EP2139456A1 - Pharmaceutical composition comprising candesartan cilexetil and method for manufacturing thereof - Google Patents

Pharmaceutical composition comprising candesartan cilexetil and method for manufacturing thereof

Info

Publication number
EP2139456A1
EP2139456A1 EP08741767A EP08741767A EP2139456A1 EP 2139456 A1 EP2139456 A1 EP 2139456A1 EP 08741767 A EP08741767 A EP 08741767A EP 08741767 A EP08741767 A EP 08741767A EP 2139456 A1 EP2139456 A1 EP 2139456A1
Authority
EP
European Patent Office
Prior art keywords
pharmaceutical composition
candesartan cilexetil
polyethylene glycol
polyvinyl alcohol
graft copolymer
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Withdrawn
Application number
EP08741767A
Other languages
German (de)
French (fr)
Inventor
Marta Wenclaw
Jolanta Haase
Mariusz Siwek
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Zaklady Farmaceutyczne Polpharma SA
Original Assignee
Zaklady Farmaceutyczne Polpharma SA
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Priority claimed from PL382080A external-priority patent/PL207244B1/en
Application filed by Zaklady Farmaceutyczne Polpharma SA filed Critical Zaklady Farmaceutyczne Polpharma SA
Publication of EP2139456A1 publication Critical patent/EP2139456A1/en
Withdrawn legal-status Critical Current

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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

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.
EP08741767A 2007-03-28 2008-03-28 Pharmaceutical composition comprising candesartan cilexetil and method for manufacturing thereof Withdrawn EP2139456A1 (en)

Applications Claiming Priority (3)

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
PL384680A PL384680A1 (en) 2007-03-28 2008-03-12 Pharmaceutical composition containing cylexyethyl candesarthan and its production method
PCT/PL2008/000026 WO2008118031A1 (en) 2007-03-28 2008-03-28 Pharmaceutical composition comprising candesartan cilexetil and method for manufacturing thereof

Publications (1)

Publication Number Publication Date
EP2139456A1 true EP2139456A1 (en) 2010-01-06

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Country Status (4)

Country Link
EP (1) EP2139456A1 (en)
PL (1) PL384680A1 (en)
RU (1) RU2009139485A (en)
WO (1) WO2008118031A1 (en)

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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
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

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AU2003302881A1 (en) * 2002-12-11 2004-06-30 Ranbaxy Laboratories Limited Coating composition for taste masking coating and methods for their application and use
WO2005079751A2 (en) * 2004-01-23 2005-09-01 Ranbaxy Laboratories Limited Oral pharmaceutical compositions of candesartan cilexetil
WO2005070398A2 (en) * 2004-01-23 2005-08-04 Ranbaxy Laboratories Limited Pharmaceutical compositions of candesartan cilexetil stabilized with co-solvents
WO2005084648A1 (en) * 2004-02-27 2005-09-15 Ranbaxy Laboratories Limited Pharmaceutical compositions comprising candesartan cilexetil

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PL384680A1 (en) 2008-09-29
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