WO2023285646A1 - Composition pharmaceutique comprenant de l'amlodipine, du candésartan cilexetil et de l'hydrochlorothiazide pour le traitement de l'hypertension - Google Patents

Composition pharmaceutique comprenant de l'amlodipine, du candésartan cilexetil et de l'hydrochlorothiazide pour le traitement de l'hypertension Download PDF

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Publication number
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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WO
WIPO (PCT)
Prior art keywords
amlodipine
hydrochlorothiazide
candesartan cilexetil
granulate
powder
Prior art date
Application number
PCT/EP2022/069840
Other languages
English (en)
Inventor
Joanna RZASA
Stephanie Cadonau
Original Assignee
Adamed Pharma S.A
Midas Pharma GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Adamed Pharma S.A, Midas Pharma GmbH filed Critical Adamed Pharma S.A
Priority to EP22751065.8A priority Critical patent/EP4370101A1/fr
Publication of WO2023285646A1 publication Critical patent/WO2023285646A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—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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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
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  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
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Abstract

La présente invention concerne des compositions pharmaceutiques à dose fixe sous la forme de capsules dures comprenant de l'amlodipine, du candésartan cilexetil et de l'hydrochlorothiazide pour le traitement de l'hypertension.
PCT/EP2022/069840 2021-07-15 2022-07-15 Composition pharmaceutique comprenant de l'amlodipine, du candésartan cilexetil et de l'hydrochlorothiazide pour le traitement de l'hypertension WO2023285646A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP22751065.8A EP4370101A1 (fr) 2021-07-15 2022-07-15 Composition pharmaceutique comprenant de l'amlodipine, du candésartan cilexetil et de l'hydrochlorothiazide pour le traitement de l'hypertension

Applications Claiming Priority (2)

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EP21185961.6 2021-07-15
EP21185961 2021-07-15

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WO2023285646A1 true WO2023285646A1 (fr) 2023-01-19

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GR1010675B (el) * 2023-02-17 2024-04-23 Ιουλια Κλεωνος Τσετη Τριπλος συνδυασμος αντι-υπερτασικων φαρμακων αναστολεα μεα, ανταγωνιστη ασβεστιου και διουρητικης ενωσης για ταυτοχρονη απο του στοματος χορηγηση

Citations (8)

* Cited by examiner, † Cited by third party
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 (fr) 1986-04-04 1987-11-11 Pfizer Limited Sels d'amlodipine
EP0459136A1 (fr) 1990-04-27 1991-12-04 Takeda Chemical Industries, Ltd. Dérivés de benzimidazole, leur préparation et utilisation
CN101584700A (zh) 2009-07-20 2009-11-25 王素云 一种药物组合物
CN102342942A (zh) 2011-07-14 2012-02-08 海南锦瑞制药股份有限公司 一种全新口服固体药用组合物及其制备方法
WO2016102705A1 (fr) * 2014-12-24 2016-06-30 Krka, D.D., Novo Mesto Composition pharmaceutique comprenant du candésartan ou des sels ou esters pharmaceutiquement acceptables de ce dernier, et de l'amlodipine ou des sels pharmaceutiquement acceptables de ce dernier
WO2017054787A1 (fr) 2015-10-02 2017-04-06 Zentiva, K.S. Composition pharmaceutique comprenant la combinaison de candésartan, d'amlopidine et d'hydrochlorothiazide
WO2017158094A1 (fr) 2016-03-17 2017-09-21 K.H.S. Pharma Holding Gmbh Composition pharmaceutique à doses fixes comprenant de l'amiodipine, du candésartan cilexétil et de l'hydrochlorothiazide pour le traitement de l'hypertension

Patent Citations (8)

* Cited by examiner, † Cited by third party
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 (fr) 1986-04-04 1987-11-11 Pfizer Limited Sels d'amlodipine
EP0459136A1 (fr) 1990-04-27 1991-12-04 Takeda Chemical Industries, Ltd. Dérivés de benzimidazole, leur préparation et utilisation
CN101584700A (zh) 2009-07-20 2009-11-25 王素云 一种药物组合物
CN102342942A (zh) 2011-07-14 2012-02-08 海南锦瑞制药股份有限公司 一种全新口服固体药用组合物及其制备方法
WO2016102705A1 (fr) * 2014-12-24 2016-06-30 Krka, D.D., Novo Mesto Composition pharmaceutique comprenant du candésartan ou des sels ou esters pharmaceutiquement acceptables de ce dernier, et de l'amlodipine ou des sels pharmaceutiquement acceptables de ce dernier
WO2017054787A1 (fr) 2015-10-02 2017-04-06 Zentiva, K.S. Composition pharmaceutique comprenant la combinaison de candésartan, d'amlopidine et d'hydrochlorothiazide
WO2017158094A1 (fr) 2016-03-17 2017-09-21 K.H.S. Pharma Holding Gmbh Composition pharmaceutique à doses fixes comprenant de l'amiodipine, du candésartan cilexétil et de l'hydrochlorothiazide pour le traitement de l'hypertension

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GR1010675B (el) * 2023-02-17 2024-04-23 Ιουλια Κλεωνος Τσετη Τριπλος συνδυασμος αντι-υπερτασικων φαρμακων αναστολεα μεα, ανταγωνιστη ασβεστιου και διουρητικης ενωσης για ταυτοχρονη απο του στοματος χορηγηση

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