WO2022132067A1 - Compositions de comprimés bicouches stables - Google Patents

Compositions de comprimés bicouches stables Download PDF

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Publication number
WO2022132067A1
WO2022132067A1 PCT/TR2020/051333 TR2020051333W WO2022132067A1 WO 2022132067 A1 WO2022132067 A1 WO 2022132067A1 TR 2020051333 W TR2020051333 W TR 2020051333W WO 2022132067 A1 WO2022132067 A1 WO 2022132067A1
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WO
WIPO (PCT)
Prior art keywords
bilayer tablet
tablet composition
pharmaceutically acceptable
composition according
layer
Prior art date
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PCT/TR2020/051333
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English (en)
Inventor
Erol KIRESEPI
Ersin Yildirim
Original Assignee
Santa Farma Ilac Sanayii A.S.
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Publication date
Application filed by Santa Farma Ilac Sanayii A.S. filed Critical Santa Farma Ilac Sanayii A.S.
Priority to PCT/TR2020/051333 priority Critical patent/WO2022132067A1/fr
Publication of WO2022132067A1 publication Critical patent/WO2022132067A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer

Definitions

  • the present invention relates to a bilayer tablet composition
  • a bilayer tablet composition comprising candesartan or pharmaceutically acceptable forms, amlodipine or a pharmaceutically acceptable salt thereof, and hydrochlorothiazide, wherein amlodipine and hydrochlorothiazide, wherein candesartan or pharmaceutically acceptable salt is present in a separate layer with optimized ratio range for polyethylene glycol and disintegrant is between 1:3 to 1:5.
  • Hypertension is one of the most serious health problems in the world, and which is regarded as one of the most common diseases associated with significant cardiovascular morbidity and mortality.
  • Current hypertension guidelines draw the attention the need to treat even small elevations of blood pressure, particularly in high-risk patients such as those with diabetes and/or renal disease.
  • effectiveness of monotherapy may be limited, since multiple mechanisms are involved in the pathogenesis of hypertension and pathophysiologic characteristics differ among patients and it is required to the multiple administration.
  • combination of antihypertensive agents has been widely used for many years to create greater synergic effect.
  • Candesartan is an atypical antagonist of angiotensin II receptor with specific selectivity against ATI receptors and is used for the treatment of high blood pressure (hypertension) and heart failure.
  • the chemical name is ethoxy- 1 -[[2’ -(lH-tetrazol5-yl)[ 1,1’ -biphenyl] -4-yl] methyl]- 1H- benzimidazole-7-carboxylic acid.
  • the empirical formula of candesartan is C24H20N6O3 and molecular weight 440.45 g/mole.
  • the chemical structure of candesartan is shown in the Formula I.
  • candesartan is used as the ester prodrug of candesartan cilexetil in order to eliminate its poorly bioavailability that is approximately 40% after oral administration.
  • the empirical formula of candesartan cilexetil is C33H34N6O6 and its relative molecular mass is 610.67 mg/mol. It is a white to off-white powder, and is practically insoluble in water and sparingly soluble in methanol.
  • Candesartan base and its pharmaceutically acceptable salt thereof was disclosed for the first time in EP459136 numbered patent document by Takeda Chemical Industries, in which it also disclosed the process for the preparation of candesartan cilexetil and many pharmaceutical compositions comprising candesartan and candesartan cilexetil.
  • a pharmaceutical final product comprising candesartan cilexetil as an active substance was firstly commercially authorized by the FDA Food & Drug Administration in June 1998 for the treatment of hypertension in adults.
  • candesartan can be also available in a combination formulation with hydrochlorothiazide to achieve an additive antihypertensive effect.
  • Takeda Chemical Industries and AstraZeneca also developed a fixed dose combination of candesartan cilexetil and hydrochlorothiazide for the treatment of high blood pressure.
