WO2023285646A1 - 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 hypertension Download PDFInfo
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- WO2023285646A1 WO2023285646A1 PCT/EP2022/069840 EP2022069840W WO2023285646A1 WO 2023285646 A1 WO2023285646 A1 WO 2023285646A1 EP 2022069840 W EP2022069840 W EP 2022069840W WO 2023285646 A1 WO2023285646 A1 WO 2023285646A1
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- Prior art keywords
- amlodipine
- hydrochlorothiazide
- candesartan cilexetil
- granulate
- powder
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- 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
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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:
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP22751065.8A EP4370101A1 (en) | 2021-07-15 | 2022-07-15 | A pharmaceutical composition comprising amlodipine, candesartan cilexetil and hydrochlorothiazide for the treatment of hypertension |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP21185961 | 2021-07-15 | ||
| EP21185961.6 | 2021-07-15 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2023285646A1 true WO2023285646A1 (en) | 2023-01-19 |
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ID=76958729
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/EP2022/069840 Ceased WO2023285646A1 (en) | 2021-07-15 | 2022-07-15 | A pharmaceutical composition comprising amlodipine, candesartan cilexetil and hydrochlorothiazide for the treatment of hypertension |
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| EP (1) | EP4370101A1 (en) |
| WO (1) | WO2023285646A1 (en) |
Cited By (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 |
Citations (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 |
| EP0244944A2 (en) | 1986-04-04 | 1987-11-11 | Pfizer Limited | Salts of amlodipine |
| EP0459136A1 (en) | 1990-04-27 | 1991-12-04 | Takeda Chemical Industries, Ltd. | Benzimidazole derivatives, their production and use |
| CN101584700A (en) | 2009-07-20 | 2009-11-25 | 王素云 | A kind of pharmaceutical composition |
| CN102342942A (en) | 2011-07-14 | 2012-02-08 | 海南锦瑞制药股份有限公司 | Novel oral solid medicinal composition 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 |
| WO2017054787A1 (en) | 2015-10-02 | 2017-04-06 | Zentiva, K.S. | Pharmaceutical composition comprising the combination of candesartan, amlodipine and hydrochlorothiazide |
| WO2017158094A1 (en) | 2016-03-17 | 2017-09-21 | K.H.S. Pharma Holding Gmbh | Fixed dosed pharmaceutical composition comprising amiodipine, candesartan cilexetil and hydrochlorothiazide for the treatment of hypertension. |
-
2022
- 2022-07-15 EP EP22751065.8A patent/EP4370101A1/en not_active Withdrawn
- 2022-07-15 WO PCT/EP2022/069840 patent/WO2023285646A1/en not_active Ceased
Patent Citations (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 |
| EP0244944A2 (en) | 1986-04-04 | 1987-11-11 | Pfizer Limited | Salts of amlodipine |
| EP0459136A1 (en) | 1990-04-27 | 1991-12-04 | Takeda Chemical Industries, Ltd. | Benzimidazole derivatives, their production and use |
| CN101584700A (en) | 2009-07-20 | 2009-11-25 | 王素云 | A kind of pharmaceutical composition |
| CN102342942A (en) | 2011-07-14 | 2012-02-08 | 海南锦瑞制药股份有限公司 | Novel oral solid medicinal composition 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 |
| WO2017054787A1 (en) | 2015-10-02 | 2017-04-06 | Zentiva, K.S. | Pharmaceutical composition comprising the combination of candesartan, amlodipine and hydrochlorothiazide |
| WO2017158094A1 (en) | 2016-03-17 | 2017-09-21 | K.H.S. Pharma Holding Gmbh | Fixed dosed pharmaceutical composition comprising amiodipine, candesartan cilexetil and hydrochlorothiazide for the treatment of hypertension. |
Cited By (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 |
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| EP4370101A1 (en) | 2024-05-22 |
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