WO2008118031A1 - Pharmaceutical composition comprising candesartan cilexetil and method for manufacturing thereof - Google Patents
Pharmaceutical composition comprising candesartan cilexetil and method for manufacturing thereof Download PDFInfo
- Publication number
- WO2008118031A1 WO2008118031A1 PCT/PL2008/000026 PL2008000026W WO2008118031A1 WO 2008118031 A1 WO2008118031 A1 WO 2008118031A1 PL 2008000026 W PL2008000026 W PL 2008000026W WO 2008118031 A1 WO2008118031 A1 WO 2008118031A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- pharmaceutical composition
- candesartan cilexetil
- polyethylene glycol
- polyvinyl alcohol
- graft copolymer
- Prior art date
Links
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 39
- GHOSNRCGJFBJIB-UHFFFAOYSA-N Candesartan cilexetil Chemical compound C=12N(CC=3C=CC(=CC=3)C=3C(=CC=CC=3)C3=NNN=N3)C(OCC)=NC2=CC=CC=1C(=O)OC(C)OC(=O)OC1CCCCC1 GHOSNRCGJFBJIB-UHFFFAOYSA-N 0.000 title claims abstract description 35
- 229960004349 candesartan cilexetil Drugs 0.000 title claims abstract description 34
- 238000000034 method Methods 0.000 title claims abstract description 32
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 19
- 239000008186 active pharmaceutical agent Substances 0.000 claims abstract description 23
- 239000002202 Polyethylene glycol Substances 0.000 claims abstract description 19
- 239000004372 Polyvinyl alcohol Substances 0.000 claims abstract description 19
- 229920001223 polyethylene glycol Polymers 0.000 claims abstract description 19
- 229920002451 polyvinyl alcohol Polymers 0.000 claims abstract description 19
- 229920000578 graft copolymer Polymers 0.000 claims abstract description 18
- 239000008187 granular material Substances 0.000 claims abstract description 12
- 239000011230 binding agent Substances 0.000 claims abstract description 11
- 239000000203 mixture Substances 0.000 claims abstract description 11
- 239000007884 disintegrant Substances 0.000 claims abstract description 9
- 239000002934 diuretic Substances 0.000 claims abstract description 9
- 239000000945 filler Substances 0.000 claims abstract description 9
- 239000000314 lubricant Substances 0.000 claims abstract description 9
- 229940030606 diuretics Drugs 0.000 claims abstract description 7
- 239000003979 granulating agent Substances 0.000 claims abstract description 5
- 239000003826 tablet Substances 0.000 claims description 28
- JZUFKLXOESDKRF-UHFFFAOYSA-N Chlorothiazide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC2=C1NCNS2(=O)=O JZUFKLXOESDKRF-UHFFFAOYSA-N 0.000 claims description 7
- 229960002003 hydrochlorothiazide Drugs 0.000 claims description 7
- 238000002844 melting Methods 0.000 claims description 7
- 230000008018 melting Effects 0.000 claims description 7
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- 239000000843 powder Substances 0.000 claims description 3
- 239000002775 capsule Substances 0.000 claims description 2
- 239000007787 solid Substances 0.000 claims description 2
- 239000003381 stabilizer Substances 0.000 abstract description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 24
- UQSXHKLRYXJYBZ-UHFFFAOYSA-N iron oxide Inorganic materials [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 description 23
- 235000013980 iron oxide Nutrition 0.000 description 13
- 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 12
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 12
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 12
- 239000011575 calcium Substances 0.000 description 12
- 229910052791 calcium Inorganic materials 0.000 description 12
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 12
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 12
- 229960001021 lactose monohydrate Drugs 0.000 description 12
- 235000019359 magnesium stearate Nutrition 0.000 description 12
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 10
- 229920002261 Corn starch Polymers 0.000 description 10
- VJHCJDRQFCCTHL-UHFFFAOYSA-N acetic acid 2,3,4,5,6-pentahydroxyhexanal Chemical compound CC(O)=O.OCC(O)C(O)C(O)C(O)C=O VJHCJDRQFCCTHL-UHFFFAOYSA-N 0.000 description 10
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 10
- 229950008138 carmellose Drugs 0.000 description 10
- 239000008120 corn starch Substances 0.000 description 10
- 239000000243 solution Substances 0.000 description 6
- 239000000126 substance 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
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 4
- 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 4
- 239000007864 aqueous solution Substances 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 238000005469 granulation Methods 0.000 description 3
- 230000003179 granulation Effects 0.000 description 3
- VBMVTYDPPZVILR-UHFFFAOYSA-N iron(2+);oxygen(2-) Chemical class [O-2].[Fe+2] VBMVTYDPPZVILR-UHFFFAOYSA-N 0.000 description 3
- 229920002785 Croscarmellose sodium Polymers 0.000 description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 2
- 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 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 2
- 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 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- MHQJUHSHQGQVTM-HNENSFHCSA-N Octadecyl fumarate Chemical compound CCCCCCCCCCCCCCCCCCOC(=O)\C=C/C(O)=O MHQJUHSHQGQVTM-HNENSFHCSA-N 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 235000021355 Stearic acid Nutrition 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 229960005069 calcium Drugs 0.000 description 2
- 235000001465 calcium Nutrition 0.000 description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 description 2