  • the fixed dose is currently marketed as non-film-coated tablet under the name of the ATACAND PLUS® in the strengths of 8 /12.5 mg, 16 /12.5 mg, 32/12.5 mg and 32/25 mg.
  • Hydrochlorothiazide is a thiazide diuretic and is used for the treatment of edema and hypertension.
  • the chemical name is 6-chloro-3,4-dihydro-2H-l,2,4-benzothiadiazine-7- sulfonamide 1,1 -dioxide.
  • the empirical formula of hydrochlorothiazide is C7H8CIN3O4S2 and its relative molecular mass is 297.72 mg/mol. It is a white or practically white crystalline powder, and is slightly soluble in water, but freely soluble in sodium hydroxide solution.
  • the chemical structure of hydrochlorothiazide is shown in the Formula II.
  • Hydrochlorothiazide base and its pharmaceutically manufacturing method was first disclosed in US3025292 number patent document.
  • a pharmaceutical final product comprising hydrochlorothiazide as an active substance was first approved by the FDA Food &Drug Administration in February 1959 and has been launched under the name of the ESIDRIX® in the strengths of 25 mg and 50 mg.
  • Amlodipine is one of the most common prescribed drug which is used for the treatment of ischemic and hypertensive heart diseases as being a calcium channel blocker.
  • the chemical name is 3-ethyl 5-methyl (4RS)-2-[(2-amino-ethoxy)-methyl]-6-methyl-l,4- dihydropyridine3,5-dicarboxylate.
  • the empirical formula of amlodipine is C20H25CIN2O5 and molecular weight is 408.876 g/mole.
  • the chemical structure of amlodipine is shown in the Formula III.
  • amlodipine is used as its besylate salt.
  • the empirical formula of amlodipine besylate is C20H25CIN2O5.C6H6O3S and its relative molecular mass is 567.1 mg/mol. It is a white crystalline powder, and is slightly soluble in water and sparingly soluble in ethanol.
  • Amlodipine base and its pharmaceutically acceptable acid addition salts thereof was disclosed for the first time in EP89167 numbered patent document by Pfizer Limited.
  • a pharmaceutical final product comprising amlodipine besylate as an active substance was firstly commercially authorized by the FDA Food & Drug Administration in 1987 and it has been launched under the name of the NORVASC® in the strengths of 2.5 mg, 5 mg and 10 mg.
  • NORVASC® is used be used alone or in combination with other antihypertensive and antianginal agents for the treatment of hypertension and coronary artery disease.
  • amlodipine with candesartan cilexetil and hydrochlorothiazide was developed by Nobel Ilac for the treatment of essential hypertension. It has been launched under the name of the TANSIFA PLUS® in strength of 16 mg candesartan cilexetil/6.94 mg amlodipine besylate /12.5 mg hydrochlorothiazide.
  • EP3219309 relates to fixed dose pharmaceutical compositions comprising candesartan cilexetil and a first matrix of excipients, and amlodipine and a second matrix of excipients comprising at least one filler, and wherein hydrochlorothiazide may be comprised in either matrix.
  • WO2017158094 relates to a fixed dose pharmaceutical composition comprising the active substances candesartan cilexetil, amlodipine and hydrochlorothiazide for the treatment of hypertension.
  • WO2017054787 relates to a pharmaceutical composition
  • a pharmaceutical composition comprising candesartan or a pharmaceutically acceptable salt thereof and hydrochlorothiazide are in the first layer and amlodipine or a pharmaceutically acceptable salt thereof in the second layer.
  • TR2015/03831 relates to solid oral pharmaceutical composition
  • solid oral pharmaceutical composition comprising candesartan or a pharmaceutically acceptable salt thereof, amlodipine or a pharmaceutically acceptable salt thereof, and hydrochlorothiazide or a pharmaceutically acceptable salt thereof, and wherein there is any contact between candesartan and amlodipine.
