WO2005051374A1 - Comprimes d'hydrobromure de citalopram - Google Patents
Comprimes d'hydrobromure de citalopram Download PDFInfo
- Publication number
- WO2005051374A1 WO2005051374A1 PCT/HU2004/000110 HU2004000110W WO2005051374A1 WO 2005051374 A1 WO2005051374 A1 WO 2005051374A1 HU 2004000110 W HU2004000110 W HU 2004000110W WO 2005051374 A1 WO2005051374 A1 WO 2005051374A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- weight
- citalopram
- particle size
- tablets
- range
- Prior art date
Links
- WIHMBLDNRMIGDW-UHFFFAOYSA-N 1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-3h-2-benzofuran-5-carbonitrile;hydron;bromide Chemical compound [Br-].O1CC2=CC(C#N)=CC=C2C1(CCC[NH+](C)C)C1=CC=C(F)C=C1 WIHMBLDNRMIGDW-UHFFFAOYSA-N 0.000 title claims abstract description 66
- 229960000584 citalopram hydrobromide Drugs 0.000 title claims abstract description 64
- 239000002245 particle Substances 0.000 claims abstract description 64
- 238000000034 method Methods 0.000 claims abstract description 57
- 239000004480 active ingredient Substances 0.000 claims abstract description 53
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims abstract description 35
- 229940016286 microcrystalline cellulose Drugs 0.000 claims abstract description 30
- 239000008108 microcrystalline cellulose Substances 0.000 claims abstract description 30
- 238000002360 preparation method Methods 0.000 claims abstract description 24
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims abstract description 23
- 239000000546 pharmaceutical excipient Substances 0.000 claims abstract description 23
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 40
- 238000007907 direct compression Methods 0.000 claims description 30
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 30
- WSEQXVZVJXJVFP-HXUWFJFHSA-N (R)-citalopram Chemical compound C1([C@@]2(C3=CC=C(C=C3CO2)C#N)CCCN(C)C)=CC=C(F)C=C1 WSEQXVZVJXJVFP-HXUWFJFHSA-N 0.000 claims description 27
- 229960001653 citalopram Drugs 0.000 claims description 27
- 235000000346 sugar Nutrition 0.000 claims description 19
- 239000000377 silicon dioxide Substances 0.000 claims description 17
- 235000012239 silicon dioxide Nutrition 0.000 claims description 17
- 235000019359 magnesium stearate Nutrition 0.000 claims description 15
- 239000000126 substance Substances 0.000 claims description 15
- 239000011248 coating agent Substances 0.000 claims description 12
- 238000000576 coating method Methods 0.000 claims description 12
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 8
- 239000007787 solid Substances 0.000 claims description 7
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 6
- 239000004615 ingredient Substances 0.000 claims description 6
- 239000008101 lactose Substances 0.000 claims description 6
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 2
- 235000010980 cellulose Nutrition 0.000 claims description 2
- 229920002678 cellulose Polymers 0.000 claims description 2
- 239000001913 cellulose Substances 0.000 claims description 2
- 229910052749 magnesium Inorganic materials 0.000 claims description 2
- 239000011777 magnesium Substances 0.000 claims description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims 2
- 101150046432 Tril gene Proteins 0.000 claims 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims 1
- 239000003826 tablet Substances 0.000 abstract description 111
- 239000007941 film coated tablet Substances 0.000 abstract description 4
- 239000000203 mixture Substances 0.000 description 20
- 229960001866 silicon dioxide Drugs 0.000 description 11
- 229940057948 magnesium stearate Drugs 0.000 description 10
- 239000000725 suspension Substances 0.000 description 10
- 235000019888 Vivapur Nutrition 0.000 description 9
- 238000005507 spraying Methods 0.000 description 9
- 238000004090 dissolution Methods 0.000 description 7
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 6
- 239000008213 purified water Substances 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 239000008187 granular material Substances 0.000 description 5
- 229910001220 stainless steel Inorganic materials 0.000 description 5
- 239000010935 stainless steel Substances 0.000 description 5
- 239000000084 colloidal system Substances 0.000 description 4
- 238000007908 dry granulation Methods 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 229960001375 lactose Drugs 0.000 description 4
- 229960003511 macrogol Drugs 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 238000005550 wet granulation Methods 0.000 description 4
- 229910002016 Aerosil® 200 Inorganic materials 0.000 description 3
- 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 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- 229930195725 Mannitol Natural products 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 230000002349 favourable effect Effects 0.000 description 3
