WO2013100630A1 - Formulation de combinaison de doses fixes comprenant du losartan, de l'amlodipine et de l'hydrochlorothiazide - Google Patents

Formulation de combinaison de doses fixes comprenant du losartan, de l'amlodipine et de l'hydrochlorothiazide Download PDF

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Publication number
WO2013100630A1
WO2013100630A1 PCT/KR2012/011569 KR2012011569W WO2013100630A1 WO 2013100630 A1 WO2013100630 A1 WO 2013100630A1 KR 2012011569 W KR2012011569 W KR 2012011569W WO 2013100630 A1 WO2013100630 A1 WO 2013100630A1
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Prior art keywords
amlodipine
fixed dose
pharmaceutically acceptable
dose combination
losartan
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PCT/KR2012/011569
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English (en)
Inventor
Yong Il Kim
Kyeong Soo Kim
Seung Jae Park
Jae Hyun Park
Jong Soo Woo
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Hanmi Pharm. Co., Ltd.
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Publication of WO2013100630A1 publication Critical patent/WO2013100630A1/fr

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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
    • 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
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5084—Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs
    • 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
    • A61K31/417—Imidazole-alkylamines, e.g. histamine, phentolamine
    • 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
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • 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
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4808—Preparations in capsules, e.g. of gelatin, of chocolate characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release
    • 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
    • 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

Definitions

  • the present invention relates to a fixed dose combination formulation for the prophylaxis or treatment of cardiovascular diseases, comprising losartan, amlodipine and hydrochlorothiazide, showing superior dissolution rate and stability.
  • Hypertension is classified as either primary (essential) hypertension or secondary hypertension. About 90-95% of cases are categorized as primary hypertension which means high blood pressure with no obvious underlying medical cause. Secondary hypertension can be treated by removing the cause. In contrast, due to unidentifiable causes, the first line of treatment of essential hypertension is preventative lifestyle changes including rest, dietary changes, physical exercise, etc. For a greater effect on blood pressure, these non-drug therapies may be used in conjunction with medication.
  • Vasodilators are most widely prescribed antihypertensive drugs, and they are divided into several groups, according to their action mechanisms, including ACE (angiotensin converting enzyme) inhibitors, angiotensin II receptor antagonists and calcium channel blockers.
  • ACE angiotensin converting enzyme
  • a prescription for the administration of two or more individual medications is apt to reduce compliance, giving rise to great inconvenience for hypertension patients who need continuous blood pressure management.
  • hypertension patients particularly those who conduct a social life, need to carry and be administered two or more individual unit medications for a single dose of the combination therapy, and hence they experience inconvenience.
  • fixed dose combination drug refers to a formulation of two or more medications or active ingredients combined in a single unit dosage form, and available in certain fixed doses.
  • free dose combination drug, as used herein, is intended to refer to a formulation of two or more medications or active ingredients combined in two or more unit dosage forms.
  • a fixed dose combination drug may show unexpected problems attributable to pharmacokinetic and pharmaceutical properties of the individual drugs to be formulated into a single dosage form.
  • losartan shows an absolute oral bioavailability of about 25 to 35%.
  • This low oral bioavailability is caused by the fact that losartan is gelled at a low pH, such as the pH of the gastrointestinal tract where the drug is predominantly absorbed (e.g., pH 1.2 to pH 2.0), and thus dissolves very slowly although it shows a very high dissolution pattern in pure water or at a relative high pH such as pH 6.8.
  • a low pH such as the pH of the gastrointestinal tract where the drug is predominantly absorbed (e.g., pH 1.2 to pH 2.0)
  • the amount of losartan released over the initial 30 minutes is less than 30% in a pH range of 1.2 to 2.0.
  • hydrochlorothiazide is low in both solubility and bioabsorption
  • FDC fluorescence-activated dimethyl methacrylate
  • Another problem with the formulation of FDC is the likelihood of poor stability attributable to interaction between different active ingredients. Particularly, compounds difficult to handle make it more difficult to develop them into a fixed dose combination drug having a physicochemically stable form.
  • an amlodipine formulation is typically prepared by combining the active ingredient amlodipine with a salt helpful in the pharmaceutical efficacy and formulation of the active ingredient.
  • the salt is responsible for the stabilization of the active ingredient amlodipine.
  • amlodipine may preferably be in a free base form, it is administered as a salt form of a pharmaceutically acceptable acid because of its poor solubility in water.