  • EP2934488 relates to a combination pharmaceutical composition
  • a combination pharmaceutical composition comprising a granulate consisting of candesartan cilexetil, polyethylene glycol and other excipients wherein the weight ratio of candesartan cilexetil to polyethylene glycol is in a range from 5.0: 1.0 to 2.0: 1.0, and wherein an extragranular phase consisting of amlodipine and other excipients.
  • WO2016122256 relates to a pharmaceutical composition
  • a pharmaceutical composition comprising candesartan cilexetil, amlodipine or a pharmaceutically acceptable salt thereof, and sugar alcohol, wherein the sugar alcohol is included in an amount of 50 weight % or less with respect to the total weight of the composition.
  • WO2018062685 relates to a pharmaceutical composition
  • a pharmaceutical composition comprising candesartan cilexetil, amlodipine or a pharmaceutically acceptable salt thereof, triethyl citrate as a stabilizer; and mannitol as a filler.
  • EP3236950 relates to a pharmaceutical composition
  • a pharmaceutical composition comprising; at least one portion comprising a granulated blend comprising candesartan or pharmaceutically acceptable salts or esters thereof and a specific single type binder that is added in the form, of an aqueous solution and, at least one another portion which is a powder blend or a granulate comprising amlodipine or pharmaceutically acceptable salts thereof, and wherein the composition is in form of multilayer tablets, preferably in the form of bilayer tablets.
  • EP2106789 relates to a solid pharmaceutical composition
  • a solid pharmaceutical composition comprising candesartan or a salt, solvate or ester thereof, a polymeric agent comprising a copolymer of polyvinyl alcohol and polyethylene glycol, and optionally at least one other excipient as well as a process for preparing the composition.
  • compositions comprising candesartan or pharmaceutically acceptable forms, in combination with amlodipine or one of its pharmaceutically acceptable salt thereof and hydrochlorothiazide in order to obtain a fixed oral dosage form by eliminating the stability problem of candesartan, amlodipine and hydrochlorothiazide when they are used with some excipients into a ph armaceu deal compo sition .
  • Candesartan cilexetil is stable against temperature, moisture and light in the presence of being alone solid state. However, this stability is decreased during time due to deformation of crystals when it is prepared into tablets. Thus, a number of different excipients are often added to the composition to solve the problem.
  • amlodipine is known to be incompatible with some commonly used excipients, and also, it is sensitive to hydrolysis when it is exposed to an alkaline medium like hydrochlorothiazide .
  • the fixed dose composition comprising candesartan or pharmaceutically acceptable salts and other two active substances amlodipine or pharmaceutically acceptable salts and hydrochlorothiazide or pharmaceutically acceptable salts are present in separate layers. Further, in the first layer the amount ratio between stabilizer and disintegrants, named as polyethylene glycol and the combination of corn starch and carmellose calcium respectively is 1:3 to 1:5.
  • the object of this invention is to provide pharmaceutical composition comprising candesartan or pharmaceutically acceptable salts, amlodipine or pharmaceutically acceptable salts and hydrochlorothiazide or pharmaceutically acceptable salts as active ingredients, wherein at least one active ingredient is present separate layer.
  • It is an object of the present invention is to develop pharmaceutical composition comprising candesartan or pharmaceutically acceptable forms, amlodipine or pharmaceutically acceptable salts and hydrochlorothiazide as active substances, which are used for the treatment of essential hypertension.
  • Candesartan is known for its low bioavailability and high tendency to promote the degradation as it is incorporated into a pharmaceutical composition.
  • amlodipine is also sensitive to degradation when it is incorporated with some excipients used in the preparations. Thus, active substances of candesartan and amlodipine are separated from each other.
  • the present invention relates to provide a pharmaceutical composition designed as bilayer tablet dosage form.
  • the present invention relates to provide a pharmaceutical composition designed as bilayer tablet dosage form by using manufacturing method.