- 239000000945 filler Substances 0.000 description 3
- 238000005469 granulation Methods 0.000 description 3
- 230000003179 granulation Effects 0.000 description 3
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 3
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 3
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 3
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 3
- 239000000594 mannitol Substances 0.000 description 3
- 235000010355 mannitol Nutrition 0.000 description 3
- 238000005204 segregation Methods 0.000 description 3
- 239000004408 titanium dioxide Substances 0.000 description 3
- 239000013543 active substance Substances 0.000 description 2
- 229940066010 citalopram 40 mg Drugs 0.000 description 2
- 229940075614 colloidal silicon dioxide Drugs 0.000 description 2
- 238000007906 compression Methods 0.000 description 2
- 230000006835 compression Effects 0.000 description 2
- 239000007888 film coating Substances 0.000 description 2
- 238000009501 film coating Methods 0.000 description 2
- -1 glidants Substances 0.000 description 2
- 238000003475 lamination Methods 0.000 description 2
- 238000005461 lubrication Methods 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 238000009725 powder blending Methods 0.000 description 2
- 238000012802 pre-warming Methods 0.000 description 2
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-UHFFFAOYSA-N 2-(hydroxymethyl)-6-[4,5,6-trihydroxy-2-(hydroxymethyl)oxan-3-yl]oxyoxane-3,4,5-triol Chemical compound OCC1OC(OC2C(O)C(O)C(O)OC2CO)C(O)C(O)C1O GUBGYTABKSRVRQ-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 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 1
- 229920003084 Avicel® PH-102 Polymers 0.000 description 1
- 241000905957 Channa melasoma Species 0.000 description 1
- GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 239000003831 antifriction material Substances 0.000 description 1
- GUBGYTABKSRVRQ-QUYVBRFLSA-N beta-maltose Chemical compound OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O GUBGYTABKSRVRQ-QUYVBRFLSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 235000013681 dietary sucrose Nutrition 0.000 description 1
- 230000003292 diminished effect Effects 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000010419 fine particle Substances 0.000 description 1
- 230000009969 flowable effect Effects 0.000 description 1
- 238000005243 fluidization Methods 0.000 description 1
- 239000003979 granulating agent Substances 0.000 description 1
- 238000001033 granulometry Methods 0.000 description 1
- 229960001021 lactose monohydrate Drugs 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 229960002160 maltose Drugs 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- 230000000485 pigmenting effect Effects 0.000 description 1
- 239000004014 plasticizer Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000009490 roller compaction Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 229940114926 stearate Drugs 0.000 description 1
- 229960004793 sucrose Drugs 0.000 description 1
- LJBBMCNHIUJBDU-UHFFFAOYSA-N talopram Chemical compound O1C(C)(C)C2=CC=CC=C2C1(CCCNC)C1=CC=CC=C1 LJBBMCNHIUJBDU-UHFFFAOYSA-N 0.000 description 1
- 229950007352 talopram Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 238000009827 uniform distribution Methods 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
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
-
- 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
- A61K31/343—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 condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
-
- 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
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
Definitions
- the invention relates to tablets containing as active ingredient citalopram hydrobromide and a process for the preparation thereof.
- Citalopram namely 1 - [ 3- (dimethylamino) - propyl ] -1 - (4 -fluorophenyl ) - 1 , 3 -dihydro -5 - isobenzofurancarboni trile hydrobromide, is a well known antidepressant drug that has the following structure:
- the substance is a white or almost white fine crystalline powder usually having a median particle size of less than 20 ⁇ m .
- citalopram hydrobromide When citalopram hydrobromide is used as a pharmaceutical, it is formulated into coated tablets, that is film-coated tablets.
- the active ingredient tablets contain excipients (fillers, binders, disin- tegr-ants , glidants, anti-friction agents), too. In order to keep the uniformity o ' f mass and content of the tablets at a low value, only mixtures of the active ingredient and excipients having a good flowability and not liable to segregation can be tabletted on up-to-date tabletting machines.
