight of alginate is then preferably at least 20% relative to the total dry weight of gelling agents, preferably at least 30%, preferably at least. at least 40%, preferably at least 50%, preferably at least 60%, preferably at least 70%, preferably at least 80%, preferably at least 90%. More preferably, the alginate is the only gelling agent of the gelled beads.
- these gelling agents are in the form of salts, for example sodium, magnesium, potassium, preferably sodium. Particularly preferred is sodium alginate.
- the gelling agents used have a Brookfield viscosity, as measured at 1% at 20 ° C, less than or equal to 2000 cps, preferably less than or equal to 1000 cps, preferably less than or equal to 800 cps , preferably less than or equal to 500 cps, preferably less than or equal to 400 cps, preferably less than or equal to 300 cps, preferably less than or equal to 250 cps, preferably less than or equal to 200 cps.
- a Brookfield viscosity as measured at 1% at 20 ° C, less than or equal to 2000 cps, preferably less than or equal to 1000 cps, preferably less than or equal to 800 cps , preferably less than or equal to 500 cps, preferably less than or equal to 400 cps, preferably less than or equal to 300 cps, preferably less than or equal to 250 cps, preferably less than or equal to 200 cps.
- this Brookfield viscosity is greater than or equal to 10 cps, preferably greater than or equal to 20 cps, preferably greater than or equal to 30 cps, preferably greater than or equal to 35 cps, preferably greater than or equal to 50 cps, preferably greater than or equal to 80 cps, preferably greater than or equal to 100 cps.
- This viscosity is for example chosen from a range going from 35 to 65 cps, or from 100 to 200 cps, or from 300 to 400 cps.
- the content by dry weight of gelling agents relative to the total dry weight of the gelled beads (dry / dry), in particular the content of alginate is at least 0.1%, of preferably at least 0.3%, preferably at least 0.5%, preferably at least 0.7%, preferably at least 1.0%, preferably at least 1 , 2%, preferably at least 1.4%.
- This content by dry / dry weight of gelling agents or more particularly of alginate is preferably less than or equal to 5.0%, preferably less than or equal to 4.0%, preferably less than or equal to 3.0%, preferably less than or equal to 2.0%, preferably less than or equal to 1.8%, preferably less than or equal to 1.6%.
- the gelled beads of the invention exhibit an isosorbide / gelling agent dry weight ratio at least equal to 40, preferably at least equal to 50, preferably at least equal to 55, preferably at least equal to 60.
- This ratio is preferably less than or equal to 200, preferably less than or equal to 150, preferably less than or equal to 140, preferably less than or equal to 130, preferably less than 120, preferably less than or equal to 100, preferably less than or equal to 80, preferably less than or equal to 75.
- the gelled beads of the invention exhibit an isosorbide / alginate dry weight ratio at least equal to 40, preferably at least equal to 50, preferably at least equal to 55, preferably at least equal to 60.
- This ratio is preferably less than or equal to 200, preferably less than or equal to 150, preferably less than or equal to 140, preferably less than or equal to 130, preferably less than 120, preferably less than or equal to 100, preferably less than or equal to 80, preferably less than or equal to 75.
- the gelled beads of the present invention comprise a solvent, preferably water, even more preferably demineralized water.
- the solvent content of the gelled beads is less than or equal to 30% by weight relative to the total weight of gelled beads, preferably less than or equal to 25%, preferably less than or equal to 20%, for example less than or equal to 18%.
- This solvent content is generally greater than or equal to 1%, or even greater than or equal to 5%, or even greater than or equal to 10%, for example greater than or equal to 13%, 14% or 15%.
- Gelled beads may contain ions, usually in the form of traces, depending on the process used for their preparation.
- the gelled beads may contain other substances than those listed above, as long as this does not contravene the desired properties, in particular as regards the taste quality of the gelled beads, and / or their stability, and / or the pharmacological activity of isosorbide.
- other substances are, for example: flavorings; sweeteners, especially intense sweeteners; encapsulating agents such as cyclodextrins; active ingredients other than isosorbide; compounds aimed at modifying the bioavailability of the active principles of the beads, in particular aimed at modifying the bioavailability of isosorbide.