- 235000010216 calcium carbonate Nutrition 0.000 description 2
- 239000001506 calcium phosphate Substances 0.000 description 2
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 2
- 239000008116 calcium stearate Substances 0.000 description 2
- 235000013539 calcium stearate Nutrition 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 235000010980 cellulose Nutrition 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 229920001577 copolymer Polymers 0.000 description 2
- 229940099112 cornstarch Drugs 0.000 description 2
- 229960001681 croscarmellose sodium Drugs 0.000 description 2
- 229960000913 crospovidone Drugs 0.000 description 2
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 230000001882 diuretic effect Effects 0.000 description 2
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 2
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 2
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 2
- 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 2
- 229940071676 hydroxypropylcellulose Drugs 0.000 description 2
- 229960001375 lactose Drugs 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 2
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 2
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 229940069328 povidone Drugs 0.000 description 2
- 229940079832 sodium starch glycolate Drugs 0.000 description 2
- 239000008109 sodium starch glycolate Substances 0.000 description 2
- 229920003109 sodium starch glycolate Polymers 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- 235000010356 sorbitol Nutrition 0.000 description 2
- 238000013112 stability test Methods 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 229940032147 starch Drugs 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 239000008117 stearic acid Substances 0.000 description 2
- 229940071138 stearyl fumarate Drugs 0.000 description 2
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 2
- 229940078499 tricalcium phosphate Drugs 0.000 description 2
- 229910000391 tricalcium phosphate Inorganic materials 0.000 description 2
- 235000019731 tricalcium phosphate Nutrition 0.000 description 2
- 229920003169 water-soluble polymer Polymers 0.000 description 2
- -1 1 -(cyclohexyloxycarbonyloxy)ethyl Chemical group 0.000 description 1
- 239000002053 C09CA06 - Candesartan Substances 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 125000003158 alcohol group Chemical group 0.000 description 1
- 239000002333 angiotensin II receptor antagonist Substances 0.000 description 1
- 208000037849 arterial hypertension Diseases 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 229960000932 candesartan Drugs 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 239000008119 colloidal silica Substances 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 238000009477 fluid bed granulation Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 125000003827 glycol group Chemical group 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 239000007898 rapid-disintegration tablet Substances 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 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
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
Definitions
- composition comprising candesartan cilexetil and method for manufacturing thereof
- the subject of the invention includes a pharmaceutical composition
- a pharmaceutical composition comprising candesartan cilexetil as the active pharmaceutical ingredient and graft copolymer of polyvinyl alcohol with polyethylene glycol as a stabilising agent as well as the method for manufacturing thereof.
- the method for manufacturing of the composition consists in the formation of candesartan cilexetil dispersion with one or more water soluble polymers in the solution of a binder, granulation, drying and granulate tableting.
- a pharmaceutical composition was disclosed comprising candesartan cilexetil with fatty substances acting as stabilising agents.
- the fatty substances listed in the publication include phospholipids, fatty acids and their esters.
- the method for manufacturing of the composition consists in the formation of candesartan cilexetil dispersion with one or more fatty substances in the solution of a binder, granulation, drying and granulate tableting.
- the objective of the present invention is to develop a new, stable pharmaceutical composition comprising candesartan cilexetil as the active pharmaceutical ingredient whose manufacturing process is simple and may be conducted using standard formulation methods.
- a graft copolymer of polyvinyl alcohol with polyethylene glycol originally meant as a" coating agent for rapid disintegration tablets, ensures stability of pharmaceutical compositions comprising candesartan cilexetil.
- the solution of the graft copolymer of polyvinyl alcohol with polyethylene glycol used as a granulating agent during the manufacturing process compensates for the negative properties of the candesartan cilexetil active pharmaceutical ingredient which consist in its electrostatic behaviour and fluffiness which result in the uncontrolled loss of the active pharmaceutical ingredient during the manufacturing process.
- the graft copolymer of polyvinyl alcohol with polyethylene glycol present in the pharmaceutical composition according to the present invention has a melting point of between 150° and 300°C, preferably between 180° and 250°C, more preferably between 200° and 220°C.
- the pharmaceutical composition according to the present invention has a content of candesartan cilexetil in the weight ratio to the graft copolymer of polyvinyl alcohol with polyethylene glycol of 4:1 to 1 :3, preferably 1 :2 to 2:1.