- the preparatory operations can be based on the following three principles : •powder blending technique •dry granulation technique •wet granulation technique
- the active ingredient is homogenized with readily tablettable excipients, and then comp ' ressed (compacted, briquetted or pre- tabletted) , the compressed substance is ground, sieved, mixed with further excipients and tabletted.
- the active ingredient or optionally a mixture of the active ingredient and the tabletting excipients are wetted with a solution of the so-called granulating agent or only with the solvent. In this way larger granules are formed, which are then dried, sieved, mixed with further excipi ' e-rits and ' compressed to tablets.
- citalopram hydrobromide prepared by the conventional processes is a crystalline powder of a fine particle size having a median particle size of less than 20 ⁇ m measured by laser granulometry .
- two p.roblems may crop up. when tabletting by direct compression citalopram hydrobromide having such a small particle size.
- the first is that as a consequence of the small particle size of the active ingredient the flowability of the homogenizate containing citalopram hydrobromide in admixture with the tabletting excipients is poor, and that is why the mass uniformity does not meet the pharmacopoeal require- ments .
- the other is that if excipients having a somewhat bigger particle size are applied in order to improve an appropriate flowability, the powder mixture may segregate during compression to tablets, which results in a high fluctuation of the active ingredient content.
- a solid pharmaceutical dosage form containing citalopram hydrobromide can be prepared by direct compression if the median particle size of the citalopram hydrobromide is at least 40 ⁇ m, preferably in the range of 40-200 ⁇ m, even more preferred 45-150 ⁇ m and the most preferred 50-100 ⁇ m .
- citalopram hydrobromide alone or in admixture with one or more ex ' ci- pient(s) is converted by roller compaction into granules having a median particle size of at least 40 ⁇ m, preferably in the range of 4-0-250 ⁇ m, more preferred 45-200 ⁇ m and the most preferred 50-180 ⁇ m .
- citalopram hydrobromide having a;, median article .
- citalopram hydrobromide granulate is then homogenized with further excipients and compressed to tablets.
- citalopram hydrobromide having a median particle size of less -than 40 ⁇ m cannot -fae compressed - by direct compression to tablets meeting the - pharmacopoeial requirements .
- the aim of the present invention was to elaborate a direct compression method enabling the preparation of tablets from citalopram hydrobromide particles with a median particle size of less than 40 ⁇ m, wherein the tablets meet the requirements raised by the pharmacopoeias.
- the invention is based on the recognition that by using appropriately chosen excipients direct compression method is also suitable for the preparation of tablets in a quality meeting even the strictest pharmacopoeial requirements from citalopram hydrobromide having a median particle size of less than .40 ⁇ m or even less than 20 ⁇ m . It has also been recognised that due to the stability and other favourable parameters of the tablets ⁇ provided according to the invention they can be used as tablet cores, that is they are suitable to be coated with substances and- according . to methods conventionally' ⁇ applied in the pharmacological industry. The thus-obtained coated tablets can be- used to advantage in the therapy.
- tablets prepared by direct compression containing as active ingredient citalopram hydrobromide namely 1- [3- (dimethylamino) - propyl ] -1 - (4 -fluorophenyl ) - 1 , 3 -dihydro -5 - isobenzofurancarboni trile hydrobromide , which comprise citalopram hydrobromide having a median particle size in the range of 5-40 ⁇ m in admixture with micro- crystalline cellulose having a median particle size in the range of 90-250 ⁇ m and other excipients conventionally applied for the preparation of tablets.
