EP1988893A2 - Mittels cyclodextrin stabilisierte desloratadine enthaltende formulierung - Google Patents
Mittels cyclodextrin stabilisierte desloratadine enthaltende formulierungInfo
- Publication number
- EP1988893A2 EP1988893A2 EP07733895A EP07733895A EP1988893A2 EP 1988893 A2 EP1988893 A2 EP 1988893A2 EP 07733895 A EP07733895 A EP 07733895A EP 07733895 A EP07733895 A EP 07733895A EP 1988893 A2 EP1988893 A2 EP 1988893A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- cyclodextrin
- oral pharmaceutical
- desloratadine
- dosage form
- stable oral
- 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.)
- Withdrawn
Links
- 229960001271 desloratadine Drugs 0.000 title claims abstract description 57
- JAUOIFJMECXRGI-UHFFFAOYSA-N Neoclaritin Chemical compound C=1C(Cl)=CC=C2C=1CCC1=CC=CN=C1C2=C1CCNCC1 JAUOIFJMECXRGI-UHFFFAOYSA-N 0.000 title claims abstract description 56
- 229920000858 Cyclodextrin Polymers 0.000 title claims description 56
- 239000000203 mixture Substances 0.000 title claims description 48
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 title claims description 34
- 238000009472 formulation Methods 0.000 title description 17
- 239000008203 oral pharmaceutical composition Substances 0.000 claims abstract description 22
- 238000004519 manufacturing process Methods 0.000 claims abstract description 14
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 39
- 239000002552 dosage form Substances 0.000 claims description 19
- 239000003826 tablet Substances 0.000 claims description 16
- 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 claims description 14
- 239000001116 FEMA 4028 Substances 0.000 claims description 13
- 235000011175 beta-cyclodextrine Nutrition 0.000 claims description 13
- 229960004853 betadex Drugs 0.000 claims description 13
- GUBGYTABKSRVRQ-QKKXKWKRSA-N lactose group Chemical group OC1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@@H](O)[C@H](O2)CO)[C@H](O1)CO GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 12
- 239000008101 lactose Substances 0.000 claims description 10
- 238000002845 discoloration Methods 0.000 claims description 8
- 239000006186 oral dosage form Substances 0.000 claims description 8
- 229920001450 Alpha-Cyclodextrin Polymers 0.000 claims description 5
- HFHDHCJBZVLPGP-RWMJIURBSA-N alpha-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)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 HFHDHCJBZVLPGP-RWMJIURBSA-N 0.000 claims description 5
- 229940043377 alpha-cyclodextrin Drugs 0.000 claims description 5
- 239000002775 capsule Substances 0.000 claims description 5
- 150000002016 disaccharides Chemical class 0.000 claims description 5
- GDSRMADSINPKSL-HSEONFRVSA-N gamma-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)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 GDSRMADSINPKSL-HSEONFRVSA-N 0.000 claims description 5
- 229940080345 gamma-cyclodextrin Drugs 0.000 claims description 5
- 239000012535 impurity Substances 0.000 claims description 5
- 150000002772 monosaccharides Chemical class 0.000 claims description 5
- 239000008188 pellet Substances 0.000 claims description 5
- 238000005550 wet granulation Methods 0.000 claims description 5
- 238000007907 direct compression Methods 0.000 claims description 4
- 238000007908 dry granulation Methods 0.000 claims description 4
- 239000003381 stabilizer Substances 0.000 claims description 4
- 229940124531 pharmaceutical excipient Drugs 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 13
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 12
- 238000000034 method Methods 0.000 description 11
- 239000004255 Butylated hydroxyanisole Substances 0.000 description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
- 235000019282 butylated hydroxyanisole Nutrition 0.000 description 8
- CZBZUDVBLSSABA-UHFFFAOYSA-N butylated hydroxyanisole Chemical compound COC1=CC=C(O)C(C(C)(C)C)=C1.COC1=CC=C(O)C=C1C(C)(C)C CZBZUDVBLSSABA-UHFFFAOYSA-N 0.000 description 8
- 229940043253 butylated hydroxyanisole Drugs 0.000 description 8
- 229940075614 colloidal silicon dioxide Drugs 0.000 description 8
- 229960001375 lactose Drugs 0.000 description 8
- QGLIUOLEDZMNSF-UHFFFAOYSA-N 4-(8-chloro-5,6-dihydrobenzo[1,2]cyclohepta[2,4-b]pyridin-11-ylidene)piperidine-1-carbaldehyde Chemical compound C=1C(Cl)=CC=C2C=1CCC1=CC=CN=C1C2=C1CCN(C=O)CC1 QGLIUOLEDZMNSF-UHFFFAOYSA-N 0.000 description 7
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- 239000011230 binding agent Substances 0.000 description 5
- 239000003085 diluting agent Substances 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 4
- 230000002378 acidificating effect Effects 0.000 description 4
- 239000003963 antioxidant agent Substances 0.000 description 4