- the pharmaceutical composition according to the present invention comprisies pharmaceutically acceptable excipients selected from a group comprising fillers, binders, disintegrants, lubricants and optionally colourants. It may additionally comprise another active pharmaceutical ingredient acting as a diuretic.
- the graft copolymer of polyvinyl alcohol with polyethylene glycol present in the pharmaceutical composition according to the present invention has hydrophilic properties.
- it is the known copolymer under the trade name of Kollicoat® IR comprising 75% polyvinyl alcohol residues and 25% polyethylene glycol residues.
- the molecular weight of the copolymer is approximately 45,000 Daltons with a melting point of 209°C.
- Kollicoat® IR is hydrophilic powder readily soluble in water, white to light yellow. To improve its flow, approximately 0.3% of colloidal silica is added.
- the fillers in the pharmaceutical composition according to the present invention are selected from a group comprising lactose, starch, cellulose, mannitol, sorbitol, tricalcium phosphate, calcium carbonate or other pharmaceutically acceptable fillers or their combination.
- the binders in the pharmaceutical composition according to the present invention are selected from a group comprising hydroxypropylcellulose, povidone, hydroxypropylmethylcellulose or other pharmaceutically acceptable binders or their combination.
- the disintegrants in the pharmaceutical composition according to the present invention are selected from a group comprising carmellose sodium or calcium, croscarmellose sodium, crospovidone, sodium starch glycolate or other pharmaceutically acceptable disintegrants or their combination.
- the lubricants in the pharmaceutical composition according to the present invention are selected from a group comprising magnesium stearate, calcium stearate, stearyl fumarate, stearic acid or other pharmaceutically acceptable lubricants or their combination.
- the colourants in the pharmaceutical composition according to the present invention are selected from a group comprising iron oxides or other pharmaceutically acceptable colourants or their combination.
- the other active pharmaceutical ingredient acting as a diuretic in the pharmaceutical composition according to the present invention is hydrochlorothiazide.
- the pharmaceutical composition according to the present invention is preferably a solid, oral pharmaceutical form, preferably tablet, capsule or powder.
- the invention includes a method for manufacturing of a pharmaceutical composition comprising candesartan cilexetil as the active pharmaceutical ingredient.
- the process comprises three steps.
- a mixture comprising candesartan cilexetil, filler and binder is wet granulated with the solution of the graft copolymer of polyvinyl alcohol with polyethylene glycol acting as a granulating agent with optionally addition of a colourant.
- the resulting granulate is dried.
- a disintegrant and optionally another active pharmaceutical ingredient selected from diuretics, optionally a colourant, and a lubricant are added to the dried granulate and the resulting mixture is tableted.
- the first step of the method for manufacturing of the pharmaceutical composition according to the invention is preferably carried out using fluid bed granulation method with the aqueous solution of the graft copolymer of polyvinyl alcohol with polyethylene glycol acting as a granulating agent with optionally addition of the colourant.
- the granulating solution constitutes 15% to 100% of the dry mass subjected to granulation, preferably 25% to 50%.
- the fillers utilised in the step are selected from a group comprising lactose, starch, cellulose, mannitol, sorbitol, tricalcium phosphate, calcium carbonate or other pharmaceutically acceptable fillers or their combination.
- the binders utilised in the step are selected from a group comprising hydroxypropylcellulose, povidone, hydroxypropylmethylcellulose or other pharmaceutically acceptable binders or their combination.
- the graft copolymer of polyvinyl alcohol with polyethylene glycol utilised in the step has a melting point of between 150° and 300°C, preferably between 180° and 250°C, more preferably between 200° and 220 0 C.
- the colourants utilised in the step are selected from a group comprising iron oxides or other pharmaceutically acceptable colourants or their combination.
- the second step of the method for manufacturing of the pharmaceutical composition according to the present invention is preferably carried out using fluid-bed drying until the moisture content is below 2%, preferably below 1%.
- the third step of the method for manufacturing of the pharmaceutical composition according to the present invention is carried out by using a disintegrant selected from a group comprising carmellose sodium or calcium, croscarmellose sodium, crospovidone, sodium starch glycolate or other pharmaceutically acceptable disintegrants or their combination.
- a disintegrant selected from a group comprising carmellose sodium or calcium, croscarmellose sodium, crospovidone, sodium starch glycolate or other pharmaceutically acceptable disintegrants or their combination.
- the other active pharmaceutical ingredient selected from diuretics used in this step is hydrochlorothiazide.
- the colourants utilised in the step are selected from a group comprising iron oxides or other pharmaceutically acceptable colourants or their combination.