- citalopram hydrobromide namely 1- [3- (dimethylamino) - propyl ] -1 - (4 -fluorophenyl ) - 1 , 3 -dihydro -5 - isobenzofurancarboni trile hydrobromide
- citalopram hydrobromide having a median particle size in the range of 5-40
- tablets containing as active ingredient citalopram hydrobromide comprising 5-50% by weight, preferably 10-30% by weight of citalopram hydrobromide having a median particle size in the range of 5-40 ⁇ m, optionally in the range of 5-20 ⁇ m, 5-85% by weight, preferably 50-80% by weight, more preferred 70-80% by weight of micro- crystalline cellulose having a median particle size in the range of 90-250 ⁇ m, preferably 150-250 ⁇ m, as excipient 5-85% by weight, preferably 5-20% by weight, more preferred 5-10% by weight of sugar 74
- suitable for direct compression 0.3-3.0% by weight, preferably 0.5-2.5% by weight, more preferred 1.0-2.0% by weight of magnesium stearate . and optionally 0.1-2.0% by weight, preferably 0.5-1.5% by weight, more preferred 0.5-1.0% by weight of
- tablets containing as active ingredient citalopram hydrobromide which comprise 5-50% by weight, preferably 10-30% by weight ' of citalopram hydrobromide having a' median particle size " in the " range of ' 5-40 ⁇ i ' v optionally- 5-20 ⁇ m ' , 5-85% -by' weight, preferably ⁇ 5.Q-8 ; 0% by weight, -more preferred 70-80% by weight of micro- crystalline cellulose having a median particle size in the range of 90-250 ⁇ m, preferably 150-250 ⁇ m , as excipient 5-85% by weight, preferably 5-20% by weight, more preferred 5-10% by weight of sugar suitable for direct- compression, 0.3-3.0% by weight, preferably 0.5-2.5% by ' weight, more preferred 1.0-2.0% by weight of magnesium stearate and optionally 0.1-2.0% by weight, preferably 0.5-1.5% by weight, more preferred 0.5-1.0% by weight of colloidal or micronized
- a process for -the -preparation of tablets containing as active ingredient citalopram hydrobromide which comprises admixing in solid form- citalopram hydrobromide having a median particle size in the -range of 5- 40 ⁇ m, microcrystalline cellulose .having a median parrti-'cle size, in- the .range of .90-' 250 ⁇ m and one or more other excipient(s) suitable for the preparation of tablets', and compressing the thus-obtained homo- genizate to tablets containing citalopram hydrobromide in an amount corresponding to 10-40 mg of citalopram base.
- a process for the preparation of tablets containing citalopram hydrobromide which comprises admixing in solid form 5-50% by weight, preferably 10-30% by weight of citalopram hydrobromide having a median particle size in the range between 5-40 ⁇ m, optionally 5-20 ⁇ m, 5-85% by weight, preferably ' 50-80-% by weight, more preferred 70-80% .' by weight of micro- crystalline cellulose' having a median particle size in the range of 90-250 ⁇ m, 5-85% by weight, preferably 5-20% by weight, more preferred 5-10% by weight of sugar suitable for direct compression, 0.3-3.0% by weight, preferably 0.5-2.5% by weight, more preferred 1.0-2.0% by weight of magnesium stearate and optionally 0.1-2.0% by weight, preferably 0.5- 1.5% by weight, more preferred 0.5-1.0% by weight of colloidal or micronized silicon dioxide, compressing the thus- obtained homogenizate to tablets containing citalopram hydrobromide in an amount
- the term faceddirect compression tabletting methods means that the active ingredient and the excipients are homogenized at room temperature without adding a liquid to the mixture and without changing the particle size of the components, and compressing the homoge-nizate to tablets.
- the term "median particle size” relates to the particle size that divides the frequency distribution in half. 50% of the particles have a larger particle size and the other 50% have a smaller one. This value is referred to as dso .
- microcrystalline cellulose- used in the citalopram hydrobromide tablets according to the invention microcrystalline celluloses applied for direct compressing having a median particle size of more than 90 ⁇ m can be applied.
- These micro- crystalline celluloses are distinguished by numbers 102, 200, 90 or 12 indicated together with the trade name.
- Such substances are e.g. Avicel PH 102, Avicel 102 SCG, Avicel 200, Vivapur 102, Vivapur 200, Vivapur 12, Microcel 102, Emcocel 90 M, Emcocel 90 HD , Emcocel LP 200 etc.
- the microcrystalline cellulose designated with No. 200 having the biggest particle size possesses the most favourable flowability.
- the median particle size of the micro- crystalline celluloses designated wi th 102 and 90 is in the range between 90-110 ⁇ m, that of the microcrystalline cellulose designated with 12 is in the range between 140-180 ⁇ m, while that of the micro- crystalline celluloses designated with 200 is about 180 ⁇ m .
- microcrystalline cellulose so-called silicified micro- crystalline celluloses having a median particle size of more than 90 ⁇ m can also be applied, which contain 2-3% by weight of silicon dioxide. In such a case it is not necessary to add silicon dioxide to the homogenizate .
- Such products are e.g. Prosolv SM CC 90 or Prosolv HD 90 (trade names ) .
