EP4370101A1 - A pharmaceutical composition comprising amlodipine, candesartan cilexetil and hydrochlorothiazide for the treatment of hypertension - Google Patents
A pharmaceutical composition comprising amlodipine, candesartan cilexetil and hydrochlorothiazide for the treatment of hypertensionInfo
- Publication number
- EP4370101A1 EP4370101A1 EP22751065.8A EP22751065A EP4370101A1 EP 4370101 A1 EP4370101 A1 EP 4370101A1 EP 22751065 A EP22751065 A EP 22751065A EP 4370101 A1 EP4370101 A1 EP 4370101A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- amlodipine
- hydrochlorothiazide
- candesartan cilexetil
- granulate
- powder
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 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 90
- JZUFKLXOESDKRF-UHFFFAOYSA-N Chlorothiazide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC2=C1NCNS2(=O)=O JZUFKLXOESDKRF-UHFFFAOYSA-N 0.000 title claims abstract description 90
- HTIQEAQVCYTUBX-UHFFFAOYSA-N amlodipine Chemical compound CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1Cl HTIQEAQVCYTUBX-UHFFFAOYSA-N 0.000 title claims abstract description 86
- 229960002003 hydrochlorothiazide Drugs 0.000 title claims abstract description 82
- 229960000528 amlodipine Drugs 0.000 title claims abstract description 78
- 229960004349 candesartan cilexetil Drugs 0.000 title claims abstract description 72
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 21
- 206010020772 Hypertension Diseases 0.000 title abstract description 8
- 239000007902 hard capsule Substances 0.000 claims abstract description 5
- 239000008187 granular material Substances 0.000 claims description 38
- 239000000843 powder Substances 0.000 claims description 32
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 28
- 239000000203 mixture Substances 0.000 claims description 25
- 229920000881 Modified starch Polymers 0.000 claims description 17
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 16
- 229960003511 macrogol Drugs 0.000 claims description 16
- 239000002202 Polyethylene glycol Substances 0.000 claims description 14
- 229920001223 polyethylene glycol Polymers 0.000 claims description 14
- 239000000314 lubricant Substances 0.000 claims description 10
- 239000011230 binding agent Substances 0.000 claims description 2
- 239000007884 disintegrant Substances 0.000 claims description 2
- 239000000945 filler Substances 0.000 claims description 2
- 239000003381 stabilizer Substances 0.000 claims description 2
- 239000002775 capsule Substances 0.000 description 49
- 238000004090 dissolution Methods 0.000 description 22
- 239000000047 product Substances 0.000 description 17
- 238000012360 testing method Methods 0.000 description 17
- 230000000052 comparative effect Effects 0.000 description 15
- 239000002053 C09CA06 - Candesartan Substances 0.000 description 11
- 229960000932 candesartan Drugs 0.000 description 11
- 229940058087 atacand Drugs 0.000 description 10
- 238000013475 authorization Methods 0.000 description 10
- 229940036132 norvasc Drugs 0.000 description 9
- 239000003814 drug Substances 0.000 description 6
- 238000002156 mixing Methods 0.000 description 6
- 239000002552 dosage form Substances 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 229940126534 drug product Drugs 0.000 description 5
- 238000011156 evaluation Methods 0.000 description 5
- 238000005469 granulation Methods 0.000 description 5
- 230000003179 granulation Effects 0.000 description 5
- 229940126602 investigational medicinal product Drugs 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 229940126601 medicinal product Drugs 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- 239000000825 pharmaceutical preparation Substances 0.000 description 5
- 229920001213 Polysorbate 20 Polymers 0.000 description 4
- 229920002472 Starch Polymers 0.000 description 4
- 238000010521 absorption reaction Methods 0.000 description 4
- 239000008186 active pharmaceutical agent Substances 0.000 description 4
- 239000013543 active substance Substances 0.000 description 4
- 239000002050 international nonproprietary name Substances 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 4
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 4
- 239000008107 starch Substances 0.000 description 4
- 235000019698 starch Nutrition 0.000 description 4
- 238000005303 weighing Methods 0.000 description 4
- GNENVASJJIUNER-UHFFFAOYSA-N 2,4,6-tricyclohexyloxy-1,3,5,2,4,6-trioxatriborinane Chemical compound C1CCCCC1OB1OB(OC2CCCCC2)OB(OC2CCCCC2)O1 GNENVASJJIUNER-UHFFFAOYSA-N 0.000 description 3
- 239000012530 fluid Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 206010019280 Heart failures Diseases 0.000 description 2
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 229940000425 combination drug Drugs 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000005538 encapsulation Methods 0.000 description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 2
- 238000011835 investigation Methods 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 239000008363 phosphate buffer Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 238000012216 screening Methods 0.000 description 2
- 238000012430 stability testing Methods 0.000 description 2
- -1 2-aminoethoxy Chemical group 0.000 description 1
- 229940123413 Angiotensin II antagonist Drugs 0.000 description 1
- 229940127291 Calcium channel antagonist Drugs 0.000 description 1
- 206010007559 Cardiac failure congestive Diseases 0.000 description 1
- 208000007342 Diabetic Nephropathies Diseases 0.000 description 1
- 206010012689 Diabetic retinopathy Diseases 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000002333 angiotensin II receptor antagonist Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical class OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000000480 calcium channel blocker Substances 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 208000029078 coronary artery disease Diseases 0.000 description 1
- 239000007857 degradation product Substances 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000007922 dissolution test Methods 0.000 description 1
- 239000002934 diuretic Substances 0.000 description 1
- 230000001882 diuretic effect Effects 0.000 description 1
- 238000009506 drug dissolution testing Methods 0.000 description 1
- 229940088679 drug related substance Drugs 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 235000020937 fasting conditions Nutrition 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000007721 medicinal effect Effects 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 238000007873 sieving Methods 0.000 description 1
- 239000002356 single layer Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 230000009747 swallowing Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 238000010200 validation analysis 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4866—Organic macromolecular compounds
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4422—1,4-Dihydropyridines, e.g. nifedipine, nicardipine
-
- 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
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/549—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame having two or more nitrogen atoms in the same ring, e.g. hydrochlorothiazide
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
Definitions
- a pharmaceutical composition comprising Amlodipine, Candesartan cilexetil and Hydrochlorothiazide for the treatment of hypertension.
- the present invention relates to fixed dose pharmaceutical compositions comprising three active pharmaceutical ingredients (APIs) Amlodipine, Candesartan cilexetil and Hydrochlorothiazide for the treatment of hypertension.
- APIs active pharmaceutical ingredients
- Candesartan is the international nonproprietary name (INN) of 2-ethoxy-l-( ⁇ 4-[2-(2H-l, 2,3,4- tetrazol-5-yl)phenyl]phenyl ⁇ methyl)-lH-l,3-benzodiazole-7-carboxylic acid.