- the lubricants used in this step are selected from a group comprising magnesium stearate, calcium stearate, stearyl fumarate, stearic acid or other pharmaceutically acceptable lubricants or their combination.
- the method for manufacturing of the pharmaceutical composition according to the present invention is characterised by the use of candesartan cilexetil active pharmaceutical ingredient in the weight ratio to the graft copolymer of polyvinyl alcohol with polyethylene glycol of 4:1 to 1 :3, preferably between 1 :2 and 2:1.
- the Kollicoat® IR and iron oxide in the GLATT GPCG3 fluid-bed granulator The resulting granulate is dried using fluid-bed method. The weighed quantity of carmellose calcium is added to the dried granulate. The content is mixed and weighed magnesium stearate is added. The content is again thoroughly mixed. The resulting tablet mass is tableted using the Kilian SlOO rotary tablet press. 8 mm flat-concave punches are used in the tableting process. The resulting tablets have a weight of 200 mg.
- Example 5 Magnesium stearate 0.9 Procedure identical to that in Example 1. The resulting tablets have a weight of 200 mg.
- Kollicoat® IR in the GLATT GPCG3 fluid-bed granulator.
- the resulting granulate is dried using fluid-bed method.
- the weighed quantity of carmellose calcium, hydrochlorothiazide and iron oxide is added to the dried granulate.
- the content is mixed and weighed magnesium stearate is added.
- the content is again thoroughly mixed.
- the resulting tablet mass is tableted using the Kilian SlOO rotary tablet press. 8 mm flat-concave punches are used in the tableting process.
- the resulting tablets have a weight of 200 mg.
- Example 2 Procedure identical to that in Example 1.
- the tablets are manufactured without Kollicoat® IR.
- the quantity of lactose monohydrate is increased to 64% of the single tablet weight.
- Example 1 Procedure identical to that in Example 6.
- the tablets are manufactured without Kollicoat® IR.
- the quantity of lactose monohydrate is increased to 63.25% of the single tablet weight.
- the stability tests are performed in stability chamber for four weeks, 50°C and 75% RH.
- the tablets are tested for candesartan cilexetil content and stability using assay methods based on high-performance liquid chromatography.
- the results of the testing, which confirm the subject matter of the invention, are specified in Table 1 and Table 2.
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
Stable pharmaceutical composition comprising candesartan cilexetil as the active pharmaceutical ingredient and graft copolymer of polyvinyl alcohol with polyethylene glycol as a stabilising agent. A method for manufacturing of pharmaceutical composition comprising candesartan cilexetil as the active pharmaceutical ingredient comprising the following steps: - a mixture comprising candesartan cilexetil, filler and binder is wet granulated with the solution of the graft copolymer of polyvinyl alcohol with polyethylene glycol acting as a granulating agent with optionally addition of a colourant, - the resulting granulate is dried, - a disintegrant and optionally another active pharmaceutical ingredient selected from diuretics, optionally a colourant, and a lubricant are added to the dried granulate and the resulting mixture is mixed and subsequently tableted.
Description
Pharmaceutical composition comprising candesartan cilexetil and method for manufacturing thereof
The subject of the invention includes a pharmaceutical composition comprising candesartan cilexetil as the active pharmaceutical ingredient and graft copolymer of polyvinyl alcohol with polyethylene glycol as a stabilising agent as well as the method for manufacturing thereof.
1 -(cyclohexyloxycarbonyloxy)ethyl 2-ethoxy- 1 - { [2 ' -( 1 H-tetrazolyl-
5)biphenylyl-4]rnethyl}-7-benzimidazolecarboxylate known under the INN of candesartan cilexetil and process for producing thereof was first disclosed in patent EP 459136B. Being a pro-drug it converts via hydrolysis into the active form of candesartan upon absorption from the gastrointestinal tract and proves efficient in the treatment of i.a. arterial hypertension together with other angiotensin II receptor antagonists.
The problem which occurs is the stability of candesartan cilexetil in pharmaceutical compositions. This was described in detail in patent EP 546358B. The solution, which is claimed herein, is the addition of an oily substance with a low melting point of between 20° and 90°C to the pharmaceutical composition along with the active pharmaceutical ingredient. According to patent EP 546358B the method for manufacturing of the composition includes pre-mixing the active pharmaceutical ingredient with the oily substance with a low melting point of between 20° and 9O0C and subjecting the mixture to the further forming process. In the international publication of patent application WO 2005/084648 a pharmaceutical composition was disclosed comprising candesartan cilexetil with one or more water soluble polymers acting as stabilising agents. The method for manufacturing of the composition consists in the formation of candesartan cilexetil dispersion with one or more water soluble polymers in the solution of a binder, granulation, drying and granulate tableting.