- any sugar-based product prepared for the purpose of direct compression can be used.
- Such products involve e.g. spray-dried or specially crystallized lactose, maltose or saccharose.
- the median particle size of these sugar-based products prepared for the purpose of direct compression is usually .in the ran.ge ,-between- • 100 ⁇ m and 200 ⁇ m. . -- -'
- magnesium stearate any magnesium stearate product meeting the pharma- copoeial requirements can be used.
- the median particle size of these products is usually less than 10 ⁇ m .
- colloidal or micronized silicon dioxide any . colloidal or micronized silicon- dioxide product meeting .the.” pharmacbpoeial requirements can be applied.
- the median particle size of the colloidal micronized silicon dioxide products is a few nm, while that of the micronized silicon dioxide products is usually in the range between 4-20 ⁇ m .
- Silicon dioxide products may also be used in mixtures formed with microcrystalline cellulose as so-called silicified microcrystalline cellulose.
- the active ingredient content of the citalopram hydrobromide tablets according to the invention is in the range between 10-30% by weight. Considering that the smallest single dose of the citalopram hydrobromide is 10 mg of citalopram base corresponding ⁇ to ⁇ 12.495-.
- the ratio of the microcrystalline cellulose and the sugar suitable for direct compression may be varied in a wide range between 5-85% by weight.
- the advantageous amount of the microcrystalline cellulose is in the range between 50-80% by weight, while the amount of the sugar suitable for direct compression is in the range between 5-20% by weight.
- a particularly advantageous amount of the micro- crystalline cellulose is in the range between 70-80% by weight, while that of the sugar suitable for direct compression is in , .the ,. range, between 5-10% by weight;
- the .amount of- -the magnesium- stearate and colloidal or -micronized silicon dioxide corresponds to the amount conventionally applied or the manufacture of tablets .
- magnesium stearate this amount is in the range between 0.3-3.0% by weight, preferably 0.5-2.5% by weight, more preferred 1.0-2.0% by weight, while in case of colloidal or micronized silicon dioxide it is in the range between 0..1-2.0% by weight, preferably 0.5-1.5% by weight, even more preferred 0.5-1.0% by weight.
- the tablets containing citalopram hydrobromide according to the invention have a suitable mechanical strength and are particularly suitable for film coating operations constituting strong mechanical effects .
- Film coating may be carried out according to methods known from the literature.
- film-forming substance e.g. a hydroxypropyl -methyl cellulose can be used together with polyethylene glycol as plasticizer and optionally titanium dioxide as pigmenting substance.
- Ready- made coating systems such as Opadry (trade name) may also be applied. These substances contain as film-forming polymer hydroxypropyl -methyl cellulose (Opadry I and Opadry II) or polyvinylal cohol (Opardry II HP) .
- composition and process according to the invention is illustrated by the following Example without limiting the scope of protection to said Examples .
- fillers The following substances. suitable for direct compression are used as fillers:
- microcrystalline cellulose Emcocel 90 M, Avicel 102, Vivapur 200
- - silicified microcrystalline cellulose Prosolv SMC 90, Prosolv HD 90
- lubricant magnesium stearate As lubricant magnesium stearate, as glidant colloidal silicon dioxide (Aerosil 200) is applied.
- the ingredients used in an amount given in the following Table are homogenized in .a Turbula mixer.
- the flowability of the homogenizates is determined according to the method provided in European Pharmacopeia, Ed. 4, 2002, p. 208-209., Council of Europe, France.
- composition of the ci talopram homogenizates and the flowability of tlSe homogenizates are shown in the following Table :
- Vivapur 200 that is the microcrystalline cellulose having the largest particle size .
- the homogenizates are compressed to tablets of mass of 180 mg on a tabletting machine of Fette EXI type using concave dies of 8 mm in diameter. In the course of the tabletting procedure adhesion could 4
- the homogenizates are compressed to tablets off mass of 180 mg on a tabletting machine of Fette ' EXI type using lentiform dies of 8 mm in diameter. In the course of the tabletting procedure adhesion could not be observed either on the punch or on the surface of the tablets. When breaking the tablets into two parts the inner surface is homogeneous, devoid of lamination .
- the average mass and mass uniformity of the tablets prepared according to the invention were also determined on 20 tablets .