- Hydrochlorothiazide (abbreviated "HCTZ” or “HCT”) is the INN of 6-chloro-l,l-dioxo-3,4- dihydro-2H-l,2,4-benzothiadiazine-7-sulfonamide.
- Amlodipine is the INN of (RS)-3-ethyl-5-methyl-2-[(2-aminoethoxy)methyl]-4-(2-chloro- phenyl)-6-methyl-l,4-dihydropyridine-3,5-dicarboxylate.
- compositions of the angiotensin II antagonist Candesartan in the modification of its prodrug Candesartan cilexetil are registered for the treatment of congestive heart failure, diabetic nephropathies, diabetic retinopathy and hypertension, being marketed under the trade name ATACAND®.
- Pharmaceutical compositions of the diuretic Hydrochlorothiazide are registered and marketed under the trade name ESIDRIX® for the treatment of hypertension, edema and heart failure.
- Pharmaceutical compositions of the calcium channel blocker Amlodipine in the modification of its benzene sulfonate (“besilate”) salt are registered and marketed under the trade name NORVASC® for the treatment of coronary artery disease and hypertension.
- a fixed-dose combination of Candesartan cilexetil and Hydrochlorothiazide is registered and marketed under the trade name ATACAND® PLUS for the treatment of hypertension.
- CN101584700 discloses a general idea that candesartan cilexetil, hydrochlorothiazide and amlodipine, may be combined in a certain weight ratio (CAN:HCTZ:AML 1-10: 2-15: 1-8). However no further details are presented as to the dosage form and suitable excipients. Experimental results confirming stability and dissolution are not provided.
- WO20 17054787 discloses bilayer tablets with CAN+HCTZ in one layer separated from AML layer.
- CN102342942 discloses capsules comprising AML+CAN granulate stabilized with PVP and a powder of HCTZ or a capsule comprising powders of the 3 actives + PVP. Also, monolayer tablets of AML CAN HCTZ + PVP are disclosed.
- WO2017158094A1 discloses tablets in which amlodipine and candesartan are in separated layers. Hydrochlorothiazide is present either in one or in the second layer. Such a dosage form requires that the step of compression must be performed and that a bilayer tabletting machine is available. Also during tabletting a mechanical stress is applied to the actives, which should be eliminated, especially in case of candesartan cilexetil.
- the object of the present invention is a pharmaceutical composition in form of a capsule comprising Amlodipine, Candesartan cilexetil and Hydrochlorothiazide.
- Amlodipine besilate may be manufactured according to processes known in the art, e.g. as disclosed in patent application EP 0 244 944 A2.
- Candesartan cilexetil may also be manufactured according to processes known in the art, e.g. as disclosed in patent application EP 0 459 136 Al.
- Hydrochlorothiazide may also be manufactured according to processes known in the art, e.g. as disclosed in patent CIS 3163645.
- compositions according to the present invention are in the form of hard capsules and comprise a) a granulate comprising Candesartan cilexetil and polyethylene glycol in the weight ratio in a range of 4.4 to 6.5 and optionally further excipients, b)a powder comprising Amlodipine, Hydrochlorothiazide, pregelatinized starch and optionally further excipients.
- compositions according to the present invention are in the form of hard capsules and comprise a) a granulate comprising Candesartan cilexetil and polyethylene glycol in the weight ratio in a range of 4.4 to 6.5 and one or more disintegrants, one or more binders, one or more fillers, one or more stabilizers and optionally one or more glidants, b)a powder comprising Amlodipine, Hydrochlorothiazide, pregelatinized starch and optionally further excipients.
- the capsule comprises a) a granulate comprising Candesartan cilexetil and polyethylene glycol selected from Macrogol 8000 or Macrogol 6000 in the weight ratio in a range of 4.8 to 6.15 and optionally further excipients, b) a powder comprising Amlodipine, Hydrochlorothiazide, pregelatinized starch and a lubricant as further excipients.
- a granulate comprising Candesartan cilexetil and polyethylene glycol selected from Macrogol 8000 or Macrogol 6000 in the weight ratio in a range of 4.8 to 6.15 and optionally further excipients
- a powder comprising Amlodipine, Hydrochlorothiazide, pregelatinized starch and a lubricant as further excipients.
- the capsule comprises a) a granulate comprising Candesartan cilexetil and polyethylene glycol selected from Macrogol 8000 or Macrogol 6000 in the weight ratio in a range of 4.8 to 6.15 and optionally further excipients, b)a powder comprising Amlodipine, Hydrochlorothiazide, pregelatinized starch in the amount of 9 to 70% wt. calculated on the total mass of granulate a) and powder b) and a lubricant as further excipients.
- the capsule comprises a) a granulate comprising Candesartan cilexetil and polyethylene glycol selected from Macrogol 8000 or Macrogol 6000 in the weight ratio in a range of 6.15 and optionally further excipients, b)a powder comprising Amlodipine, Hydrochlorothiazide, pregelatinized starch in the amount of 9 to 30% wt., especially in the amount of 9.5 to 9.8 % wt. calculated on the total mass of granulate a) and powder b) and a lubricant as further excipients.
- a granulate comprising Candesartan cilexetil and polyethylene glycol selected from Macrogol 8000 or Macrogol 6000 in the weight ratio in a range of 6.15 and optionally further excipients
- the capsule comprises a) a granulate comprising Candesartan cilexetil and polyethylene glycol selected from Macrogol 8000 in the weight ratio of 6.15 and optionally further excipients, b)a powder comprising Amlodipine, Hydrochlorothiazide, pregelatinized starch in the amount of 9.59 or 9.79 % wt. calculated on the total mass of granulate a) and powder b) and a lubricant as further excipients.
- the capsule comprises a) a granulate comprising Candesartan cilexetil and polyethylene glycol selected from Macrogol 8000 in the weight ratio of 6.15 and optionally further excipients, b)a powder comprising Amlodipine, Hydrochlorothiazide, pregelatinized starch in the amount of 9.59 or 9.79 % wt. calculated on the total mass of granulate a) and powder b) and a lubricant, wherein further excipients are not present in the powder b).
- Candesartan cilexetil/Amlodipine/Hydrochlorothiazide capsules, hard are produced according to the following manufacturing steps: weighing, preparation of granulation liquid, high-shear mixing of granulate a) components, granulation solution addition, wet massing, fluid bed drying, granulate screening, weighing, sieving the components of the powder b), blending the components of the powder b), blending the granulate a) with powder b) and final encapsulation.
- Blending II Blend all components to obtain Candesartan cilexetil/Amlodipine/Hydrochlorothiazide encapsulation blend.