In the international publication of patent application WO 2005/079751 a pharmaceutical composition was disclosed comprising candesartan cilexetil with fatty substances acting as stabilising agents. The fatty substances listed in the publication include phospholipids, fatty acids and their esters. The method for manufacturing of the composition consists in the formation of candesartan cilexetil dispersion with one or more fatty substances in the solution of a binder, granulation, drying and granulate tableting.
The objective of the present invention is to develop a new, stable pharmaceutical composition comprising candesartan cilexetil as the active pharmaceutical ingredient whose manufacturing process is simple and may be conducted using standard formulation methods.
Surprisingly it has been found that the presence of a graft copolymer of polyvinyl alcohol with polyethylene glycol, originally meant as a" coating agent for rapid disintegration tablets, ensures stability of pharmaceutical compositions comprising candesartan cilexetil. Furthermore, surprisingly it has been found that the solution of the graft copolymer of polyvinyl alcohol with polyethylene glycol used as a granulating agent during the manufacturing process compensates for the negative properties of the candesartan cilexetil active pharmaceutical ingredient which consist in its electrostatic behaviour and fluffiness which result in the uncontrolled loss of the active pharmaceutical ingredient during the manufacturing process.
The graft copolymer of polyvinyl alcohol with polyethylene glycol present in the pharmaceutical composition according to the present invention has a melting point of between 150° and 300°C, preferably between 180° and 250°C, more preferably between 200° and 220°C.
The pharmaceutical composition according to the present invention has a content of candesartan cilexetil in the weight ratio to the graft copolymer of polyvinyl alcohol with polyethylene glycol of 4:1 to 1 :3, preferably 1 :2 to 2:1. Additionally, the pharmaceutical composition according to the present invention comprisies pharmaceutically acceptable excipients selected from a
group comprising fillers, binders, disintegrants, lubricants and optionally colourants. It may additionally comprise another active pharmaceutical ingredient acting as a diuretic.
The graft copolymer of polyvinyl alcohol with polyethylene glycol present in the pharmaceutical composition according to the present invention has hydrophilic properties. Preferably, it is the known copolymer under the trade name of Kollicoat® IR comprising 75% polyvinyl alcohol residues and 25% polyethylene glycol residues. The molecular weight of the copolymer is approximately 45,000 Daltons with a melting point of 209°C. Kollicoat® IR is hydrophilic powder readily soluble in water, white to light yellow. To improve its flow, approximately 0.3% of colloidal silica is added.
The fillers in the pharmaceutical composition according to the present invention are selected from a group comprising lactose, starch, cellulose, mannitol, sorbitol, tricalcium phosphate, calcium carbonate or other pharmaceutically acceptable fillers or their combination.
The binders in the pharmaceutical composition according to the present invention are selected from a group comprising hydroxypropylcellulose, povidone, hydroxypropylmethylcellulose or other pharmaceutically acceptable binders or their combination. The disintegrants in the pharmaceutical composition according to the present invention are selected from a group comprising carmellose sodium or calcium, croscarmellose sodium, crospovidone, sodium starch glycolate or other pharmaceutically acceptable disintegrants or their combination.
The lubricants in the pharmaceutical composition according to the present invention are selected from a group comprising magnesium stearate, calcium stearate, stearyl fumarate, stearic acid or other pharmaceutically acceptable lubricants or their combination.
The colourants in the pharmaceutical composition according to the present invention are selected from a group comprising iron oxides or other pharmaceutically acceptable colourants or their combination.
The other active pharmaceutical ingredient acting as a diuretic in the pharmaceutical composition according to the present invention is hydrochlorothiazide.
The pharmaceutical composition according to the present invention is preferably a solid, oral pharmaceutical form, preferably tablet, capsule or powder.
Additionally, the invention includes a method for manufacturing of a pharmaceutical composition comprising candesartan cilexetil as the active pharmaceutical ingredient. The process comprises three steps. In the first step a mixture comprising candesartan cilexetil, filler and binder is wet granulated with the solution of the graft copolymer of polyvinyl alcohol with polyethylene glycol acting as a granulating agent with optionally addition of a colourant. In the second step, the resulting granulate is dried. In the third step a disintegrant and optionally another active pharmaceutical ingredient selected from diuretics, optionally a colourant, and a lubricant are added to the dried granulate and the resulting mixture is tableted.
The first step of the method for manufacturing of the pharmaceutical composition according to the invention is preferably carried out using fluid bed granulation method with the aqueous solution of the graft copolymer of polyvinyl alcohol with polyethylene glycol acting as a granulating agent with optionally addition of the colourant. The granulating solution constitutes 15% to 100% of the dry mass subjected to granulation, preferably 25% to 50%. The fillers utilised in the step are selected from a group comprising lactose, starch, cellulose, mannitol, sorbitol, tricalcium phosphate, calcium carbonate or other pharmaceutically acceptable fillers or their combination. The binders utilised in the step are selected from a group comprising hydroxypropylcellulose, povidone, hydroxypropylmethylcellulose or other pharmaceutically acceptable binders or their combination. The graft copolymer of polyvinyl alcohol with polyethylene glycol utilised in the step has a melting point of between 150° and 300°C, preferably between 180° and 250°C, more preferably between 200° and 2200C.