  • amlodipine maleate When such acid addition salt of amlodipine, for example, amlodipine maleate is formulated, it may be degraded into amlodiphidine aspartate or amlo-pyridine, represented by the following Chemical Formulas 1 and 2, respectively, with the passage of time (U.S. Pat. No. 6,919,087).
  • a pharmaceutical composition comprising amlodipine maleate has the problem of poor stability caused by degradation.
  • amlodipine besylate disclosed in EP 244 944 (corresponding to U.S. Pat. No. 4,879,303).
  • amlodipine besylate is also susceptible to decomposition into various breakdown products although to a lesser degree than amlodipine maleate.
  • pharmaceutical compositions comprising the amlodipine besylate become poor in stability and thus in pharmaceutical efficacy over time.
  • amlodipine camsylate which is superior to amlodipine besylate in terms of physical properties such as solubility and stability, and formulated the salt into a commercially available product under the brand name of Amodipin ® .
  • amlodipine camsylate which is the most stable amlodipine salt, it was found to degrade into various breakdown products, in contrast to the salt in a single dosage form. This is because amlodipine itself is unstable with regard to light and moisture.
  • amlodipine when it is formulated into a fixed dose combination drug with, for example, losartan and hydrochlorothiazide.
  • losartan potassium known as having good stability, is degraded by heat under an acidic condition, with the concomitant production of degradation products E and F (see Z. Zhao et al., J. Pharm. Biomed. Anal, 20: 129-136, 1999).
  • hydrochlorothiazide is readily degraded into benzothiadiazine-related substance A.
  • the present invention provides a fixed dose combination formulation for the prophylaxis or treatment of cardiovascular diseases, comprising losartan or a pharmaceutically acceptable salt thereof; amlodipine or a pharmaceutically acceptable salt thereof; and hydrochlorothiazide as active ingredients, which is in the form of a capsule into which the active ingredients, each of which forms a discrete layer, are contained.
  • a fixed dose combination formulation of the present invention For a fixed dose combination formulation of the present invention, the side effects can be minimized compared to conventional individual single or combined dosage forms. Also, the formulation exhibits biologically equivalent or superior behaviors to the conventional forms owing to a higher dissolution, and shows higher stability over time. Accordingly, a fixed dose combination formulation of the present invention can be effectively used to prevent or treat cardiovascular diseases.
  • FIG. 1 is a schematic view showing a fixed dose combination formulation comprising losartan, amlodipine and hydrochlorothiazide in accordance with the present invention.
  • FIG. 2 is a graph showing dissolution rates of hydrochlorothiazide as measured by the method described in Test Example 1.
  • FIG. 3 is a graph showing dissolution rates of amlodipine as measured by the method described in Test Example 1. DETAILED DESCRIPTION OF THE INVENTION
  • the present invention relates to a fixed dose combination formulation for the prevention or treatment of cardiovascular diseases, comprising, as active ingredients, losartan or a pharmaceutically acceptable salt thereof; amlodipine or a pharmaceutically acceptable salt thereof; and hydrochlorothiazide, which is in the form of a capsule into which the active ingredients, each of which constitutes a discrete layer, are contained.
  • Losartan is the general name for 2-butyl-4-chloro-l-[[2'-(lH-tetrazol-5- yl)[l ,l'-biphenyl]-4-yl]methyl]-lH-imidazol-5-methanol, which has been disclosed in U.S. Pat. Nos.
  • Losartan potassium is commercially available under a brand name of Cozaar ® .
  • Losartan potassium is a preferred pharmaceutically acceptable salt of losartan.
  • Losartan or its pharmaceutically acceptable salt may be administered at a daily dose of from 0.1 to 500 mg based on the weight of losartan, preferably at a daily dose of from 1 to 200 mg, and more preferably at a daily dose of from 25 to 200 mg.
  • Amlodipine is the general name for 3-ethyl-5-methyl-2-(2-aminoethoxy- methyl)-4-(2-chlorophenyl)-6-methyl-l,4-dihydro-3,5-pyridine dicarboxylate.
  • the phannaceutically acceptable salt of amlodipine useful for the present invention may be prepared by using an acid containing a pharmaceutically acceptable anion which can form a non-toxic acid addition salt.