- the blended granulate a) and powder b) fractions are packed into hard gelatin capsules size “0” Table 5: composition of the capsules q.s.p. quantitate sufficient per
- Dissolution profiles of Amlodipine (AML), Hydrochlorothiazide (HCTZ) from tested and reference products were performed in 0.1M HC1, and Candesartan cilexetil (CAN) from tested and reference products were performed in phosphate buffer pH 6.8 with 0.35% Tween 20 (only for CAN), 37°C. The same conditions were applied for comparative Examples.
- Example 1.2 Candesartan cilexetil / Amlodipine / Hydrochlorothiazide capsule, hard, 16mg/10mg/12.5mg, of Example 1.2 according to the invention and
- Dissolution studies were performed in respect to the current, official requirements and acceptance criteria for dissolution testing with fully validated HPLC methods for medium 0.1M HC1 for AML and HCTZ and for phosphate buffer pH 6.8 + 0.35% Tween 20 (for CAN only).
- Dissolution volume 900 ml
- Rotating speed 100 rpm
- Apparatus type Ph. Eur. 1 - baskets
- Temperature 37°C.
- Sampling time 15 minutes for Amlodipine and Hydrochlorothiazide, 30 minutes for Candesartan cilexetil.
- Table. 7 Dissolution profiles of Amlodipine from reference, comparative Example 4.4 and tested products; Ph. Eur. apparatus 1, 100 rpm, 900 ml, 0.1M HC1. Dissolution profile of Amlodipine from Candesartan cilexetil / Amlodipine/Hydrochlorothiazide capsule, hard 16mg/10mg/12.5mg, Batch No. 12565178 (Example 1.2), Ph. Eur. apparatus 1, 100 rpm, 900 ml, 0.1M HC1, 37°C.
- Candesartan cilexetil dissolution profile from developed drug product Candesartan cilexetil/Amlodipine/Hydrochlorothiazide capsule, hard 16mg/10mg/12.5mg and from reference drug products Atacand 16 mg tablets.
- compositions according to the invention revealed superior stability comparing to the comparative Examples not containing pregelatinized starch in the fraction b).
- the fixed dose compositions according to the invention may be used as an alternative to the respective combination therapy based on administration of Candesartan cilexetil, Amlodipine and Hydrochlorothiazide in separate dosage forms.
- the compositions are obtained by simple and economic manufacturing process and will ensure better patients compliance comparing to adherence to 3 separate dosing regimens.
- Pharmacokinetic study was performed for Candesartan cilexetil/Amlodipine/Hydrochlorothiazide capsule, hard 16mg/ 10 mg/ 12.5 mg according to Example 1.2.
- the primary aim of the study was to evaluate the pharmacokinetic properties and to compare the bioavailability of the test investigational medicinal product (IMP) versus the reference medicinal products in healthy volunteers under fasting conditions.
- the secondary study objective was to evaluate the safety of the test and reference medicinal products.
- the results of the study are presented in Tables A-F.
- Table A Candesartan PK data for Candesartan cilexetil/Amlodipine/Hydrochlorothiazide capsule, hard 16mg/ 10 mg/ 12.5 mg according to Example 1.2; reference: Atacand 16 mg tablets.
- Table D Candesartan bioequivalence evaluation for Candesartan cilexetil/ Amlodipine/Hydrochlorothiazide capsule, hard 16mg/ 10 mg/ 12.5 mg according to Example 1.2;, reference: Atacand 16 mg tablets.
- Test product Candesartan cilexetil/Amlodipine/Hydrochlorothiazide capsule, hard 16mg/ 10 mg/ 12.5 mg according to Example 1.2demonstrated a comparable extent and rate of absorption of Candesartan to the Reference product Atacand 16 mg tablets with Test/Reference (T/R) geometric mean ratios (GMR) of approximately 100% and 89% for AUQo- t) and Cmax, respectively and with the corresponding 90% CIs contained within the EMA- acceptance range 80.00% - 125.00%.
- T/R Test/Reference
- GMR geometric mean ratios
- Test product Candesartan cilexetil/Amlodipine/Hydrochlorothiazide capsule, hard 16mg/ 10 mg/ 12.5 mg according to Example 1.2demonstrated a comparable extent and rate of absorption of Amlodipine to the Reference product Norvasc 10 mg tablets with Test/Reference (T/R) geometric mean ratios (GMR) of approximately 104% and 102% for AUC ( o-72 h) and Cmax, respectively and with the corresponding 90% CIs contained within the EMA-acceptance range 80.00% - 125.00%.
- T/R Test/Reference
- GMR geometric mean ratios
- Test product Candesartan cilexetil/Amlodipine/Hydrochlorothiazide capsule, hard 16mg/ 10 mg/ 12.5 mg according to Example 1.2demonstrated a comparable extent and rate of absorption of Hydrochlorothiazide to the Reference product Esidrex 25 mg tablets (half tablet containing 12.5 mg of hydrochlorothiazide) with Test/Reference (T/R) geometric mean ratios (GMR) of approximately 101% and 115% for AUQo- t) and Cmax, respectively and with the corresponding 90% CIs contained within the EMA-acceptance range 80.00% - 125.00%.
- T/R Test/Reference
- GMR geometric mean ratios
Landscapes
- 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)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Inorganic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to fixed dose pharmaceutical compositions in the form of hard capsules comprising Amlodipine, Candesartan cilexetil and Hydrochlorothiazide for the treatment of hypertension.
Description
A pharmaceutical composition comprising Amlodipine, Candesartan cilexetil and Hydrochlorothiazide for the treatment of hypertension.
The present invention relates to fixed dose pharmaceutical compositions comprising three active pharmaceutical ingredients (APIs) Amlodipine, Candesartan cilexetil and Hydrochlorothiazide for the treatment of hypertension.
Candesartan is the international nonproprietary name (INN) of 2-ethoxy-l-({4-[2-(2H-l, 2,3,4- tetrazol-5-yl)phenyl]phenyl}methyl)-lH-l,3-benzodiazole-7-carboxylic acid. Hydrochlorothiazide (abbreviated "HCTZ" or "HCT") is the INN of 6-chloro-l,l-dioxo-3,4- dihydro-2H-l,2,4-benzothiadiazine-7-sulfonamide.
Amlodipine is the INN of (RS)-3-ethyl-5-methyl-2-[(2-aminoethoxy)methyl]-4-(2-chloro- phenyl)-6-methyl-l,4-dihydropyridine-3,5-dicarboxylate.
Pharmaceutical compositions of the angiotensin II antagonist Candesartan in the modification of its prodrug Candesartan cilexetil are registered for the treatment of congestive heart failure, diabetic nephropathies, diabetic retinopathy and hypertension, being marketed under the trade name ATACAND®. Pharmaceutical compositions of the diuretic Hydrochlorothiazide are registered and marketed under the trade name ESIDRIX® for the treatment of hypertension, edema and heart failure. Pharmaceutical compositions of the calcium channel blocker Amlodipine in the modification of its benzene sulfonate ("besilate") salt are registered and marketed under the trade name NORVASC® for the treatment of coronary artery disease and hypertension. A fixed-dose combination of Candesartan cilexetil and Hydrochlorothiazide is registered and marketed under the trade name ATACAND® PLUS for the treatment of hypertension.