- Breaking 83 73 67 strength (N) (77-90) (68-75) ; (53-80)
- the mass uniformity of the tablets meets the pharmacopoeial requirements (+/- 7,5% in case of an average mass of 180 mg) .
- the ingredients enumerated in the following Table are homogenized in a Turbula mixer.
- the homogenizates are compressed to tablets of 180 mg on' a tab- letting machine of Fette EXI type using concave dies of 8 mm in diameter.
- lubrication problems occur in case of the homogenizates containing spray-dried mannitol (Pearlitol SD 200) , , friction" can be experienced on the inner surface of the dies and the breaking strength of the tablets is unsuitable (a low breaking strength with high deviation) .
- the lubrication problems can be diminished by gradually decreasing the amount of Perlitol SD 200 (mannitol) and gradually increasing the amount of microcrystalline cellulose Emcocel 90 M, but the tablets become more and more laminated.
- Perlitol SD 200 mannitol
- microcrystalline cellulose Emcocel 90 M the amount of microcrystalline cellulose
- the lubrication problems can be diminished by gradually decreasing the amount of Perlitol SD 200 (mannitol) and gradually increasing the amount of microcrystalline cellulose Emcocel 90 M, but the tablets become more and more laminated.
- compositions containing only micro- crystalline cellulose Vivapur 200
- lubri- • cation problems- canno-t ⁇ be experienced, but the structure " of ' - the- tablet is laminated.
- Emcocel 90 M (mg) 132.55 7.5 —
- Aerosil 200 (mg) 0.625 0.625 1.26 '
- Tabletting of the homogenizates is carried out on a Manesty Betapress 16 station rotary press at a speed of 750 pieces of tablet/minute. 100,000 pieces of biconvex tablets 10 mm in diameter weighting 360 mg and containing 40 mg of citalopram base each are compressed. By dividing the manufacture time into identical intervals 8 samples per lot were taken and the uniformity of mass and content of the tablets are determined.
- the ' mass uniformity data are calculated on the basis of the individual masses of 20 tablets per lot.
- the data relating to the uniformity of content are calculated on the basis of the individual masses of 10 tablets per lot
- a coating suspension for 50,000 pieces of tablets containing 40 mg of active ingredient produced according to Example 4 are prepared as follows:
- the coating suspension When pre-warming has been finished the coating suspension is sprayed.
- the parameters of ⁇ the- introduction and drying are set so that the temperature of the outgoing- air remains in the ran.ge between 38- 45°C.. - ' . " . -
- the homogenizate is divided into two parts. One part is compressed to 100,000 pieces of lentiform tablets 8 mm in diameter weighting 180 mg and containing 20 mg of citalopram base, the other part is used for the preparation of 200,000 pieces of lentiform tablets 6 mm in diameter weighting 90 mg and containing 10 mg of citalopram base. Tabletting is carried out on a Manesty Betapress 16 station rotary press at a speed of 750 pieces of tablet/minute. By dividing the manufacture time into identical intervals 8 samples per lot were taken from tablets containing 20 mg of citalopram base and 16 samples per lot from tablets containing 10 mg of citalopram base. The uniformity of mass and content of the tablets are determined. The results are summarized in the following Table.
- Mass uniformity is calculated by measuring the individual masses of 20 tablets per lot for each sample.
- Uniformity of content is calculated by measuring the individual masses of 10 tablets per lot for each sample.
- Coating suspensions for 100,000 pieces of tablets containing 20 g of active ingredient and for 200,000 pieces of tablets containing 10 mg of active ingredient are prepared as follows :
- the coating of the tablets is carried out in a coating apparatus of Driacoater 500/600 Vario type.
- the tablets are filled into the apparatus and pre-warmed until the temperature of the outgoing air has achieved 42°C ( ⁇ 10 minutes) .
- the coating suspension is sprayed.
- the parameters of the introduction and drying are set so that the temperature of the outgoing air remains in the range between 38-45°C.