- the gelled beads comprise less than 30% by dry weight of other substances relative to the total weight of gelled beads, preferably less than 20%, preferably less than 10%, preferably less than 5%, preferably less than 1%, more preferably 0%. It has in fact been demonstrated in the examples below that the other substances are not necessary for solving the problem posed here.
- the gelled beads are free from other substances.
- the gelled beads in this case consist only of isosorbide, gelling agents, and a solvent which is preferably water, more preferably demineralized water.
- the gelled beads consist only of isosorbide, alginate and a solvent which is preferably water, more preferably demineralized water.
- the gelled beads have an average diameter less than or equal to 5.0 mm, preferably less than or equal to 3.0 mm, preferably less than or equal to 2.0 mm, preferably less than or equal to 1.5 mm.
- This average diameter is generally greater than or equal to 0.1 mm, or even greater than or equal to 0.2 mm, or even greater than or equal to 0.3 mm, or even greater than or equal to 0.4 mm, or even greater than or equal to 0 , 5 mm.
- the beads are insoluble in water at a temperature of 20 ° C.
- the invention also relates to a pharmaceutical composition
- a pharmaceutical composition comprising the gelled beads of the invention.
- isosorbide fulfills the role of active principle.
- pharmaceutical composition is meant a composition in its final dosage form intended to be administered to a patient.
- This pharmaceutical composition can also consist only of the gel beads of the invention.
- the gelled beads can quite be administered as they are.
- the gel beads can be administered with other substances, for example in the form of a suspension of the gel beads in a syrup.
- the pharmaceutical composition of the invention contains an amount of isosorbide per intake of at least 10 g, preferably at least 20 g, preferably at least 25 g, for example 28 g.
- the pharmaceutical composition of the invention is intended to be administered 1, 2 or 3 times per day, preferably 3 times per day.
- the pharmaceutical composition of the invention contains an isosorbide content of at least 20% by dry weight relative to the total weight of said pharmaceutical composition, preferably at least 30% by dry weight, of preferably at least 40% by dry weight, preferably at least 50% by dry weight, preferably at least 60% by dry weight, preferably at least 70% by dry weight, preferably d at least 75% by dry weight, more preferably at least 80% by dry weight.
- This isosorbide dry weight content is generally less than or equal to 95%, or even less than or equal to 90%, or even less than or equal to 85%.
- the pharmaceutical composition according to the invention is for use as a medicament, in particular for the treatment of Mérier's disease.
- Another object of the invention relates to a method of treatment, in particular of Mérier's disease, comprising the administration of a pharmaceutical composition of the invention.
- it is a composition for its use in the treatment of Mérier's disease.
- the composition according to the invention for the manufacture of a medicament intended for therapeutic use in Mérier's disease.
- the patient to be treated is an individual suffering from Méayne's disease.
- a subject of the present invention is also a process for preparing gelled beads according to the invention, said process comprising the following steps:
- step (c) dropwise addition of the solution prepared in step (a), to the gelling solution prepared in step (b);
- the gelling agent is solubilized first in a solvent which is preferably water, more preferably demineralized water, and the isosorbide is then added.
- a solvent which is preferably water, more preferably demineralized water, and the isosorbide is then added.
- the solution of step (a) has an isosorbide content chosen from a range of 30 to 80% by weight relative to the total weight of said solution.
- this content is at least equal to 40%, preferably at least equal to 45%, preferably at least equal to 50%, preferably at least equal to 55%.
- this content is at most equal to 80%, preferably at most equal to 75%, preferably at most equal to 70%, preferably at most equal to 65%. This content is for example equal to 50%, or to 60%.
- the solution of step (a) has a content of gelling agents, in particular an alginate content, chosen in a range ranging from 0.1 to 5.0% by weight relative to the total weight. of said solution.
- this content is at least equal to 0.2%, preferably at least equal to 0.3%, preferably at least equal to 0.4%, preferably at least equal to 0.5%.
- this content is maximum equal to 4.5%, preferably maximum equal to 4.0%, preferably maximum equal to 3.5%, preferably maximum equal to 3.0%, preferably at most equal to 2.5%, preferably at most equal to 2.0%, preferably at most equal to 1.5%, preferably at most equal to 1.0%.