  • the salt include hydrogen chloride, hydrogen bromide, sulfate, phosphate, acetate, malate, furmarate, lactate, tartrate, citrate, gluconate, besylate and camsylate, but are not limited thereto.
  • amlodipine besylate is currently marketed as Norvasc ® .
  • Amlodipine camsylate is superior to besylate salt in solubility and stability, as disclosed in Korean Patent No. 452491.
  • amlodipine camsylate is most preferred as the pharmaceutically acceptable salt of amlodipine for the present invention.
  • Amlodipine is a long-acting calcium channel blocker useful for treating cardiovascular disorders such as angina, hypertension, and congestive heart failure.
  • Amlodipine or a pharmaceutically acceptable salt thereof may be administered at a daily dose of from 0.5 to 20 mg based on the weight of amlodipine, preferably from 1 to 10 mg, and more preferably from 2.5 to 10 mg.
  • Hydrochlorothiazide is the general name for 6-chloro-l ,l-dioxy-3,4-dihydro- 2H-l ,2,4-benzothiazine-7-sulfone amide, and is commercially available under various brand names.
  • Hydrochlorothiazide is a diuretic drug of the thiazide class that acts on kidneys to reduce sodium reabsorption in the distal convoluted tubule by inhibiting the Na/Cl co -transporter. As a result, by increasing levels of sodium and chloride in the tubular fluid, hydrochlorothiazide induces natriuresis and concomitant diuresis.
  • hydrochlorothiazide is used in the treatment of hypertension, heart failure, hypercalciuria and diabetes insipidus.
  • the daily dose of hydrochlorothiazide ranges from 1 to 100 mg, preferably from 3 to 50 mg, and more preferably from 6.25 to 25 mg.
  • a fixed dose combination formulation of the present invention comprising losartan or a pharmaceutically acceptable salt thereof, amlodipine or a pharmaceutically acceptable salt thereof and hydrochlorothiazide may be used for the prophylaxis or therapy of cardiovascular diseases.
  • cardiovascular diseases include angina pectoris, hypertension, arteriospasm, cardiac arrhythmia, cardiomegaly, cerebral infarction, congestive heart failure and myocardial infarction, but are not limited thereto.
  • a fixed dose combination formulation comprising losartan or a pharmaceutically acceptable salt thereof, amlodipine or a pharmaceutically acceptable salt thereof and hydrochlorothiazide in accordance with the present invention exhibits higher preventive and therapeutic effects on cardiovascular diseases, with decreased side effects and increased compliance, compared to conventional single formulations.
  • a simple combination of losartan, amlodipine and hydrochlorothiazide for making a fixed dose combination formulation suffers from the following disadvantages due to differences in their intrinsic physical properties.
  • a first problem comes from the gelation of losartan.
  • Losartan readily dissolves in purified water and is easily released at a relatively high pH (e.g., pH 6.8), but is released very slowly at a low pH (e.g., pH 2.0 or pH 1.2) because of the gelation.
  • This problem significantly imparts undesired effects on the dissolution rate and bioavailability of the formulation because the formulation is first exposed to the acidic gastric juice having a low pH value when orally administered.
  • As the gelation of losartan progresses in the composition amlodipine and hydrochlorothiazide are trapped within the losartan gel and dissolve poorly, which is demonstrated in Test Example 1 as shown in the graphs of dissolution rates of FIGS. 2 and 3.
  • a second problem is associated with formulation stability.
  • losartan, amlodipine and hydrochlorothiazide are simply combined and tableted, impurities are increasingly produced under an accelerated condition, thus greatly decreasing the stability of the formulation. This is believed to be caused by physicochemical reactions among losartan, amlodipine and hydrochlorothiazide having negative influences on the stability of each active ingredient.
  • amlodipine which contains an intramolecular ester bond
  • losartan is likely to degrade in an acidic condition.
  • the amlodipine-losartan complex formulation could not be sufficiently stabilized within a pH range of from 5.5 to 7.0.
  • the present invention provides a fixed dose combination formulation which is in the form of a capsule in which losartan or a pharmaceutically acceptable salt thereof, amlodipine or a pharmaceutically acceptable salt thereof, and hydrochlorothiazide forming respective discrete layers are charged. Because the active ingredients are physically separated from one another, the formulation of the present invention easily secures bioequivalence, and shows excellent stability. In addition, individual ingredients are produced, thereby avoiding reactions therebetween.