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- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Biomedical Technology (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Psychiatry (AREA)
- Pain & Pain Management (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
PL379864A PL379864A1 (pl) | 2003-11-25 | 2004-11-24 | Tabletki bromowodorku citalopramu |
EP04798748A EP1694321A1 (fr) | 2003-11-25 | 2004-11-24 | Comprimes d'hydrobromure de citalopram |
EA200600932A EA010290B1 (ru) | 2003-11-25 | 2004-11-24 | Таблетки циталопрама гидробромида |
SK5053-2006A SK50532006A3 (sk) | 2003-11-25 | 2004-11-24 | Tablety hydrobromidu citalopramu |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
HU0303790A HU227491B1 (en) | 2003-11-25 | 2003-11-25 | Tablet containing citalopram hydrogen bromide |
HUP0303790 | 2003-11-25 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2005051374A1 true WO2005051374A1 (fr) | 2005-06-09 |
Family
ID=89981808
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/HU2004/000110 WO2005051374A1 (fr) | 2003-11-25 | 2004-11-24 | Comprimes d'hydrobromure de citalopram |
Country Status (9)
Country | Link |
---|---|
EP (1) | EP1694321A1 (fr) |
BG (1) | BG109587A (fr) |
CZ (1) | CZ2006376A3 (fr) |
EA (1) | EA010290B1 (fr) |
HU (1) | HU227491B1 (fr) |
PL (1) | PL379864A1 (fr) |
SK (1) | SK50532006A3 (fr) |
UA (1) | UA83094C2 (fr) |
WO (1) | WO2005051374A1 (fr) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CZ301286B6 (cs) * | 2005-06-22 | 2009-12-30 | H. Lundbeck A/S | Tableta, rozpadající se v ústech a zpusob její výroby |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2001080619A2 (fr) * | 2000-08-10 | 2001-11-01 | H. Lundbeck A/S | Composition pharmaceutique contenant du citalopram |
WO2002053133A1 (fr) * | 2001-01-05 | 2002-07-11 | H. Lundbeck A/S | Composition pharmaceutique contenant du citalopram |
US6607751B1 (en) * | 1997-10-10 | 2003-08-19 | Intellipharamaceutics Corp. | Controlled release delivery device for pharmaceutical agents incorporating microbial polysaccharide gum |
-
2003
- 2003-11-25 HU HU0303790A patent/HU227491B1/hu unknown
-
2004
- 2004-11-24 SK SK5053-2006A patent/SK50532006A3/sk not_active Application Discontinuation
- 2004-11-24 EA EA200600932A patent/EA010290B1/ru not_active IP Right Cessation
- 2004-11-24 PL PL379864A patent/PL379864A1/pl not_active Application Discontinuation
- 2004-11-24 CZ CZ20060376A patent/CZ2006376A3/cs unknown
- 2004-11-24 WO PCT/HU2004/000110 patent/WO2005051374A1/fr active Application Filing
- 2004-11-24 UA UAA200607053A patent/UA83094C2/ru unknown
- 2004-11-24 EP EP04798748A patent/EP1694321A1/fr not_active Withdrawn
-
2006
- 2006-06-23 BG BG109587A patent/BG109587A/bg unknown
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6607751B1 (en) * | 1997-10-10 | 2003-08-19 | Intellipharamaceutics Corp. | Controlled release delivery device for pharmaceutical agents incorporating microbial polysaccharide gum |
WO2001080619A2 (fr) * | 2000-08-10 | 2001-11-01 | H. Lundbeck A/S | Composition pharmaceutique contenant du citalopram |
WO2002053133A1 (fr) * | 2001-01-05 | 2002-07-11 | H. Lundbeck A/S | Composition pharmaceutique contenant du citalopram |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CZ301286B6 (cs) * | 2005-06-22 | 2009-12-30 | H. Lundbeck A/S | Tableta, rozpadající se v ústech a zpusob její výroby |
Also Published As
Publication number | Publication date |
---|---|
HUP0303790A2 (hu) | 2005-08-29 |
SK50532006A3 (sk) | 2006-09-07 |
HUP0303790A3 (en) | 2005-09-28 |
EA010290B1 (ru) | 2008-08-29 |
EP1694321A1 (fr) | 2006-08-30 |
HU0303790D0 (en) | 2004-03-01 |
CZ2006376A3 (cs) | 2006-10-11 |
UA83094C2 (en) | 2008-06-10 |
PL379864A1 (pl) | 2006-11-27 |
BG109587A (bg) | 2006-12-29 |
EA200600932A1 (ru) | 2006-10-27 |
HU227491B1 (en) | 2011-07-28 |
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