- the amounts of isosorbide and gelling agents in the solution of step (a) are chosen such that the weight ratio isosorbide / gelling agents is at least equal to 40, preferably at least equal to 50, preferably at least equal to 60.
- This ratio is preferably less than or equal to 200, preferably less than or equal to 150, preferably less than or equal to 140, preferably less than or equal to 110, preferably less than or equal to 100.
- the amounts of isosorbide and alginate in the solution of step (a) are chosen such that the isosorbide / alginate weight ratio is at least equal to 40, preferably at least equal to 50, preferably at least equal to 60.
- This ratio is preferably less than or equal to 200, preferably less than or equal to 150, preferably less than or equal to 140, preferably less than or equal to 110, preferably less than or equal to 100.
- the total amount of solids in the solution of step (a) is chosen from a range of 30 to 80% by weight relative to the total weight of said solution.
- this amount of solids is chosen from a range of 50 to 70%, preferably 60 to 65%.
- the gelation solution of step (b) comprises one or more polyvalent metal ion (s).
- the gelling agents of the invention are preferably polymers capable of undergoing crosslinking gelation in the presence of polyvalent metal ions.
- the gelling solution can be a solution having a temperature lower than that of the solution of step (a), so that gelling occurs by cooling.
- These polyvalent metal ions are for example chosen from calcium, aluminum, iron, copper, zinc ions or a mixture thereof.
- Calcium ions are particularly preferred.
- These calcium ions can preferably be in the form of inorganic salts such as calcium chloride, calcium sulfate, calcium monohydrogenophosphate or calcium carbonate. They can also be in the form of organic salts such as calcium lactate, calcium gluconate, calcium citrate. Preferably, it is a water soluble salt.
- the polyvalent metal ions useful in the invention comprise at least chloride of calcium. More preferably, calcium chloride is the only polyvalent metal ion used.
- the polyvalent metal ions are in the form of water insoluble salts (as is the case for example of calcium carbonate), it will be necessary to add an acid to dissolve the salt, in particular an organic acid such as citric acid, adipic acid, glucono-delta-lactone acid etc. Therefore, calcium salts which are soluble in water, in particular calcium chloride, are preferably used.
- the gelation solution of step (b) has a content of polyvalent metal ions, in particular a content of calcium chloride, chosen in a range ranging from 1 to 20% by dry weight relative to the content. total weight of said solution.
- this content is at least equal to 3%, preferably at least equal to 5%, preferably at least equal to 7%, preferably at least equal to 9%.
- this content is at most equal to 18%, preferably at most equal to 16%, preferably at most equal to 14%, preferably at most equal to 12%, preferably at most equal to 11%. This content is for example equal to 10%.
- step (c) it is possible to pump the solution of step (a) contained in a storage unit in order to bring it to the gelling solution contained in another. storage unit.
- the pump used will typically depend on the viscosity of the solution from step (a) containing the gelling agent (s). Adding the solution prepared in step (a) dropwise to the gelation solution prepared in step (b) allows the instantaneous formation of beads.
- the process for preparing gelled beads further comprises, between steps (c) and (d), a step of washing the gelled beads, preferably with demineralized water.
- This step is typically carried out in order to rid the product of salts optionally used in the process, such as, for example, calcium chloride.
- the process for preparing gelled beads preferably comprises a step of drying the gelled beads, between steps (c) and (d). This step will preferably be subsequent to the washing step if the latter is carried out. This drying can be carried out in an oven. On an industrial scale, however, techniques using the action of a heated air flow applied to the moving balls will be preferred. An example is drying in a fluidized air bed.
- Drying in addition to increasing the stability of the gel beads, also has the effect of reducing the diameter of the beads. So to control the desired diameter, in addition to choosing a suitable system for the formation of the drops to gel, it will be necessary to take into account the effect of this heating step.
- the gelled beads Preferably before drying, the gelled beads contain a liquid core. Indeed in this case, the drying step will advantageously be able to concentrate the isosorbide of the beads.
- the gelled beads do not contain a liquid core.
- the present invention also relates to gelled beads, in particular for oral administration, which may be obtained by or obtained by according to the process for preparing gelled beads of the invention.