No fixed-dose pharmaceutical formulation comprising Candesartan cilexetil, Hydrochlorothiazide and Amlodipine has been registered and marketed yet.
CN101584700 discloses a general idea that candesartan cilexetil, hydrochlorothiazide and amlodipine, may be combined in a certain weight ratio (CAN:HCTZ:AML 1-10: 2-15: 1-8). However no further details are presented as to the dosage form and suitable excipients. Experimental results confirming stability and dissolution are not provided.
WO20 17054787 discloses bilayer tablets with CAN+HCTZ in one layer separated from AML layer.
CN102342942 discloses capsules comprising AML+CAN granulate stabilized with PVP and a powder of HCTZ or a capsule comprising powders of the 3 actives + PVP. Also, monolayer tablets of AML CAN HCTZ + PVP are disclosed.
WO2017158094A1 discloses tablets in which amlodipine and candesartan are in separated layers. Hydrochlorothiazide is present either in one or in the second layer. Such a dosage form requires
that the step of compression must be performed and that a bilayer tabletting machine is available. Also during tabletting a mechanical stress is applied to the actives, which should be eliminated, especially in case of candesartan cilexetil.
Also in case of dosage forms comprising rather bigger amounts of actives and excipients, as it is the case with triple-actives combination, some patients comply better with the capsule dosage form because the dimensions of a hard capsules bodies is better suited for swallowing.
Therefore, there is still a need to simplify pharmaceutical processes for economic and environmental reasons. Secondly, any unnecessary manipulation steps of the actives have to be avoided since potential influence of different factors occurring in such a step. Also unnecessary validation and control is avoided. There is also a need to improve dissolution profile of the active substances as to obtain the dissolution characteristic as close to the respective referent drugs as possible.
The object of the present invention is a pharmaceutical composition in form of a capsule comprising Amlodipine, Candesartan cilexetil and Hydrochlorothiazide.
Amlodipine besilate may be manufactured according to processes known in the art, e.g. as disclosed in patent application EP 0 244 944 A2. Candesartan cilexetil may also be manufactured according to processes known in the art, e.g. as disclosed in patent application EP 0 459 136 Al. Hydrochlorothiazide may also be manufactured according to processes known in the art, e.g. as disclosed in patent CIS 3163645.
The pharmaceutical compositions according to the present invention, are in the form of hard capsules and comprise a) a granulate comprising Candesartan cilexetil and polyethylene glycol in the weight ratio in a range of 4.4 to 6.5 and optionally further excipients, b)a powder comprising Amlodipine, Hydrochlorothiazide, pregelatinized starch and optionally further excipients.
In one aspect the pharmaceutical compositions according to the present invention, are in the form of hard capsules and comprise a) a granulate comprising Candesartan cilexetil and polyethylene glycol in the weight ratio in a range of 4.4 to 6.5 and one or more disintegrants, one or more binders, one or more fillers, one or more stabilizers and optionally one or more glidants, b)a powder comprising Amlodipine, Hydrochlorothiazide, pregelatinized starch and optionally further excipients.
Preferably, the capsule comprises
a) a granulate comprising Candesartan cilexetil and polyethylene glycol selected from Macrogol 8000 or Macrogol 6000 in the weight ratio in a range of 4.8 to 6.15 and optionally further excipients, b) a powder comprising Amlodipine, Hydrochlorothiazide, pregelatinized starch and a lubricant as further excipients.
More preferably, the capsule comprises a) a granulate comprising Candesartan cilexetil and polyethylene glycol selected from Macrogol 8000 or Macrogol 6000 in the weight ratio in a range of 4.8 to 6.15 and optionally further excipients, b)a powder comprising Amlodipine, Hydrochlorothiazide, pregelatinized starch in the amount of 9 to 70% wt. calculated on the total mass of granulate a) and powder b) and a lubricant as further excipients.
Also preferably, the capsule comprises a) a granulate comprising Candesartan cilexetil and polyethylene glycol selected from Macrogol 8000 or Macrogol 6000 in the weight ratio in a range of 6.15 and optionally further excipients, b)a powder comprising Amlodipine, Hydrochlorothiazide, pregelatinized starch in the amount of 9 to 30% wt., especially in the amount of 9.5 to 9.8 % wt. calculated on the total mass of granulate a) and powder b) and a lubricant as further excipients.
In one of most preferable embodiment, the capsule comprises a) a granulate comprising Candesartan cilexetil and polyethylene glycol selected from Macrogol 8000 in the weight ratio of 6.15 and optionally further excipients, b)a powder comprising Amlodipine, Hydrochlorothiazide, pregelatinized starch in the amount of 9.59 or 9.79 % wt. calculated on the total mass of granulate a) and powder b) and a lubricant as further excipients.
In the second most preferable embodiment, the capsule comprises a) a granulate comprising Candesartan cilexetil and polyethylene glycol selected from Macrogol 8000 in the weight ratio of 6.15 and optionally further excipients, b)a powder comprising Amlodipine, Hydrochlorothiazide, pregelatinized starch in the amount of 9.59 or 9.79 % wt. calculated on the total mass of granulate a) and powder b) and a lubricant, wherein further excipients are not present in the powder b).
All of the above embodiments and variants are workable with the following combination of dosages: 5 mg/16 mg/12.5 mg, 10 mg/16 mg/12.5 mg, 5 mg/32 mg/25 mg, 10 mg/32 mg/25 mg Amlodipine/Candesartan cilexetil/Hydrochlorothiazide.
In third most preferable embodiment the capsule of the present invention comprises one of the following variants of a quantitative composition:
In fourth most preferable embodiment the capsule of the present invention comprises one of the following quantitative compositions:
Experimental examples: The qualitative and quantitative compositions of the capsules according to the invention and comparative Examples are presented in the Tables below:
Candesartan cilexetil/Amlodipine/Hydrochlorothiazide capsules, hard, are produced according to the following manufacturing steps: weighing, preparation of granulation liquid, high-shear mixing of granulate a) components, granulation solution addition, wet massing, fluid bed drying, granulate screening, weighing, sieving the components of the powder b), blending the components of the powder b), blending the granulate a) with powder b) and final encapsulation.
In more detail:
• Weighing - Weigh the specified amount of candesartan granulate except for Hydroxypropylcellulose type LF, Water, Purified and Candesartan cilexetil separately into containers.