  • the formulation is expected to induce high medication compliance because its volume can be reduced by minimizing the amount of excipients for each layer.
  • the formulation of the present invention can exert higher preventive and therapeutic effects on cardiovascular diseases with the concomitant reduction of the side effects of conventional single formulations or combinations.
  • losartan, amlodipine and hydrochlorothiazide in a fixed dose combination formulation of the present invention are charged into a capsule while forming respective discrete layers in the form of tablets.
  • a fixed dose combination formulation of the present invention may be a capsule comprising a tablet having losartan or a pharmaceutically acceptable salt thereof, a tablet having amlodipine or a pharmaceutically acceptable salt thereof and a tablet having hydrochlorothiazide.
  • Each tablet of losartan, amlodipine and hydrochlorothiazide is prepared by mixing or granulization with a pharmaceutically acceptable excipient before compression in a tablet press machine.
  • the tablet hardness is dependent on the compression pressure of the press machine. Tablets can be given various densities under various compression pressures even though they have the same weight. Typical tablets have a density of 0.8 g/ml or greater.
  • the tablets may be prepared so as to have a circular, rectangular or oval shape, preferably circular in shape. In case of a circular shape, a tablet preferably ranges in diameter from 1 mm to 7 mm, and more preferably from 2 mm to 6 mm. A larger tablet results in increase of the capsule size into which the tablet is charged, thus causing inconvenience to the patient who takes the medication. On the other hand, when the tablet diameter becomes smaller, the tableting process cannot be properly conducted.
  • At least one of the tablets existing as individual discrete layers may be coated with a polymer film.
  • Any conventional pharmaceutically acceptable polymer may be employed for the coating. Representative among them are methyl cellulose, ethyl cellulose, polyvinyl alcohol, hydroxyethyl cellulose, hydroxypropyl methyl cellulose and polyvinylpyrrolidone.
  • the polymer is preferably used in a minimal amount in order to effectively prepare the formulation in an optimal size. Its amount preferably ranges from about 1 to about 20 wt% based on the total weight of the formulation, and preferably from about 2 to about 10 wt%.
  • the discrete layers comprising, as active ingredients, losartan or a pharmaceutically acceptable salt thereof, amlodipine or a pharmaceutically acceptable salt thereof, and hydrochlorothiazide, respectively, may further comprise a pharmaceutically acceptable excipient.
  • the pharmaceutically acceptable excipient may include a pharmaceutically acceptable diluent, a pharmaceutically acceptable disintegrant, a pharmaceutically acceptable binder, a pharmaceutically acceptable stabilizer, a pharmaceutically acceptable lubricant, a pharmaceutically acceptable pigment, etc.
  • an active ingredient may be mixed at a weight ratio of 1 : 0.25 to 1 : 20 with a pharmaceutically acceptable excipient.
  • the pharmaceutically acceptable diluent examples include microcrystalline cellulose, lactose, Ludipress, mannitol, monocalcium phosphate, starch, low- substituted hydroxypropylcellulose and a mixture thereof.
  • the diluent may be used in an amount of from about 5 to about 95 wt% based on the total weight of the formulation, and preferably in an amount of from about 10 to about 85 wt%.
  • the diluent can be a soluble diluent. When the diluent is used, its ratio to the active ingredient in each discrete layer is very important.
  • soluble diluents refers to a diluent which is dissolved in water, like lactose, Ludipress (BASF, a mixture of lactose, crospovidone and povidone (93 : 3.5 : 3.5, w/w(%))), mannitol and sorbitol.
  • the soluble diluents when mixed with the active ingredient losartan, allows for a maximal dissolution rate at a certain mixing ratio. This can be accounted for by the physical property that induces the gelation of losartan at a low pH value.
  • the losartan layer can dissolve at a high rate.
  • Losartan is preferably mixed with an aqueous diluent at a weight ratio of 1 : 0.1 to 1 : 40, and more preferably at a weight ratio of 1 : 0.25 to 1 : 20.
  • the granules used in the tableting process for the losartan layerj it is advantageous in terms of stability to manufacture them in a simple mixing or dry method which employs neither water nor an organic solvent.
  • the stability of the losartan layer becomes rapidly worse under a high moisture condition, which might be attributed to losartan's high water solubility which causes losartan to undergo hydrolysis or a change in physical property.
  • the losartan layer in the present invention preferably contains a moisture content of 5% or less and more preferably 3% or less.