- 235000006708 antioxidants Nutrition 0.000 description 4
- 239000006172 buffering agent Substances 0.000 description 4
- 229920002678 cellulose Chemical class 0.000 description 4
- 239000001913 cellulose Chemical class 0.000 description 4
- 235000010980 cellulose Nutrition 0.000 description 4
- 229940097362 cyclodextrins Drugs 0.000 description 4
- 239000007884 disintegrant Substances 0.000 description 4
- 239000006185 dispersion Substances 0.000 description 4
- 239000000796 flavoring agent Substances 0.000 description 4
- 235000003599 food sweetener Nutrition 0.000 description 4
- 239000008187 granular material Substances 0.000 description 4
- 239000003755 preservative agent Substances 0.000 description 4
- 239000003765 sweetening agent Substances 0.000 description 4
- 239000000454 talc Substances 0.000 description 4
- 229910052623 talc Inorganic materials 0.000 description 4
- 229940033134 talc Drugs 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 229920002785 Croscarmellose sodium Polymers 0.000 description 3
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 3
- 230000015556 catabolic process Effects 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 239000011248 coating agent Substances 0.000 description 3
- 238000000576 coating method Methods 0.000 description 3
- 229960001681 croscarmellose sodium Drugs 0.000 description 3
- 229960000913 crospovidone Drugs 0.000 description 3
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 3
- 238000006731 degradation reaction Methods 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 235000019634 flavors Nutrition 0.000 description 3
- 235000019359 magnesium stearate Nutrition 0.000 description 3
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 3
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 3
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 3
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 2
- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical compound O.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O WSVLPVUVIUVCRA-KPKNDVKVSA-N 0.000 description 2
- 229920002261 Corn starch Polymers 0.000 description 2
- 229920000881 Modified starch Chemical class 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 229920002472 Starch Chemical class 0.000 description 2
- 235000021355 Stearic acid Nutrition 0.000 description 2
- 230000001387 anti-histamine Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 239000008120 corn starch Substances 0.000 description 2
- 229940099112 cornstarch Drugs 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- -1 formyl desloratadine Chemical compound 0.000 description 2
- 229960001021 lactose monohydrate Drugs 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 235000019426 modified starch Nutrition 0.000 description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 238000012216 screening Methods 0.000 description 2
- 238000009491 slugging Methods 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 239000008107 starch Chemical class 0.000 description 2
- 239000008117 stearic acid Substances 0.000 description 2
- UCTWMZQNUQWSLP-VIFPVBQESA-N (R)-adrenaline Chemical compound CNC[C@H](O)C1=CC=C(O)C(O)=C1 UCTWMZQNUQWSLP-VIFPVBQESA-N 0.000 description 1
- 229930182837 (R)-adrenaline Natural products 0.000 description 1
- OKMWKBLSFKFYGZ-UHFFFAOYSA-N 1-behenoylglycerol Chemical compound CCCCCCCCCCCCCCCCCCCCCC(=O)OCC(O)CO OKMWKBLSFKFYGZ-UHFFFAOYSA-N 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- 229930003347 Atropine Natural products 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- RKUNBYITZUJHSG-UHFFFAOYSA-N Hyosciamin-hydrochlorid Natural products CN1C(C2)CCC1CC2OC(=O)C(CO)C1=CC=CC=C1 RKUNBYITZUJHSG-UHFFFAOYSA-N 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 208000003251 Pruritus Diseases 0.000 description 1
- 206010039085 Rhinitis allergic Diseases 0.000 description 1
- GUGOEEXESWIERI-UHFFFAOYSA-N Terfenadine Chemical compound C1=CC(C(C)(C)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 GUGOEEXESWIERI-UHFFFAOYSA-N 0.000 description 1
- 229960001138 acetylsalicylic acid Drugs 0.000 description 1
- 150000001447 alkali salts Chemical class 0.000 description 1
- 201000010105 allergic rhinitis Diseases 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 230000003266 anti-allergic effect Effects 0.000 description 1
- 239000000739 antihistaminic agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- RKUNBYITZUJHSG-SPUOUPEWSA-N atropine Chemical compound O([C@H]1C[C@H]2CC[C@@H](C1)N2C)C(=O)C(CO)C1=CC=CC=C1 RKUNBYITZUJHSG-SPUOUPEWSA-N 0.000 description 1
- 229960000396 atropine Drugs 0.000 description 1