• Preparation of granulation solution - Add a specified amount of Hydroxypropylcellulose type LF into a container with Purified Water while stirring and mix
• High-shear mixing - Dose and mix granulate components using a high-shear mixer
• Granulation solution addition - Add granulation solution into granulate components blend using a pump
• Wet massing - Mix a wet granulate for additional time
• Fluid bed drying - Load wet granules into fluid bed dried to reduce water content in granulate below 3.0%. Do not exceed the product temperature over 45°C.
• Granulate screening - Screen dried granulate through the final screen size 0.5 - 0.8 mm to obtain the granulate in which not more than 30% of granules > 0.5 mm.
• Weighing - Weigh the calculated specified amount of Starch Pregelatinised (or MCC, DCP coprocessed starch for comparative examples), Magnesium Stearate, Amlodipine Besilate and Hy drochl orothi azi de .
• Sieving I - Dose Starch Pregelatinised (or MCC, DCP coprocessed starch for comparative examples), Amlodipine Besilate and Hydrochlorothiazide through the screen to the container with Candesartan granulate
• Blending I - Blend all components.
• Sieving II - Dose Magnesium Stearate through the screen to the container with previous blend.
• Blending II - Blend all components to obtain Candesartan cilexetil/Amlodipine/Hydrochlorothiazide encapsulation blend.
The blended granulate a) and powder b) fractions are packed into hard gelatin capsules size “0”
Table 5: composition of the capsules
q.s.p. quantitate sufficient per
In vitro dissolution study
Dissolution profiles of Amlodipine (AML), Hydrochlorothiazide (HCTZ) from tested and reference products were performed in 0.1M HC1, and Candesartan cilexetil (CAN) from tested and reference products were performed in phosphate buffer pH 6.8 with 0.35% Tween 20 (only for CAN), 37°C. The same conditions were applied for comparative Examples.
Table 6 Dissolution profiles conditions.
Dissolution tests were conducted for 12 dosage units of the following products:
- Candesartan cilexetil / Amlodipine / Hydrochlorothiazide capsule, hard, 16mg/10mg/12.5mg, of Example 1.2 according to the invention and
- Candesartan cilexetil / Amlodipine / Hydrochlorothiazide capsule, hard, 16mg/10mg/12.5mg, Examples 4.1 and 4.3 and 4.4 as Comparative Examples
- Norvasc 10 mg tablets, Batch No. EE3662,
- Esidrex 25 mg tablets, Batch No. F2055, half tablets were used for all the analyses (12.5mg)
- Atacand 16 mg tablets, Batch No ZBDU.
The dissolution studies were performed in respect to the current, official requirements and acceptance criteria for dissolution testing with fully validated HPLC methods for medium 0.1M HC1 for AML and HCTZ and for phosphate buffer pH 6.8 + 0.35% Tween 20 (for CAN only). Dissolution volume: 900 ml, Rotating speed: 100 rpm, Apparatus type: Ph. Eur. 1 - baskets,
Temperature: 37°C. Sampling time: 15 minutes for Amlodipine and Hydrochlorothiazide, 30 minutes for Candesartan cilexetil.
Table. 7 Dissolution profiles of Amlodipine from reference, comparative Example 4.4 and tested products; Ph. Eur. apparatus 1, 100 rpm, 900 ml, 0.1M HC1. Dissolution profile of Amlodipine from Candesartan cilexetil / Amlodipine/Hydrochlorothiazide capsule, hard 16mg/10mg/12.5mg, Batch No. 12565178 (Example 1.2), Ph. Eur. apparatus 1, 100 rpm, 900 ml, 0.1M HC1, 37°C.
Results obtained for compositions according to Comparative Examples 4.1 and 4.3 were consistent with those obtained for Example 4.4, i.e. deviating by no more than 2%.
Table. 8 Dissolution profiles of Hydrochlorothiazide from reference, comparative Example and tested products; Ph. Eur. apparatus 1, 100 rpm, 900 ml, 0.1M HC1. Dissolution profile of Hydrochlorothiazide from Candesartan cilexetil /Amlodipine/ Hydrochlorothiazide capsule, hard 16mg/10mg/12.5mg, Batch No. 12565178 (Example 1.2) and comparative Example 4.4; Batch No. CAH 24C Ph.Eur. apparatus 1, 100 rpm, 900 ml, 0.1M HC1, 37C.
Results obtained for compositions according to Comparative Examples 4.1 and 4.3 were consistent with those obtained for Example 4.4, i.e. deviating by no more than 2%.
Table 9. Dissolution profiles of Candesartan cilexetil from reference, comparison and tested products; Candesartan cilexetil from Candesartan cilexetil / Amlodipine/ Hydrochlorothiazide capsule, hard 16/10/12.5mg, Batch 12565178, (Example 1.2) and Comparative Example 4.4 (Batch CAH 24C), Ph.Eur. apparatus 1, 100 rpm, 900 ml, pH 6.8, 0.35% Tween 20, 37°C.
Results obtained for compositions according to Comparative Examples 4.1 and 4.3 were consistent with those obtained for Example 4.4, i.e. deviating by no more than 2%.
As it is seen from data presented above dissolved amounts of Amlodipine and Hydrochlorothiazide from Candesartan cilexetil/Amlodipine/Hydrochlorothiazide capsule, hard 16mg/10mg/12.5mg
and from reference products Norvasc 10 mg tablets and Esidrex 25mg half tablet - 12.5mg) tablets are above 85 % within 15 minutes. Thus the dissolution profiles of API from tested drugs (Example 1.2) are assumed similar to dissolution profiles of Amlodipine and Hydrochlorothiazide from corresponding reference drugs in 0.1M HC1 without further mathematical evaluation according to “ Guideline on the Investigation of Bioeijuivale nce'ICPMV ! VIV !QVIV ! \ 401 /98 Rev. 1/Corr).
As dissolved amount of Candesartan cilexetil in pH 6.8 + 0.35% Tween 20 buffer from tested and reference drug products is below 85 % within 15 minutes to compare two dissolution profiles further mathematical evaluation was performed. For this purpose F2 calculation method was applied. Obtained F2 values are as follows:
That proved similarity of Candesartan cilexetil dissolution profile from developed drug product Candesartan cilexetil/Amlodipine/Hydrochlorothiazide capsule, hard 16mg/10mg/12.5mg and from reference drug products Atacand 16 mg tablets.
Thus, the similarity of the dissolution profiles of Candesartan cilexetil/Amlodipine/ Hydrochlorothiazide capsule, hard 16mg/10mg/12.5mg to dissolution profiles of active substance from reference drug products Norvasc 10 mg tablets, Esidrex 25 mg tablets and Atacand 16 mg tablets has been confirmed .