  • Another object of the present invention is to develop a bilayer tablet composition
  • a bilayer tablet composition comprising two layers wherein candesartan or pharmaceutically acceptable salts present in the first layer with at least one pharmaceutically acceptable excipient and amlodipine or pharmaceutically acceptable salts and hydrochlorothiazide or pharmaceutically acceptable salts with at least one pharmaceutically acceptable excipient in the second layer.
  • one of the active substance is the ester prodrug of candesartan, preferably it is candesartan cilexetil and one of the other active substance is amlodipine besylate salt, other active substance is hydrochlorothiazide.
  • Another object of the present invention is to provide a composition designed as bilayer tablet wherein the first layer comprises candesartan cilexetil and diluent, binder, stabilizer, disintegrant, colorant, lubricant, and solvent as pharmaceutically acceptable excipient manufactured by using wet granulation method.
  • It is a further object of the present invention relates to a bilayer tablet formulation
  • a bilayer tablet formulation comprising; candesartan cilexetil with at least one pharmaceutically acceptable excipient in the first layer, amlodipine besylate and hydrochlorothiazide with at least one pharmaceutically acceptable excipient in the second layer, wherein the optimized amount ratio between stabilizer and disintegrants present in the first layer of the composition is between 1:3 to 1:5.
  • the present invention provides bilayer tablet composition comprising two formulation layers wherein candesartan or pharmaceutically acceptable salts with at least one pharmaceutically acceptable excipient are present in the first layer and amlodipine or pharmaceutically acceptable salts and hydrochlorothiazide or pharmaceutically acceptable salts with at least one pharmaceutically acceptable excipients that are present in the second layer.
  • the pharmaceutical composition comprising candesartan or pharmaceutically acceptable salts, preferably it is candesartan cilexetil.
  • Candesartan cilexetil is the ester prodrug of candesartan and it is commercially used in the marketed product.
  • the pharmaceutical composition comprising amlodipine or pharmaceutically acceptable salts, preferably it is besylate salt which is the commercial salt used in the marketed product.
  • the conventional manufacturing processes are direct compression, dry granulation or wet granulation.
  • the properties of the active ingredients and the excipients preferred have an impact on optimizing the manufacturing process.
  • wet granulation and direct compression are commonly used in development studies of solid pharmaceutical formulations.
  • Wet granulation process refers to obtain a granulation by mixing the powder particles in a suitable blender with adding a suitable granulation solvent or a granulation solution under shear. However, it has a challenge that it could affect adversely the degradation of solid dosage forms due to interference of moisture during manufacture.
  • Candesartan cilexetil is known for stability problem against temperature, moisture and light.
  • amlodipine besylate and hydrochlorothiazide are used also as other active ingredients in the present invention and both of them have challenge about being sensitive to hydrolysis when they are exposed to an alkaline medium.
  • the proper manufacturing process must be selected to obtain stable dosage form.
  • the stability of candesartan can be enhanced by adding a number of different excipients to the designed pharmaceutical composition.
  • Polyethylene glycols (PEGs) are one of the commonly used versatile excipient in the pharmaceutical formulations.
  • PEG is used as a stabilizer in the first layer comprising candesartan cilexetil to inhibit the degradation.
  • amlodipine besylate in the presence of commonly used excipients such as lactose, polyethylene glycol and water.
  • the formulation design was performed by considering the prevention of the possible degradation of amlodipine, wherein candesartan and amlodipine was separated from each other to enhance their stability.
  • Direct compression is another commonly used manufacturing method during the developing studies for solid dosage form which refers to be a relatively quick process, in which the powder particles are compressed directly without changing the physical and chemical properties of the drug.
  • a pharmaceutical composition comprising amlodipine besylate and hydrochlorothiazide with at least one pharmaceutically acceptable excipient is preferred to be manufactured as using direct compression process to eliminate the possibly degradation due to arising from alkaline medium.
  • an embodiment of the in the present invention relates to a bilayer tablet composition
  • a bilayer tablet composition comprising candesartan cilexetil with at least one pharmaceutically acceptable excipients manufactured wet granulation process in the first layer and amlodipine besylate and hydrochlorothiazide with at least one pharmaceutically acceptable excipients manufactured direct compression process in the second layer.