- 229940125717 barbiturate Drugs 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- ZPEIMTDSQAKGNT-UHFFFAOYSA-N chlorpromazine Chemical compound C1=C(Cl)C=C2N(CCCN(C)C)C3=CC=CC=C3SC2=C1 ZPEIMTDSQAKGNT-UHFFFAOYSA-N 0.000 description 1
- 229960001076 chlorpromazine Drugs 0.000 description 1
- 208000030949 chronic idiopathic urticaria Diseases 0.000 description 1
- 206010072757 chronic spontaneous urticaria Diseases 0.000 description 1
- 208000024376 chronic urticaria Diseases 0.000 description 1
- 239000008199 coating composition Substances 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 239000007857 degradation product Substances 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- XEYBRNLFEZDVAW-ARSRFYASSA-N dinoprostone Chemical group CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1C\C=C/CCCC(O)=O XEYBRNLFEZDVAW-ARSRFYASSA-N 0.000 description 1
- 239000002934 diuretic Substances 0.000 description 1
- 229940030606 diuretics Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 229960005139 epinephrine Drugs 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 125000002791 glucosyl group Chemical group C1([C@H](O)[C@@H](O)[C@H](O)[C@H](O1)CO)* 0.000 description 1
- 229940049654 glyceryl behenate Drugs 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- JCCNYMKQOSZNPW-UHFFFAOYSA-N loratadine Chemical class C1CN(C(=O)OCC)CCC1=C1C2=NC=CC=C2CCC2=CC(Cl)=CC=C21 JCCNYMKQOSZNPW-UHFFFAOYSA-N 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 229940094443 oxytocics prostaglandins Drugs 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229940069328 povidone Drugs 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- 239000003223 protective agent Substances 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 238000009490 roller compaction Methods 0.000 description 1
- 230000001932 seasonal effect Effects 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 230000001624 sedative effect Effects 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 229960003885 sodium benzoate Drugs 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 229940032147 starch Drugs 0.000 description 1
- 229960004274 stearic acid Drugs 0.000 description 1
- 239000003270 steroid hormone Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000000080 wetting agent Substances 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; 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
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
-
- 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
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
-
- 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
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
-
- 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
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
-
- 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
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
- A61K31/716—Glucans
- A61K31/724—Cyclodextrins
Definitions
- the present invention relates to a stable oral pharmaceutical composition. More particularly the invention relates to a stable oral pharmaceutical composition containing desloratadine and a process for preparing the stable oral pharmaceutical composition.
- Desloratadine a metabolic derivative of loratadine is a long acting tricyclic antihistamine with selective Hi -receptor antagonist activity. Desloratadine is chemically 8-chloro-6,l 1-dihydro-l l-(4-piperidylidene)-5H-benzo[5,6]-cyclohepta 1,2- b]pyridine.
- U.S. Patent No. 4,659,716 discloses desloratadine possessing antihistaminic properties with substantially no sedative properties.
- Maillard reaction is a nonenzymatic chemical reaction involving condensation of an amino group and a reducing group.
- Desloratadine is a secondary amine, which makes it susceptible to maillard reaction when formulated with wide variety of excipients commonly used in oral formulations resulting in degradation. This maillard type degradation is pronounced in the presence of water and/or elevated temperature.
- N-formyl desloratadine has been reported to be the major decomposition product of desloratadine.
- U.S. Patent No. 6,100,274 discloses that desloratadine discolors and decomposes in the presence acidic excipients and avoiding the use of acidic excipients and combining desloratadine with acceptable carrier medium comprising a basic salt substantially solve that problem.
- Published application 2002/0123054 describes various methods of providing stable desloratadine formulation including providing desloratadine formulation free of reactive excipients such as lactose or other mono- or di- saccharides, use of anhydrous desloratadine, use of desloratadine with increased particle size, providing non hygroscopic desloratadine containing formulations, coating desloratadine with a protective agent.