Dissolution studies for comparative Examples (Examples 4.1, 4.3, 4.4, without pregelatinized starch in the powder fraction b)) resulted in lower profiles, i.e. less API was dissolved over a specified period of time comparing to the referents and to the inventive capsule of Example 1.2. The % RSD values obtained for Comparative Examples exceeded 25% and thus were unacceptable, because such compositions cannot serve as equivalent in respect to the therapy with the use of referent medicinal product. Thus, compositions without pregelatinized starch in powder fraction b) were excluded from further studies as unacceptable to provide candesartan, amlodipine and hydrochlorothiazide fixed dose combination resulting in medical effects comparable to the referents mono-products.
Stability studies
The stability studies of Candesartan cilexetil/Amlodipine/Hydrochlorothiazide capsule, hard, 16mg/10mg/12.5mg have been performed according to the guidelines CPMP/ICH/2736/99-ICH Q1A (R2) Stability Testing of New Drug Substances and Drug Products, CPMP/QWP/ 122/02 Rev. 1 corn Stability Testing of Existing Active Ingredients and Related Finished Products and EMA/CHMP/QWP/545525/2017 Guideline on the requirements for the chemical and pharmaceutical quality documentation concerning investigational medicinal products in clinical trials.
The stability of Candesartan cilexetil/Amlodipine/Hydrochlorothiazide capsule, hard, 16mg/10mg/12.5mg has been based on stability study for two batches of composition according to Example 1.2. The qualitative and quantitative composition, the manufacturing process and the packaging is the same for both stability batches.
No significant change has been observed during 1.5-month stability study.
In the related substances analysis, levels of degradation products have not exceeded the shelf-life limits from the specification. Assay of the active substances did not exceed the limits 95.0 % - 105.0 % from the label claim as well as 5 % from the initial point. Requirements for other tests such as: appearance and dissolution of active substances have been also fulfilled. There were no significant trends in these parameters.
Based on 1.5-month stability data, evaluated according to EMA/CHMP/QWP/545525/2017 Guideline on the requirements for the chemical and pharmaceutical quality documentation concerning investigational medicinal products in clinical trials, 6 months shelf-life for investigational medicinal product of Candesartan cilexetil/Amlodipine/Hydrochlorothiazide capsule, hard, 16mg/10mg/12.5mg may be proposed.
The 6 months stability studies in accelerated conditions confirm that the composition according to the invention is suitable to be used in human medicine. Compositions according to the invention revealed superior stability comparing to the comparative Examples not containing pregelatinized starch in the fraction b). Based on the stability and dissolution data, the fixed dose compositions according to the invention may be used as an alternative to the respective combination therapy based on administration of Candesartan cilexetil, Amlodipine and Hydrochlorothiazide in separate dosage forms. The compositions are obtained by simple and economic manufacturing process and will ensure better patients compliance comparing to adherence to 3 separate dosing regimens.
The bioequivalence study
The bioequivalence study was conducted in compliance with the Study Protocol and its Amendment 01, Declaration of Helsinki, International Council for Harmonisation (ICH), current Good Clinical Practice and Good Laboratory Practice guidelines, CHMP Guideline on the Investigation of Bioequivalence, Guideline on clinical development of fixed combination medicinal products, and other applicable international and national regulatory requirements and local laws.
Pharmacokinetic study was performed for Candesartan cilexetil/Amlodipine/Hydrochlorothiazide capsule, hard 16mg/ 10 mg/ 12.5 mg according to Example 1.2. The primary aim of the study was to evaluate the pharmacokinetic properties and to compare the bioavailability of the test investigational medicinal product (IMP) versus the reference medicinal products in healthy
volunteers under fasting conditions. The secondary study objective was to evaluate the safety of the test and reference medicinal products. The results of the study are presented in Tables A-F.
Pharmacokinetic Results Summary
Table A. Candesartan PK data for Candesartan cilexetil/Amlodipine/Hydrochlorothiazide capsule, hard 16mg/ 10 mg/ 12.5 mg according to Example 1.2; reference: Atacand 16 mg tablets.
Test: Candesartan cilexetil/Amlodipine/Hydrochlorothiazide capsule, hard 16 mg/ 10 mg/ 12.5 mg; Batch No / Size: 12568203/320000 capsules, hard; Manufactured by: Adamed Pharma S.A., Poland
Reference: Atacand 16 mg tablets; Batch No: ZBDU; Manufactured by: Takeda Pharmaceutical Company Ltd., Japan; Current Marketing Authorization Holder: CHEPLAPHARM Arzneimittel GmbH, Germany, Former Marketing Authorization Holder: AstraZeneca AB, Sweden.
Table B. Amlodipine PK data for Candesartan cilexetil/Amlodipine/Hydrochlorothiazide capsule, hard 16mg/ 10 mg/ 12.5 mg according to Example 1.2; reference: Norvasc 10 mg tablets.
Test: Candesartan cilexetil/Amlodipine/Hydrochlorothiazide capsule, hard 16 mg/ 10 mg/ 12.5 mg; Batch No / Size: 12568203/320000 capsules, hard; Manufactured by: Adamed Pharma S.A., Poland
Reference: Norvasc 10 mg tablets; Batch No: EE3662; Manufactured by: Pfizer Manufacturing Deutschland GmbH, Germany; Current Marketing Authorization Holder: Upjohn EESV, the Netherlands; Former Marketing Authorization Holder: Pfizer Europe MA EEIG, Belgium
Table C. Hydrochlorothiazide PK data for Candesartan cilexetil/Amlodipine/Hydrochlorothiazide capsule, hard 16mg/ 10 mg/ 12.5 mg according to Example 1.2; reference: Esidrex 25 mg tablets (half tablet containing 12.5 mg of hydrochlorothiazide).
Test: Candesartan cilexetil/Amlodipine/Hydrochlorothiazide capsule, hard 16 mg/ 10 mg/ 12.5 mg; Batch No / Size: 12568203/320000 capsules, hard; Manufactured by: Adamed Pharma S.A., Poland
Reference: Esidrex 25 mg tablets; Batch No: F2055; Manufactured by: Cenexi, France; Marketing Authorization Holder: Laboratories Juvise Pharmaceuticals, France
Bioequivalence Results Summary
Table D. Candesartan bioequivalence evaluation for Candesartan cilexetil/ Amlodipine/Hydrochlorothiazide capsule, hard 16mg/ 10 mg/ 12.5 mg according to Example 1.2;, reference: Atacand 16 mg tablets.
Test: Candesartan cilexetil/Amlodipine/Hydrochlorothiazide capsule, hard 16 mg/ 10 mg/ 12.5 mg; Batch No / Size: 12568203/320 000 capsules, hard; Manufactured by: Adamed Pharma S.A., Poland
Reference: Atacand 16 mg tablets; Batch No: ZBDU; Manufactured by: Takeda Pharmaceutical Company Ltd., Japan; Current Marketing Authorization Holder: CHEPLAPHARM Arzneimittel GmbH, Germany, Former Marketing Authorization Holder: AstraZeneca AB, Sweden Table E. Amlodipine bioequivalence evaluation for Candesartan cilexetil/Amlodipine/ Hydrochlorothiazide capsule, hard 16mg/ 10 mg/ 12.5 mg according to Example 1.2;, reference: Norvasc 10 mg tablets.