The colourants utilised in the step are selected from a group comprising iron oxides or other pharmaceutically acceptable colourants or their combination.
The second step of the method for manufacturing of the pharmaceutical composition according to the present invention is preferably carried out using fluid-bed drying until the moisture content is below 2%, preferably below 1%.
The third step of the method for manufacturing of the pharmaceutical composition according to the present invention is carried out by using a disintegrant selected from a group comprising carmellose sodium or calcium, croscarmellose sodium, crospovidone, sodium starch glycolate or other pharmaceutically acceptable disintegrants or their combination. The other active pharmaceutical ingredient selected from diuretics used in this step is hydrochlorothiazide. The colourants utilised in the step are selected from a group comprising iron oxides or other pharmaceutically acceptable colourants or their combination. The lubricants used in this step are selected from a group comprising magnesium stearate, calcium stearate, stearyl fumarate, stearic acid or other pharmaceutically acceptable lubricants or their combination.
The method for manufacturing of the pharmaceutical composition according to the present invention is characterised by the use of candesartan cilexetil active pharmaceutical ingredient in the weight ratio to the graft copolymer of polyvinyl alcohol with polyethylene glycol of 4:1 to 1 :3, preferably between 1 :2 and 2:1.
The invention is illustrated by the following examples which in no way restrict its scope:
Example 1
[%/tablet] Candesartan cilexetil 8
Lactose monohydrate 60
Corn starch 17
Hydroxypropylcellulose 3
Kollicoat® IR 4 Iron oxide 0.1
Carmellose calcium 7
Magnesium stearate 0.9
The weighed quantity of candesartan cilexetil, lactose monohydrate, corn starch and hydroxypropylcellulose is wet granulated using aqueous solution of
Kollicoat® IR and iron oxide in the GLATT GPCG3 fluid-bed granulator. The resulting granulate is dried using fluid-bed method. The weighed quantity of carmellose calcium is added to the dried granulate. The content is mixed and weighed magnesium stearate is added. The content is again thoroughly mixed. The resulting tablet mass is tableted using the Kilian SlOO rotary tablet press. 8 mm flat-concave punches are used in the tableting process. The resulting tablets have a weight of 200 mg.
Example 2 [%/tablet]
Candesartan cilexetil 8
Lactose monohydrate 56
Corn starch 17
Hydroxypropylcellulose 3 Kollicoat® IR 8
Iron oxide 0.1
Carmellose calcium 7
Magnesium stearate 0.9
Procedure identical to that in Example 1. The resulting tablets have a weight of 200 mg.
Example 3 [%/tablet]
Candesartan cilexetil 8
Lactose monohydrate 48
Corn starch 17
Hydroxypropylcellulose 3 Kollicoat® IR 16
Iron oxide 0.1
Carmellose calcium 7
Magnesium stearate 0.9 Procedure identical to that in Example 1. The resulting tablets have a weight of 200 mg.
Example 4
[%/tablet]
Candesartan cilexetil 8 Lactose monohydrate 61.5
Corn starch 17
Hydroxypropylcellulose 3
Kollicoat® IR 2.5
Iron oxide 0.1 Carmellose calcium 7
Magnesium stearate 0.9 Procedure identical to that in Example 1. The resulting tablets have a weight of 200 mg.
Example 5
[%/tablet]
Candesartan cilexetil 8
Lactose monohydrate 40 Corn starch 17
Hydroxypropylcellulose 3
Kollicoat® IR 24
Iron oxide 0.1
Carmellose calcium 7 Magnesium stearate 0.9
Procedure identical to that in Example 1. The resulting tablets have a weight of 200 mg.
Example 6
[%/tablet]
Candesartan cilexetil 8
Hydrochlorothiazide 6.25
Kollicoat® IR 4 Lactose monohydrate 59.25
Corn starch 12.5
Hydroxypropylcellulose 2
Iron oxide 0.1
Carmellose calcium 7 Magnesium stearate 0.9
The weighed quantity of candesartan cilexetil, lactose monohydrate, corn starch and hydroxypropylcellulose is wet granulated using aqueous solution of
Kollicoat® IR in the GLATT GPCG3 fluid-bed granulator. The resulting granulate is dried using fluid-bed method. The weighed quantity of carmellose calcium, hydrochlorothiazide and iron oxide is added to the dried granulate. The
content is mixed and weighed magnesium stearate is added. The content is again thoroughly mixed. The resulting tablet mass is tableted using the Kilian SlOO rotary tablet press. 8 mm flat-concave punches are used in the tableting process.