  • disintegrant useful in the fixed dose combination formulation of the present invention examples include crospovidone, sodium starch glycolate, croscarmellose sodium, low-substituted hydroxypropylcellulose, starch, alginic acid or sodium salt thereof, and a mixture thereof, preferably, crospovidone, sodium starch glycolate, croscarmellose sodium, low-substituted hydroxypropylcellulose, and a mixture thereof, more preferably, crospovidone and sodium starch glycolate.
  • the disintegrant may be used in an amount of about 1 to about 30 wt% based on the total weight of the formulation, and preferably in an amount of about 2 to about 15 wt%.
  • binder useful in the fixed dose combination formulation of the present invention include hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, copovidone, macrogol, silicate derivatives such as hard silica, synthesized aluminum silicate, calcium silicate and magnesium metasilicate aluminate, phosphates such as calcium monohydrogen phosphate, carbonates such as calcium carbonate, and a mixture thereof.
  • the stabilizer usable in the fixed dose combination formulation of the present invention may be an anti-oxidant.
  • an antioxidant enhances stability of the active ingredients, particularly amlodipine, against the undesirable reaction with other pharmaceutically acceptable additives and against modification by heat or moisture with time.
  • antioxidants include butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), ascorbic acid, ascorbyl palmitic acid, ethylene diamine tetracetic acid (EDTA), sodium pyrosulfite, and a mixture thereof.
  • BHT butylated hydroxytoluene
  • BHA butylated hydroxyanisole
  • EDTA ethylene diamine tetracetic acid
  • sodium pyrosulfite sodium pyrosulfite
  • the anti-oxidant is butylated hydroxytoluene.
  • lubricant useful in the fixed dose combination formulation of the present invention include stearic acid, a metal stearate such as calcium stearate and magnesium stearate, talc, colloidal silica, sucrose fatty acid esters, hydrogenated vegetable oils, waxes having a high melting point, glyceryl fatty acid esters, glycerol dibehenate, and a mixture thereof.
  • any hard capsule may be used for the fixed dose combination formulation of the present invention.
  • the hard capsule may be prepared from a base material such as gelatin, hypromellose, pullulan (NP capsTM, Capsugel), or polyvinylalcohol.
  • a gelatin capsule as an initial dissolution rate is important for the fixed dose combination formulation of the present invention.
  • any capsule size is possible for the hard capsule of the fixed dose combination formulation of the present invention.
  • the capsule size has different internal volume. In consideration of the convenience of administration, smaller sizes are preferred. However, it is recommended to select an optimal capsule size so that the allowable lower limit of the amount may be charged into the capsule.
  • the size of the hard capsule useful for the formulation of the present invention may be No. 0, No. 1 , No. 2, No. 3, or No. 4.
  • a schematic view showing a fixed dose combination formulation described above is given in FIG. 1.
  • a fixed dose combination formulation of the present invention allows both amlodipine or a pharmaceutically acceptable salt thereof and hydrochlorothiazide to reach a dissolution rate of 80% or higher within 30 minutes after the initiation of a dissolution test.
  • the present invention also provides a method for manufacturing a fixed dose combination formulation for the prophylaxis or therapy of cardiovascular diseases, which comprises the steps of: a) mixing or granulizing losartan or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, and tableting the mixture or the granule to obtain a losartan tablet; b) mixing or granulizing amlodipine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, and tableting the mixture or the granule to obtain an amlodipine tablet; c) mixing or granulizing hydrochlorothiazide and a pharmaceutically acceptable excipient, and tableting the mixture or the granule to obtain a hydrochlorothiazide tablet; and d) filling the losartan tablet, the amlodipine tablet and the hydrochlorothiazide tablet into a capsule.
  • the method may further comprise coating the tablet obtained from at least one of the steps a) to c) with a pharmaceutical
  • the fixed dose combination formulation of the present invention is equivalent or superior to currently marketed single formulations in terms of the dissolution rates of losartan, amlodipine and hydrochlorothiazide, and exhibits excellent stability with time because it undergoes a very small change of related substances as tested under a accelerated condition. Accordingly, the formulation of the present invention may be effectively used for the treatment of cardiovascular diseases including, for example, angina pectoris, hypertension, arteriospasm, cardiac arrhythmia, cardiomegaly, cerebral infarction, congestive heart failure and myocardial infarction.