- a stable oral pharmaceutical composition comprising desloratadine, cyclodextrin as stabilizer and pharmaceutically acceptable excipients.
- an embodiment of the stable oral pharmaceutical composition includes one or more of the following features.
- the cyclodextrin is selected from alpha cyclodextrin, beta cyclodextrin, gamma cyclodextrin, their derivatives or mixtures thereof.
- beta cyclodextrin is used.
- the ratio of desloratadine to cyclodextrin is from about 1 :5 to about 1:25, preferably from about 1 :10 to about 1:15.
- the stable oral pharmaceutical composition contains less than 0.5 % w/w of N- formyl desloratadine when stored at 40° C and 75% relative humidity over an extended period of time.
- the stable oral pharmaceutical composition does not undergo discoloration when stored at 40° C and 75% relative humidity over an extended period of time.
- the oral pharmaceutical composition is stable even in the presence of excipients, which are reactive with desloratadine, wherein the reactive excipient may be lactose and /or other mono- or disaccharides.
- a process for preparing stable oral pharmaceutical dosage form comprising a) forming a mixture of desloratadine, cyclodextrin with one or more pharmaceutical excipients b) processing the mixture into an oral dosage form.
- Embodiments of process may include one or more of the features as described above.
- the cyclodextrin may be alpha cyclodextrin, beta cyclodextrin, gamma cyclodextrin, their derivatives or mixtures thereof, preferably beta cyclodextrin.
- the ratio of desloratadine to cyclodextrin is from about 1:5 to about 1:25, preferably from about 1:10 to about 1:15.
- the stable oral pharmaceutical dosage form of the process contains less than 0.5
- % w/w of N-formyl desloratadine when stored at 40° C and 75% relative humidity over an extended period of time.
- the stable oral pharmaceutical composition does not undergo discoloration when stored at 40° C and 75% relative humidity over an extended period of time.
- the stable oral pharmaceutical dosage form of the process is stable even in the presence of excipients, which are reactive with desloratadine.
- the reactive excipient may be lactose and /or other mono- or disaccharides.
- forming of mixture involves wet granulation, dry granulation or direct compression.
- the mixture is processed into oral dosage forms like tablet, capsules or pellets.
- the present invention provides a stable pharmaceutical composition
- a stable pharmaceutical composition comprising descarbonylethoxyloratadine (Desloratadine), cyclodextrin as stabilizer and pharmaceutically acceptable excipients.
- compositions of the present invention comprise desloratadine in an anti allergically effective amount.
- the anti allergic effective amount of desloratadine in the pharmaceutical compositions of the present invention is from about 0.1 mg to about 15 mg, preferably from about 1 mg to about 10 mg.
- Cyclodextrins have been used to enhance the solubility and stability of drugs in aqueous solution.
- Passington, in chemistry of England, May 1987, page 457 has reported that beta cyclodextrin complexes or inclusion compounds enhance the solubility of prostaglandins, steroid hormones, diuretics and barbiturates and stabilize the hydrolysis of aspirin, atropine, and procaine, stabilize the oxidation of chlorpromazine and epinephrine, stabilize the dehydration of prostaglandin E groups.
- Other reference, which provides the characteristics of cyclodextrin and describes its use in pharmaceutical compositions include the following "Cyclodextrin Chemistry" by M. L.
- compositions comprising desloratadine are however accompanied by such drawbacks that they are unstable when stored for a long periods of time.
- Desloratadine compositions are known to be susceptible to chemical and physical instability. Desloratadine chemically degrades to N-formyl deslortadine impurity. Desloratadine composition is also known to undergo discoloration in the presence of wide variety of conventional excipients commonly used in oral formulations.
- compositions comprising desloratadine can be obtained using cyclodextrin as stabilizer, wherein cyclodextrin is used in amounts such that it prevents discoloration of the composition and/or minimizes the degradation of desloratadine to its N-formyl desloratadine
- the pharmaceutical composition of the instant invention in addition to providing stability provides freedom for the use of conventional excipients and process.
- the compositions of the present invention in the presence of cyclodextrin are found to be stable when stored at 40° C and 75% relative humidity as represented in Example 1.
- Example 1 the formation of N-formyl desloratadine is significantly minimized and there is no color change when compared to pharmaceutical compositions without cyclodextrin (Comparative Example).