  • the first layer composition comprising candesartan cilexetil manufactured by using wet granulation process, with pharmaceutically acceptable diluent, binder, stabilizer, disintegrant, colorant, lubricant and solvent.
  • the first layer composition comprises at least a diluent which can be selected from lactose, starch, microcrystalline cellulose, sucrose, mannitol, dicalcium phosphate, calcium carbonate, magnesium carbonate, low substituted hydroxypropyl cellulose, and mixtures thereof.
  • the diluent is lactose monohydrate.
  • the first layer composition comprises at least a binder which can be selected from hypromellose, sodium carboxymethyl cellulose, cellulose or cellulose derivatives, povidone, starch, sucrose, polyethylene glycol, or mixtures thereof.
  • the binder is hypromellose.
  • the first layer composition comprises at least a disintegrant which can be selected from carmellose calcium, croscarmellose sodium, sodium starch glycolate, crospovidone, com starch, pregelatinized starch, low-substituted hydroxypropyl cellulose and microcrystalline cellulose.
  • the disintegrants are carmellose calcium and com starch.
  • a first layer composition comprises at least one colorant which can be selected from the group of pigments such as metal oxides like iron oxides and/or titanium dioxide and hydroxides, and/or from the group of pharmaceutically acceptable water soluble colorants, and similar and any mixture thereof.
  • the colorant is yellow iron oxide.
  • the first layer composition comprises at least one lubricant which can be selected from sodium stearyl fumarate, magnesium stearate, calcium stearate talc, stearic acid and mixtures thereof.
  • the lubricant is magnesium stearate.
  • the first layer composition comprises at least one solvent which can be selected from deionized water, ethanol and isopropanol, either alone or in combination.
  • the solvent is deionized water.
  • the embodiment in accordance with the present invention was designed with adjusted quantitative composition composed of pharmaceutically acceptable ingredients mentioned above by using wet granulation process.
  • Example 1 The embodiment prepared of the first layer composition, Example 1 was given in the below.
  • the proposed embodiment based on the invention provides a pharmaceutical composition comprising candesartan cilexetil in the first layer is as stated in the table below.
  • Another object of the present invention relates to provide wet granulation process for preparing a first layer composition, providing the steps of: i. Com starch and yellow iron oxide were weighed and screened through a proper sieve, ii. Candesartan cilexetil, polyethylene glycol, lactose monohydrate and specified amount of the carmellose calcium were weighed and screened through a proper sieve and stirred to obtain a uniform a blend, iii. The prepared uniform blend in Step (ii) was added to the granules prepared in Step (i) into fluid bed dryer and stirred, iv. Hypromellose was dissolved in a sufficient amount of deionized water till to dissolve completely, v.
  • the prepared binder solution was sprayed on the prepared blend in Step (iii) to perform granulation process, vi.
  • the granules prepared in Step (v) were dried in fluid bed dryer and screened through a proper sieve vii.
  • the rest of the carmellose calcium were weighed and screened through a proper sieve, then added to the granules prepared in Step (vi) and stirred, viii.
  • Magnesium stearate was screened through a proper sieve and added to the granules prepared in Step (vii) and stirred to obtain a uniform final blend, ix. Tablet compression was performed with the final blend in Step (viii).
  • the prepared first layer was investigated for the requirements regarding the stability and dissolution profile.
  • polyethylene glycol was used as a stabilizer to enhance the stability of candesartan cilexetil against moisture and temperature during manufacturing.
  • excess amount of the polyethylene can cause counter-effect on dissolution, thus, the amounts of stabilizer and disintegrants effective on dissolution should also have a specific ratio.
  • the ratio between polyethylene glycol and com starch and carmellose calcium as disintegrants are used in particular ratios as stated in Table-2.