The resulting tablets have a weight of 200 mg.
Example 7 (Comparative example)
[%/tablet]
Candesartan cilexetil 8
Lactose monohydrate 64 Corn starch 17
Hydroxypropylcellulose 3
Iron oxide 0.1
Carmellose calcium 7
Magnesium stearate 0.9
Procedure identical to that in Example 1. The tablets are manufactured without Kollicoat® IR. In order to obtain tablets of the same weight the quantity of lactose monohydrate is increased to 64% of the single tablet weight.
Example 8 (Comparative example)
[%/tablet]
Candesartan cilexetil 8
Hydrochlorothiazide 6.25
Lactose monohydrate 63.25 Corn starch 12.5
Hydroxypropylcellulose 2
Iron oxide 0.1
Carmellose calcium 7
Magnesium stearate 0.9
Procedure identical to that in Example 6. The tablets are manufactured without Kollicoat® IR. In order to obtain tablets of the same weight the quantity of lactose monohydrate is increased to 63.25% of the single tablet weight.
For all batches from Example 1 to 8 the stability tests are performed in stability chamber for four weeks, 50°C and 75% RH.
The tablets are tested for candesartan cilexetil content and stability using assay methods based on high-performance liquid chromatography. The results of the testing, which confirm the subject matter of the invention, are specified in Table 1 and Table 2.
10 Table 1. Candesartan cilexetil content in tablet before the stability tests.
20
Claims
1. A pharmaceutical composition comprising candesartan cilexetil as the active pharmaceutical ingredient characterised in that it comprises a graft copolymer of polyvinyl alcohol with polyethylene glycol.
2. The pharmaceutical composition of Claim 1 characterised in that the melting point of the graft copolymer of polyvinyl alcohol with polyethylene glycol is between 150° and 300°C, preferably between 180° and 2500C, more preferably between 200° and 2200C.
3. The pharmaceutical composition of Claim 1 characterised in that the weight ratio of the active pharmaceutical ingredient to the graft copolymer of polyvinyl alcohol with polyethylene glycol is 4:1 to 1 :3, preferably 1 :2 to 2:1.
4. The pharmaceutical composition of Claim 1 characterised in that it also comprises one or more pharmaceutically acceptable excipients.
5. The pharmaceutical composition of Claim 4 characterised in that the pharmaceutically acceptable excipients are selected from a group comprising fillers, binders, disintegrants, lubricants and optionally colourants.
6. The pharmaceutical composition of Claim 1 characterised in that it also comprises another active pharmaceutical ingredient selected from diuretics.
7. The pharmaceutical composition of Claim 6 characterised in that the other active pharmaceutical ingredient selected from diuretics is hydrochlorothiazide.
8. The pharmaceutical composition of Claims 1-7 characterised in that it is a solid, oral pharmaceutical form, preferably tablet, capsule or powder.
9. A method for manufacturing of a pharmaceutical composition comprising candesartan cilexetil as the active pharmaceutical ingredient characterised in that the method comprises the following steps: a) a mixture comprising candesartan cilexetil, filler and binder is wet granulated with the solution of the graft copolymer of polyvinyl alcohol with polyethylene glycol acting as a granulating agent with optionally addition of a colourant, b) the granulate manufactured in step a) is dried, c) a disintegrant and optionally another active pharmaceutical ingredient selected from diuretics, optionally a colourant, and a lubricant are added to the dried granulate produced in step b) and the resulting mixture is mixed and subsequently tableted.
10. The method for manufacturing of the pharmaceutical composition of Claim 9 characterised in that the melting point of the graft copolymer of polyvinyl alcohol with polyethylene glycol is between 150° and 300°C, preferably between 180° and 250°C, more preferably between 200° and 220°C.
11. The method for manufacturing of the pharmaceutical composition of Claim 9 characterised in that the other active pharmaceutical ingredient selected from diuretics is hydrochlorothiazide.