  • cardiovascular diseases including, for example, angina pectoris, hypertension, arteriospasm, cardiac arrhythmia, cardiomegaly, cerebral infarction, congestive heart failure and myocardial infarction.
  • Amlodipine camsylate 7.84 mg (amlodipine 5 mg) Microcrystalline cellulose 43.76 mg
  • Distilled water (l l .O mg)
  • the ingredients listed above for the losartan layer were admixed.
  • the resulting mixture was pressed into a tablet using a tablet press machine with the 5 mm diameter of the dye, followed by coating the resulting tablet with a coating solution prepared by dissolving Opadry Y- 1-7000 (Colorcon) in distilled water to prepare a losartan 50 mg tablet.
  • amlodipine layer 2.0 mg of hydroxypropyl cellulose was dissolved in 35 mg of distilled water, and it was used, as a binder, in wet granulation, followed by passing through a 20 mesh screen and drying to obtain the granule.
  • the resulting mixture was pressed into a tablet using a tablet machine, and then the resulting tablet was coated with a coating solution prepared by dissolving Opadry Y-l-7000 (Colorcon) in distilled water to prepare an amlodipine 5 mg tablet.
  • a hydrochlorothiazide 12.5 mg tablet was prepared by tableting and coating based on the same method as the procedure of preparing amlodipine tablet.
  • the three tablets were charged in a No. 2 hard capsule to obtain a fixed dose combination formulation comprising losartan (50 mg), amlodipine (5 mg) and hydrochlorothiazide (12.5 mg).
  • the total mass of the three tablets that are charged in the hard capsule is 226.6 mg, which was very small value.
  • Example 3 Preparation of fixed dose combination formulation III
  • Example 2 The procedure of Example 1 was repeated to prepare losartan, amlodipine and hydrochlorothiazide coated tablets and the three tablets were charged in a No. 2 hard capsule to obtain a fixed dose combination formulation comprising losartan (50 mg), amlodipine (5 mg) and hydrochlorothiazide (25 mg).
  • the total mass of the three tablets that are charged in the hard capsule is 206 mg, which was very small value.
  • Example 2 The procedure of Example 1 was repeated to prepare losartan, amlodipine and hydrochlorothiazide coated tablets and the three tablets were charged in a No. 2 hard capsule to obtain a fixed dose combination formulation comprising losartan (50 mg), amlodipine (10 mg) and hydrochlorothiazide (12.5 mg).
  • the total mass of the three tablets that are charged in the hard capsule is 206 mg, which was very small value.
  • losartan, amlodipine, hydrochlorothiazide and excipients were mixed together and tabletized to obtain a fixed dose combination formulation comprising losartan (50 mg), amlodipine (5 mg) and hydrochlorothiazide (12.5 mg).
  • losartan In accordance with the ingredients used in Comparative Example 1, losartan, amlodipine, hydrochlorothiazide and excipients were mixed together and charged in a No. 2 hard capsule to obtain a fixed dose combination formulation comprising losartan (50 mg), amlodipine (5 mg) and hydrochlorothiazide (12.5 mg).
  • Dissolution media 900 raL of 0.01N HC1 (pH 2.0)
  • the fixed dose combination formulations prepared in Examples 1 and 2 which comprises separate tablets of losartan, amlodipine and hydrochlorothiazide exhibited higher dissolution rates than Comparative Examples 1 and 2, which was prepared by direct mixing.
  • the dissolution rate of the tablet prepared in Examples 1 and 2 met the required criteria of hydrochlorothiazide and amlodipine, whereas the formulations prepared by direct mixing of Comparative Examples 1 and 2 did not meet the criteria of hydrochlorothiazide and amlodipine.
  • Injection volume 10 ⁇ _.
  • the fixed dose combination formulations comprising losartan, amlodipine and hydrochlorothiazide obtained in Examples 1 and 2 exhibited higher stability with respect to losartan, amlodipine and hydrochlorothiazide related substances.
  • the fixed dose combination formulations obtained in Comparative Examples 1 and 2 which were prepared by direct-compression, produced related substances at least 10 times greater than Examples 1 and 2. This result indicates that fixed dose combination formulations prepared in accordance with the present invention have significantly improved storage stability as compared to fixed dose combination formulations prepared in a conventional manner.