Test: Candesartan cilexetil/Amlodipine/Hydrochlorothiazide capsule, hard 16 mg/ 10 mg/ 12.5 mg; Batch No / Size: 12568203/320 000 capsules, hard; Manufactured by: Adamed Pharma S.A., Poland
Reference: Norvasc 10 mg tablets; Batch No: EE3662; Manufactured by: Pfizer Manufacturing Deutschland GmbH, Germany; Current Marketing Authorization Holder: Upjohn EESV, the Netherlands; Former Marketing Authorization Holder: Pfizer Europe MA EEIG, Belgium
Table F. Hydrochlorothiazide bioequivalence evaluation for Candesartan cilexetil/ Amlodipine/Hydrochlorothiazide capsule, hard 16mg/ 10 mg/ 12.5 mg according to Example 1.2;, reference: Esidrex 25 mg tablets (half tablet containing 12.5 mg of hydrochlorothiazide).
Test: Candesartan cilexetil/Amlodipine/Hydrochlorothiazide capsule, hard 16 mg/ 10 mg/ 12.5 mg; Batch No / Size: 12568203/320 000 capsules, hard; Manufactured by: Adamed Pharma S.A., Poland
Reference: Esidrex 25 mg tablets; Batch No: F2055; Manufactured by: Cenexi, France; Marketing Authorization Holder: Laboratories Juvise Pharmaceuticals, France
Conclusion: The Test product Candesartan cilexetil/Amlodipine/Hydrochlorothiazide capsule, hard 16mg/ 10 mg/ 12.5 mg according to Example 1.2demonstrated a comparable extent and rate of absorption of Candesartan to the Reference product Atacand 16 mg tablets with Test/Reference (T/R) geometric mean ratios (GMR) of approximately 100% and 89% for AUQo- t) and Cmax, respectively and with the corresponding 90% CIs contained within the EMA- acceptance range 80.00% - 125.00%.
The Test product Candesartan cilexetil/Amlodipine/Hydrochlorothiazide capsule, hard 16mg/ 10 mg/ 12.5 mg according to Example 1.2demonstrated a comparable extent and rate of absorption of Amlodipine to the Reference product Norvasc 10 mg tablets with Test/Reference (T/R) geometric mean ratios (GMR) of approximately 104% and 102% for AUC(o-72h) and Cmax, respectively and with the corresponding 90% CIs contained within the EMA-acceptance range 80.00% - 125.00%.
The Test product Candesartan cilexetil/Amlodipine/Hydrochlorothiazide capsule, hard 16mg/ 10 mg/ 12.5 mg according to Example 1.2demonstrated a comparable extent and rate of absorption of Hydrochlorothiazide to the Reference product Esidrex 25 mg tablets (half tablet containing 12.5 mg of hydrochlorothiazide) with Test/Reference (T/R) geometric mean ratios (GMR) of approximately 101% and 115% for AUQo-t) and Cmax, respectively and with the corresponding 90% CIs contained within the EMA-acceptance range 80.00% - 125.00%.
Hence, the study proved bioequivalence of the test and the reference medicinal products as assessed by the amount of candesartan, amlodipine and hydrochlorothiazide present in plasma as described by AUQo-t) (candesartan and hydrochlorothiazide) and AUC(o-72h) (amlodipine) as well as by the absorption rate given by Cmax. The 90% confidence intervals of the parameters AUQo-t),
AUC(0-72h) and Cmax were found well within the required standard bioequivalence acceptance range of 80.00% to 125.00%. This study also demonstrated that the test product Candesartan cilexetil/Amlodipine/Hydrochlorothiazide capsule, hard 16 mg/ 10 mg/ 12.5 mg given in a single dose has a good safety and tolerability profile.
Claims
1. A pharmaceutical composition in the form of hard capsules comprising a) a granulate comprising Candesartan cilexetil and polyethylene glycol in the weight ratio in a range of 4.4 to 6.5 and optionally further excipients, b)a powder comprising Amlodipine, Hydrochlorothiazide, pregelatinized starch and optionally further excipients
2. The pharmaceutical composition according to claim 1 comprising a) a granulate comprising Candesartan cilexetil and polyethylene glycol in the weight ratio in a range of 4.4 to 6.5 and one or more disintegrants, one or more binders, one or more fillers, one or more stabilizers and optionally one or more glidants b)a powder comprising Amlodipine, Hydrochlorothiazide, pregelatinized starch and optionally further excipients
3. The pharmaceutical composition according to claim 1 or 2 comprising a) a granulate comprising Candesartan cilexetil and polyethylene glycol selected from Macrogol 8000 or Macrogol 6000 in the weight ratio in a range of 4.8 to 6.15 and optionally further excipients, b) a powder comprising Amlodipine, Hydrochlorothiazide, pregelatinized starch and a lubricant as further excipients.
4. The pharmaceutical composition according to claim 3 comprising a) a granulate comprising Candesartan cilexetil and polyethylene glycol selected from Macrogol 8000 or Macrogol 6000 in the weight ratio in a range of 4.8 to 6.15 and optionally further excipients, b)a powder comprising Amlodipine, Hydrochlorothiazide, pregelatinized starch in the amount of 9 to 70% wt. calculated on the total mass of granulate a) and powder b) and a lubricant as further excipients
5. The pharmaceutical composition according to claims 3 or 4 comprising a) a granulate comprising Candesartan cilexetil and polyethylene glycol selected from Macrogol 8000 or Macrogol 6000 in the weight ratio of 6.15 and optionally further excipients, b)a powder comprising Amlodipine, Hydrochlorothiazide, pregelatinized starch in the amount of 9 to 30% wt., especially in the amount of 9.5 to 9.8 % wt. calculated on the total mass of granulate a) and powder b) and a lubricant as further excipients
6. The pharmaceutical composition according to claims 3 to 5 comprising a) a granulate comprising Candesartan cilexetil and polyethylene glycol selected from Macrogol 8000 in the weight ratio of 6.15 and optionally further excipients,
b)a powder comprising Amlodipine, Hydrochlorothiazide, pregelatinized starch in the amount of 9.59 or 9.79 % wt. calculated on the total mass of granulate a) and powder b) and a lubricant as further excipients
7. The pharmaceutical composition according to claim 6 comprising a) a granulate comprising Candesartan cilexetil and polyethylene glycol selected from Macrogol 8000 in the weight ratio of 6.15 and optionally further excipients, b)a powder comprising Amlodipine, Hydrochlorothiazide, pregelatinized starch in the amount of 9.59 or 9.79 % wt. calculated on the total mass of granulate a) and powder b) and a lubricant, wherein further excipients are not present in the powder b).