  • Example- 1 and Example-2 related first layer were subjected to in vitro dissolution study and the dissolution conditions were designated considering the gastrointestinal pathway of orally applied solid dosage forms.
  • the dissolution test is carried out at pH 6.5 with 0.35% Polysorbate 20 in 0.05M phosphate buffer. Other conditions are defined as; volume of dissolution media is 900 ml, temperature is 37°C ⁇ 0.5, rotation speed is 50 rpm, apparatus is paddle and the duration of dissolution study is 60-minute.
  • the amount ratio between polyethylene glycol and disintegrants was optimized as 1:3 to 1:5 to get proper dissolution profile.
  • Example- 1 and Example-2 impurity analysis was carried out with the Example- 1 and Example-2 for the tablets subjected to accelerated stability studies under the conditions of 40°C/75% relative humidity for 3-month period. Then, the samples at the beginning and under stability condition at 3-month storage were analyzed with a validated analytical method by using HPLC.
  • Example- 1 and Example-2 total candesartan cilexetil impurity results of Example- 1 and Example-2 were similar at the initial period and the accelerated stability study for 3-month period.
  • a stable bilayer tablet composition with proper dissolution profile was obtained as stated below: candesartan cilexetil with at least one pharmaceutically acceptable excipient in the first layer, amlodipine besylate and hydrochlorothiazide with at least one pharmaceutically acceptable excipient in the second layer, wherein the optimized amount ratio between stabilizer and disintegrants present in the first layer of the composition is between 1:3 to 1:5.

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  • Health & Medical Sciences (AREA)
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  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne une composition de comprimé bicouche comprenant du candésartan ou des formes pharmaceutiquement acceptables, de l'amlodipine ou un sel pharmaceutiquement acceptable de celle-ci, et de l'hydrochlorothiazide, l'amlodipine et l'hydrochlorothiazide, le candésartan ou le sel pharmaceutiquement acceptable étant présent dans une couche séparée ayant une plage de rapport optimisée pour le polyéthylène glycol et le délitant étant compris entre 1 : 3 et 1 : 5.
PCT/TR2020/051333 2020-12-18 2020-12-18 Compositions de comprimés bicouches stables WO2022132067A1 (fr)

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PCT/TR2020/051333 WO2022132067A1 (fr) 2020-12-18 2020-12-18 Compositions de comprimés bicouches stables

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120164218A1 (en) * 2006-06-27 2012-06-28 Yu Cao Solid dosage forms of valsartan, amlodipine and hydrochlorothiazide and method of making the same
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
TR201503831A2 (tr) * 2015-03-30 2016-10-21 Deva Holdi̇ng Anoni̇m Şi̇rketi̇ Antimipertansif kombinasyon formülasyonları
WO2017054787A1 (fr) * 2015-10-02 2017-04-06 Zentiva, K.S. Composition pharmaceutique comprenant la combinaison de candésartan, d'amlopidine et d'hydrochlorothiazide

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120164218A1 (en) * 2006-06-27 2012-06-28 Yu Cao Solid dosage forms of valsartan, amlodipine and hydrochlorothiazide and method of making the same
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
TR201503831A2 (tr) * 2015-03-30 2016-10-21 Deva Holdi̇ng Anoni̇m Şi̇rketi̇ Antimipertansif kombinasyon formülasyonları
WO2017054787A1 (fr) * 2015-10-02 2017-04-06 Zentiva, K.S. Composition pharmaceutique comprenant la combinaison de candésartan, d'amlopidine et d'hydrochlorothiazide

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
MACGREGOR G A , ET AL: "Efficacy of candesartan cilexetil alone or in combination with amlodipine and hydrochlorothiazide in moderate-to-severe hypertension", HYPERTENSION, LIPPINCOTT WILLIAMS & WILKINS, US, vol. 36, no. 3, 1 January 2000 (2000-01-01), US , pages 454 - 460, XP002251650, ISSN: 0194-911X *

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