- gelled beads in particular for oral administration, which may be obtained by or obtained by according to the process for preparing gelled beads of the invention.
- the preferred embodiments of these gelled beads are as described before, in the description relating to the gelled beads.
- Another object of the invention relates to a method for masking the unwanted taste of isosorbide, comprising putting said isosorbide in the form of gel beads.
- the gelled beads make it possible to statistically significantly reduce the bitterness of isosorbide, compared to an isosorbide solution having the same concentration and quantity of isosorbide, said bitterness being detected by an electronic tongue equipped with lipid membrane bitterness sensors for example using equipment such as Insent® Electronic Taste Sensing System TS-5000Z (Atsugi-Chi, Japan) equipped for example with bitterness sensors SB2AC0 (Bitterness 1, cationic substances), SB2AN0 (Bitterness 2, cationic substances) and SB2C00 (Bitterness 3, anionic substances).
- the gelled beads make it possible to statistically significantly improve the taste of isosorbide, compared to an isosorbide solution having the same concentration and quantity of isosorbide, said improvement being determined using a panel of tasters.
- the gelled beads make it possible to completely mask the undesirable taste of the isosorbide, and in particular its bitterness.
- the gelled beads are as described before.
- the isosorbide is formed into gelled beads by the process for preparing gelled beads of the invention as described above.
- an amount by “dry weight” refers to an amount by weight of anhydrous substance.
- an amount simply expressed in “weight” refers to amounts of so-called “commercial” materials, that is to say to quantities of generally powdery product used as such. These contents by weight therefore include the water which may be inherently present in these commercial powders.
- the isosorbide and the salts typically and preferably contain 0% by weight of water, and that the gelling agents, in particular the alginate, comprise a maximum of 15% by weight of water.
- Example 1 Masking of the taste of isosorbide using intense sweeteners (liquid medium)
- Example 2 Masking of the taste of isosorbide using encapsulation techniques (liquid medium)
- Example 3 Masking of the taste of isosorbide using texturing techniques (gelled medium) [80]
- Various formulations in gel form were tested, in order to examine the effectiveness of texturing techniques for masking the taste. isosorbide.
- the formulations used are presented in Tables 5 and 6 below, and the percentages are expressed by weight relative to the total weight of the formulation.
- isosorbide was ground (Moulin IKA) beforehand, in order to facilitate its solubilization.
- Formulations with the MCC / CMC compound and pectin had limited impact on isosorbide bitterness, even when strong sweeteners were added to the formulation.
- Formulations based on soluble hydrolyzed hydroxypropyl pea starch failed to improve the taste of the isosorbide.
- Example 4 Masking of the taste of isosorbide using texturing techniques (gelled medium) and the use of flavorings [86]
- the inventors attempted to improve the gels of Example 3 which had only a limited impact on the bitterness of the isosorbide.
- gels with added flavorings were tested.
- the formulations used are presented in Tables 7 and 8 below, and the percentages are expressed by weight relative to the total weight of the formulation.
- the isosorbide was ground (Moulin IKA) beforehand, in order to facilitate its solubilization.
- Example 5 Masking of the taste of isosorbide by the formation of gelled beads
- a gelation solution [B] was then prepared, consisting of 90% by weight of demineralized water, and 10% by weight of calcium chloride.
- the resulting beads had a diameter of about 2-3 mm. They were then dried in an oven, and then had a diameter of about 1 mm.
- Beads obtained from Formulation 38 were analyzed by gas chromatography with flame ionization detection and internal calibration to determine their isosorbide dry weight content.
- the capillary column used had a length of 30 meters, an internal diameter of 0.32 millimeters, a film thickness of 1 micron.
- the isosorbide content is expressed in dry g per 100 g of gelled beads and is given by the following equation:
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Abstract
Description
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Application Number | Priority Date | Filing Date | Title |
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FR1911102A FR3101546B1 (fr) | 2019-10-07 | 2019-10-07 | Masquage du goût de l’isosorbide |
PCT/FR2020/051766 WO2021069836A1 (fr) | 2019-10-07 | 2020-10-07 | Masquage du goût de l'isosorbide |
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EP (1) | EP4041197A1 (fr) |
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