8. The pharmaceutical composition according to any preceding claims comprising combination of dosages of Amlodipine, Candesartan cilexetil and Hydrochlorothiazide accordingly: 5 mg/16 mg/12.5 mg, 10 mg/16 mg/12.5 mg, 5 mg/32 mg/25 mg, 10 mg/32 mg/25 mg
9. The pharmaceutical composition according to any preceding claims comprising one of the following quantitative compositions:
10. The pharmaceutical composition according to any preceding claims comprising one of the following quantitative compositions:
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP21185961 | 2021-07-15 | ||
| PCT/EP2022/069840 WO2023285646A1 (en) | 2021-07-15 | 2022-07-15 | A pharmaceutical composition comprising amlodipine, candesartan cilexetil and hydrochlorothiazide for the treatment of hypertension |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| EP4370101A1 true EP4370101A1 (en) | 2024-05-22 |
Family
ID=76958729
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP22751065.8A Pending EP4370101A1 (en) | 2021-07-15 | 2022-07-15 | A pharmaceutical composition comprising amlodipine, candesartan cilexetil and hydrochlorothiazide for the treatment of hypertension |
Country Status (2)
| Country | Link |
|---|---|
| EP (1) | EP4370101A1 (en) |
| WO (1) | WO2023285646A1 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GR1010675B (en) * | 2023-02-17 | 2024-04-23 | Ιουλια Κλεωνος Τσετη | Orally administrated anti-hypertension drug composed of a triple combination of an ace inhibitor, a calcium antagonist and a diuretic composition |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3163645A (en) | 1964-09-25 | 1964-12-29 | Ciba Geigy Corp | Derivatives of 3, 4-dihydro-2-h-[1, 2, 4]-benzothiadiazine-1, 1-dioxides |
| GB8608335D0 (en) | 1986-04-04 | 1986-05-08 | Pfizer Ltd | Pharmaceutically acceptable salts |
| US5196444A (en) | 1990-04-27 | 1993-03-23 | Takeda Chemical Industries, Ltd. | 1-(cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate and compositions and methods of pharmaceutical use thereof |
| CN101584700A (en) | 2009-07-20 | 2009-11-25 | 王素云 | A kind of pharmaceutical composition |
| CN102342942B (en) | 2011-07-14 | 2016-08-31 | 海南锦瑞制药有限公司 | A kind of New oral solid medicinal compositions and preparation method thereof |
| WO2016102705A1 (en) * | 2014-12-24 | 2016-06-30 | Krka, D.D., Novo Mesto | Pharmaceutical composition comprising candesartan or pharmaceutically acceptable salts or esters thereof and amlodipine or pharmaceutically acceptable salts thereof |
| CZ2015687A3 (en) | 2015-10-02 | 2017-04-12 | Zentiva, K.S. | A pharmaceutical composition comprising a combination of candesartan, amlodipine and hydrochlorothiazide |
| EP3219309A1 (en) | 2016-03-17 | 2017-09-20 | K.H.S. Pharma Holding GmbH | Fixed dosed pharmaceutical composition comprising amlodipine, candesartan cilexetil and hydrochlorothiazide for the treatment of hypertension |
-
2022
- 2022-07-15 WO PCT/EP2022/069840 patent/WO2023285646A1/en active Application Filing
- 2022-07-15 EP EP22751065.8A patent/EP4370101A1/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| WO2023285646A1 (en) | 2023-01-19 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| AU2016208417B2 (en) | Therapeutic compositions comprising rilpivirine HCl and tenofovir disoproxil fumarate | |
| AU2009349125B2 (en) | Solid pharmaceutical fixed dose compositions comprising irbesartan and amlodipine, their preparation and their therapeutic application | |
| MXPA05006513A (en) | Solid drug for oral use. | |
| KR101665641B1 (en) | Composite formulation comprising tadalafil and amlodipine | |
| JP2002326927A (en) | Quick-releasing tablet containing metformin hydrochloride | |
| KR20210084053A (en) | Pharmaceutical composite formulation comprising empagliflozin and metformin and method for manufacturing the same | |
| AU2013365715B2 (en) | A pharmaceutical composition containing candesartan cilexetil and amlodipine | |
| US20030124186A1 (en) | Efavirenz tablet formulation having unique biopharmaceutical characteristics | |
| EA029586B1 (en) | Pharmaceutical composition for treatment of hiv infections | |
| EP4370101A1 (en) | A pharmaceutical composition comprising amlodipine, candesartan cilexetil and hydrochlorothiazide for the treatment of hypertension | |
| AU2014332200B2 (en) | HIV treatment formulation of atazanavir and cobicistat | |
| HUE034564T2 (en) | Prasugrel-containing immediate release stable oral pharmaceutical compositions | |
| EP2538924B1 (en) | Solid pharmaceutical formulations of ramipril and amlodipine besylate, and their preparation | |
| US20230263777A1 (en) | Stable solid formulation of azilsartan or pharmaceutically acceptable salts thereof | |
| US20110305757A1 (en) | New pharmaceutical combinations | |
| Yasmeen et al. | Comparative study of different formulations of atenolol | |
| HU231052B1 (en) | Stable pharmaceutical composition containing bisoprolol and ramipril | |
| CN102614188A (en) | Capsule containing valsartan, levoamlodipine and hydrochlorothiazide and preparing method thereof | |
| RU2760129C1 (en) | Solid pharmaceutical composition for manufacturing oral antiretroviral therapeutic agent | |
| Arunkumar et al. | Formulation and evaluation of bilayer matrix tablets of nebivolol hydrochloride and valsartan | |
| RU2759544C1 (en) | Solid pharmaceutical composition for manufacture of oral therapeutic agent for prevention and/or treatment of hiv infection | |
| RU2359672C1 (en) | Solid medicinal form intended for treatment of arterial hypertensia and stenocardia, and way of its reception | |
| WO2024047208A1 (en) | Anticoagulant therapy with an improved dosage regimen | |
| GR1010320B (en) | Solid pharmaceutical forms of irbesartan, hydrochlorothiazine and amlodipine | |
| WO2022132067A1 (en) | Stable bilayer tablet compositions |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: UNKNOWN |
|
| STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE INTERNATIONAL PUBLICATION HAS BEEN MADE |
|
| PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
| STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: REQUEST FOR EXAMINATION WAS MADE |
|
| 17P | Request for examination filed |
Effective date: 20240205 |
|
| AK | Designated contracting states |
Kind code of ref document: A1 Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR |
|
| DAV | Request for validation of the european patent (deleted) | ||
| DAX | Request for extension of the european patent (deleted) |