12. The method for manufacturing of the pharmaceutical composition of Claim 9 characterised in that the weight ratio of the active pharmaceutical ingredient to the graft copolymer of polyvinyl alcohol with polyethylene glycol is 4:1 to 1:3, preferably 1 :2 to 2:1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP08741767A EP2139456A1 (en) | 2007-03-28 | 2008-03-28 | Pharmaceutical composition comprising candesartan cilexetil and method for manufacturing thereof |
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PL382080A PL207244B1 (en) | 2007-03-28 | 2007-03-28 | Oral pharmaceutical composition containing cylexetil candesartan and its production method |
| PLP.382080 | 2007-03-28 | ||
| PLP.384680 | 2008-03-12 | ||
| PL384680A PL384680A1 (en) | 2007-03-28 | 2008-03-12 | Pharmaceutical composition containing cylexyethyl candesarthan and its production method |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2008118031A1 true WO2008118031A1 (en) | 2008-10-02 |
Family
ID=39672763
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/PL2008/000026 WO2008118031A1 (en) | 2007-03-28 | 2008-03-28 | Pharmaceutical composition comprising candesartan cilexetil and method for manufacturing thereof |
Country Status (4)
| Country | Link |
|---|---|
| EP (1) | EP2139456A1 (en) |
| PL (1) | PL384680A1 (en) |
| RU (1) | RU2009139485A (en) |
| WO (1) | WO2008118031A1 (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101632678B (en) * | 2009-09-01 | 2011-09-14 | 严洁 | Losartan potassium hydrochlorothiazide composition and preparation method thereof |
| JP2013075833A (en) * | 2011-09-29 | 2013-04-25 | Nihon Generic Co Ltd | Solid preparation containing candesartan cilexetil |
| CN110638764A (en) * | 2019-09-23 | 2020-01-03 | 珠海润都制药股份有限公司 | Candesartan cilexetil quick-release pellet |
| CN117442577A (en) * | 2023-12-21 | 2024-01-26 | 山东则正医药技术有限公司 | Candesartan cilexetil microchip and preparation method and application thereof |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004052345A1 (en) * | 2002-12-11 | 2004-06-24 | Ranbaxy Laboratories Limited | Coating composition for taste masking coating and methods for their application and use |
| WO2005070398A2 (en) * | 2004-01-23 | 2005-08-04 | Ranbaxy Laboratories Limited | Pharmaceutical compositions of candesartan cilexetil stabilized with co-solvents |
| WO2005079751A2 (en) * | 2004-01-23 | 2005-09-01 | Ranbaxy Laboratories Limited | Oral pharmaceutical compositions of candesartan cilexetil |
| WO2005084648A1 (en) * | 2004-02-27 | 2005-09-15 | Ranbaxy Laboratories Limited | Pharmaceutical compositions comprising candesartan cilexetil |
-
2008
- 2008-03-12 PL PL384680A patent/PL384680A1/en not_active Application Discontinuation
- 2008-03-28 EP EP08741767A patent/EP2139456A1/en not_active Withdrawn
- 2008-03-28 WO PCT/PL2008/000026 patent/WO2008118031A1/en active Application Filing
- 2008-03-28 RU RU2009139485/15A patent/RU2009139485A/en unknown
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004052345A1 (en) * | 2002-12-11 | 2004-06-24 | Ranbaxy Laboratories Limited | Coating composition for taste masking coating and methods for their application and use |
| WO2005070398A2 (en) * | 2004-01-23 | 2005-08-04 | Ranbaxy Laboratories Limited | Pharmaceutical compositions of candesartan cilexetil stabilized with co-solvents |
| WO2005079751A2 (en) * | 2004-01-23 | 2005-09-01 | Ranbaxy Laboratories Limited | Oral pharmaceutical compositions of candesartan cilexetil |
| WO2005084648A1 (en) * | 2004-02-27 | 2005-09-15 | Ranbaxy Laboratories Limited | Pharmaceutical compositions comprising candesartan cilexetil |
Non-Patent Citations (1)
| Title |
|---|
| JANSSENS ET AL: "The use of a new hydrophilic polymer, Kollicoat IR<(>R), in the formulation of solid dispersions of Itraconazole", EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES, ELSEVIER, AMSTERDAM, NL, vol. 30, no. 3-4, 23 February 2007 (2007-02-23), pages 288 - 294, XP005901598, ISSN: 0928-0987 * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101632678B (en) * | 2009-09-01 | 2011-09-14 | 严洁 | Losartan potassium hydrochlorothiazide composition and preparation method thereof |
| JP2013075833A (en) * | 2011-09-29 | 2013-04-25 | Nihon Generic Co Ltd | Solid preparation containing candesartan cilexetil |
| CN110638764A (en) * | 2019-09-23 | 2020-01-03 | 珠海润都制药股份有限公司 | Candesartan cilexetil quick-release pellet |
| CN117442577A (en) * | 2023-12-21 | 2024-01-26 | 山东则正医药技术有限公司 | Candesartan cilexetil microchip and preparation method and application thereof |
| CN117442577B (en) * | 2023-12-21 | 2024-03-15 | 山东则正医药技术有限公司 | Candesartan cilexetil microchip and preparation method and application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| RU2009139485A (en) | 2011-05-10 |
| EP2139456A1 (en) | 2010-01-06 |
| PL384680A1 (en) | 2008-09-29 |
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