- Cyclodextrin includes any of the known cyclodextrins such as unsubstituted cyclodextrins containing from six to twelve glucose units, especially alpha-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin and/or their derivatives and/or mixtures thereof. Unsubstituted cyclodextrins are preferred and more preferably beta-cyclodextrin is preferred.
- the ratio of desloratadine to cyclodextrin in the composition may range from about 1:5 to about 1 :25, preferably about 1 :10 to about 1 :15.
- the pharmaceutically acceptable excipients of the present invention may be solids or liquids, that include but not limited to diluents, binders, disintegrating agents, solubilizers, lubricants, glidants, suspending agents, coating aids, encapsulating materials.
- the diluents or fillers may be one ore more selected from lactose, and other mono- or disaccharides, cellulose derivatives like microcrystalline cellulose.
- the binders may be one or more selected from crospovidone, starch or starch derivatives and cellulose derivatives.
- the disintegrant may be one or more selected from crospovidone, croscarmellose sodium, starch, starch derivatives or cellulose polymers.
- the lubricant may be one or more selected from talc, colloidal silicon dioxide, magnesium stearate, stearic acid, stearic acid salts and glycols.
- the glidants include colloidal silicon dioxide, talc and the like.
- the pharmaceutical composition of the present invention can be formulated into oral dosage forms, in the form of tablets, capsules, pellets, dispersible granules and powder preferably in the form of tablet.
- tablette used here encompasses compressed dosage formulations of all shapes and sizes whether coated or uncoated.
- the pharmaceutical composition of the present invention may also contain one or more additional formulation ingredients known in the pharmaceutical formulation art, such excipients include but not limited to flavoring agents, anti oxidants, sweeteners, wetting agents, coloring agents, buffering agents, preservatives and mixtures thereof.
- the pharmaceutical composition of the present invention can be processed into oral dosage forms by conventional process of wet granulation, dry granulation or direct compression.
- wet granulation the drug along with cyclodextrin and various excipients selected from a diluent, a binder, disintegrant and optionally other conventional excipients selected from antioxidants, flavors, sweeteners, preservatives, buffering agents are mixed, granulated, followed by screening and drying of the damp mass.
- the dried granules are further processed into desired oral dosage form.
- Dry granulation cane be done by slugging which involves blending the drug with cyclodextrin and excipients selected from a diluent, a binder, disintegrant and optionally other conventional excipients selected from antioxidants, flavors, sweeteners, preservatives, buffering agents, followed by slugging, dry screening, compression or roller compaction and processed into desired oral dosage form such as tablets, capsules or pellets.
- slugging involves blending the drug with cyclodextrin and excipients selected from a diluent, a binder, disintegrant and optionally other conventional excipients selected from antioxidants, flavors, sweeteners, preservatives, buffering agents, followed by slugging, dry screening, compression or roller compaction and processed into desired oral dosage form such as tablets, capsules or pellets.
- the composition can be prepared by direct compression, the process comprising; forming a blend of desloratadine and cyclodextrin with excipients by mixing with a diluent, a binder, a disintegrant, and optionally one. or more conventional excipients selected from antioxidants, flavors, sweeteners, preservatives and buffering agents.
- the above blend can be further processed into the desired oral dosage forms such as tablets, capsules or pellets.
- the resulting tablets optionally may be coated with a suitable coating composition.
- the pharmaceutical composition of the present invention represents a stable formulation of desloratadine, which can be used for the relief of the nasal and non-nasal symptoms of allergic rhinitis (seasonal and perennial) and also for the symptomatic relief of pruritus, in patients with chronic idiopathic urticaria.
- Desloratadine, ⁇ -Cyclodextrin, Cornstarch, a portion of Low substituted Hydroxy Propyl Cellulose, a portion of Colloidal silicon dioxide were mixed and granulated with Butylated Hydroxy Anisole solution (Butylated Hydroxy Anisole dissolved in Isopropyl Alcohol and water). The resulting granules were dried, mixed with remaining portion of Low substituted Hydroxy Propyl Cellulose, Croscarmellose sodium and lubricated with remaining portion of Colloidal silicon dioxide, Magnesium stearate. The resulting mixture is compressed in to tablets and coated with aqueous dispersion of Opadry Blue.
- Butylated Hydroxy Anisole solution (Butylated Hydroxy Anisole dissolved in Isopropyl Alcohol) to ⁇ -cyclodextrin and dried.
- the resultant is mixed with Desloratadine, low substituted Hydroxy Propyl Cellulose, Colloidal silicon dioxide and talc.