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Abstract

L'invention concerne une formulation de combinaison de dose fixe pour la prophylaxie ou la thérapie de maladies cardiovasculaires, comprenant du losartan, de l'amlodipine et de l'hydrochlorothiazide, formulation qui présente des vitesses de dissolution et stabilité supérieures, ayant une vitesse de dissolution supérieure par comparaison aux formes posologiques simples ou combinées, individuelles, classiques, la formulation de combinaison de dose fixe de la présente invention présentant des comportements biologiquement équivalents ou supérieurs aux formes classiques et garantissant une stabilité supérieure au cours du temps. Par conséquent, la formulation de combinaison de dose fixe de la présente invention peut être appliquée efficacement à la prophylaxie ou à la thérapie de maladies cardiovasculaires.
PCT/KR2012/011569 2011-12-30 2012-12-27 Formulation de combinaison de doses fixes comprenant du losartan, de l'amlodipine et de l'hydrochlorothiazide WO2013100630A1 (fr)

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WO2015080433A1 (fr) * 2013-11-29 2015-06-04 Hanmi Pharm. Co., Ltd. Préparation de combinaison pharmaceutique comportant de l'amlodipine, du losartan et de la rosuvastatine
CN105412029A (zh) * 2015-12-03 2016-03-23 南京多宝生物科技有限公司 一种抗高血压的苯磺酸左旋氨氯地平片
WO2016052866A1 (fr) * 2014-09-30 2016-04-07 Hanmi Pharm. Co., Ltd. Composition pharmaceutique solide comportant de l'amlodipine et du losartan
WO2016159535A1 (fr) * 2015-03-31 2016-10-06 Hanmi Pharm. Co., Ltd. Formulation complexe pharmaceutique comportant de l'amlodipine, du losartan et de la chlorthalidone
WO2017068532A1 (fr) * 2015-10-23 2017-04-27 Ftf Pharma Private Limited Solution orale de dérivés de dihydropyridine

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KR102229798B1 (ko) * 2013-12-12 2021-03-19 한미약품 주식회사 메트포르민 및 로자탄을 포함하는 이층정 복합 제제

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WO2015080433A1 (fr) * 2013-11-29 2015-06-04 Hanmi Pharm. Co., Ltd. Préparation de combinaison pharmaceutique comportant de l'amlodipine, du losartan et de la rosuvastatine
CN105792813A (zh) * 2013-11-29 2016-07-20 韩美药品株式会社 一种含有氨氯地平、氯沙坦和罗苏伐他汀的药物组合制剂
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KR102369607B1 (ko) 2014-09-30 2022-03-03 한미약품 주식회사 암로디핀 및 로잘탄을 포함하는 고형 약제학적 조성물
WO2016052866A1 (fr) * 2014-09-30 2016-04-07 Hanmi Pharm. Co., Ltd. Composition pharmaceutique solide comportant de l'amlodipine et du losartan
KR20160038734A (ko) * 2014-09-30 2016-04-07 한미약품 주식회사 암로디핀 및 로잘탄을 포함하는 고형 약제학적 조성물
RU2698703C2 (ru) * 2014-09-30 2019-08-29 Ханми Фарм. Ко., Лтд. Твердая фармацевтическая композиция, содержащая амлодипин и лозартан
US10034862B2 (en) 2014-09-30 2018-07-31 Hanmi Pharm. Co., Ltd. Solid pharmaceutical composition comprising amlodipine and losartan
CN108289850A (zh) * 2015-03-31 2018-07-17 韩美药品株式会社 含有氨氯地平、氯沙坦和氯噻酮的药物复合制剂
WO2016159535A1 (fr) * 2015-03-31 2016-10-06 Hanmi Pharm. Co., Ltd. Formulation complexe pharmaceutique comportant de l'amlodipine, du losartan et de la chlorthalidone
RU2713883C2 (ru) * 2015-03-31 2020-02-10 Ханми Фарм. Ко., Лтд. Сложный фармацевтический состав, включающий амлодипин, лозартан и хлорталидон
CN108289850B (zh) * 2015-03-31 2021-04-09 韩美药品株式会社 含有氨氯地平、氯沙坦和氯噻酮的药物复合制剂
WO2017068532A1 (fr) * 2015-10-23 2017-04-27 Ftf Pharma Private Limited Solution orale de dérivés de dihydropyridine
CN105412029A (zh) * 2015-12-03 2016-03-23 南京多宝生物科技有限公司 一种抗高血压的苯磺酸左旋氨氯地平片

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