- the resulting mixture is compressed into tablets and coated with aqueous dispersion of Opadry blue.
- desloratadine was formulated with a reactive excipient such as lactose.
- Desloratadine, ⁇ -Cyclodextrin, Cornstarch, a portion of Low substituted Hydroxy Propyl Cellulose, a portion of Colloidal silicon dioxide were mixed and granulated with Butylated Hydroxy Anisole solution (Butylated Hydroxy Anisole dissolved in Isopropyl Alcohol and water). The resulting granules were dried, mixed with remaining portion of Low substituted Hydroxy Propyl Cellulose, Croscarmellose sodium, Lactose Monohydrate and lubricated with remaining portion of Colloidal silicon dioxide, Magnesium stearate. The resulting mixture is compressed in to tablets and coated with aqueous dispersion of Opadry Blue.
- desloratadine was formulated without cyclodextrin.
- Butylated Hydroxy Anisole solution (Butylated Hydroxy Anisole dissolved in Isopropyl Alcohol) to Microcyrstalline cellulose and dried.
- the resultant is mixed with Desloratadine, low substituted Hydroxy Propyl Cellulose, Colloidal silicon dioxide and talc.
- the resulting mixture is compressed into tablets and coated with aqueous dispersion of Opadry blue.
- compositions of desloratadine can be achieved by formulating desloratadine with cyclodextrin.
- the compositions of desloratadine of the present invention are stable even in the presence of reactive excipients thereby offering freedom for selecting excipients from a wide range of available excipients.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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IN289CH2006 | 2006-02-22 | ||
PCT/IB2007/000385 WO2007096733A2 (en) | 2006-02-22 | 2007-02-19 | Desloratadine-containing formulation stabilized with cyclodextrin |
Publications (2)
Publication Number | Publication Date |
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EP1988893A2 true EP1988893A2 (de) | 2008-11-12 |
EP1988893A4 EP1988893A4 (de) | 2010-05-26 |
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EP07733895A Withdrawn EP1988893A4 (de) | 2006-02-22 | 2007-02-19 | Mittels cyclodextrin stabilisierte desloratadine enthaltende formulierung |
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EP (1) | EP1988893A4 (de) |
WO (1) | WO2007096733A2 (de) |
Families Citing this family (2)
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EP2269586B1 (de) | 2009-07-01 | 2011-09-21 | Alfred E. Tiefenbacher (GmbH & Co. KG) | Pharmazeutische Zusammensetzung mit Desloratadin |
CN102697711B (zh) * | 2012-05-24 | 2013-10-30 | 广州新济药业科技有限公司 | 地氯雷他定口服液体制剂及其制备方法 |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
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EP1110543A2 (de) * | 1999-12-20 | 2001-06-27 | Schering Corporation | Orale Dosiszusammensetzung mit verlängerter Freigabe |
WO2005065047A2 (en) * | 2003-12-23 | 2005-07-21 | Sun Pharmaceutical Industries Limited | Stable oral composition containing desloratadine |
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AU2003264859A1 (en) * | 2001-12-21 | 2003-12-19 | Sampad Bhattacharya | Intranasal pharmaceutical compositions comprising an antihistamine and a leukotriene inhibitor |
DE10332314B4 (de) * | 2003-07-16 | 2006-10-26 | Infineon Technologies Ag | Halbleiterspeicher mit kurzer effektiver Wortleitungszykluszeit sowie Verfahren zum Lesen von Daten aus einem derartigen Halbleiterspeicher |
JP2005053825A (ja) * | 2003-08-04 | 2005-03-03 | Nidek Co Ltd | 点眼点鼻用組成物 |
-
2007
- 2007-02-19 WO PCT/IB2007/000385 patent/WO2007096733A2/en active Application Filing
- 2007-02-19 EP EP07733895A patent/EP1988893A4/de not_active Withdrawn
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1110543A2 (de) * | 1999-12-20 | 2001-06-27 | Schering Corporation | Orale Dosiszusammensetzung mit verlängerter Freigabe |
WO2005065047A2 (en) * | 2003-12-23 | 2005-07-21 | Sun Pharmaceutical Industries Limited | Stable oral composition containing desloratadine |
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See also references of WO2007096733A2 * |
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EP1988893A4 (de) | 2010-05-26 |
WO2007096733A3 (en) | 2007-11-08 |
WO2007096733A2 (en) | 2007-08-30 |
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