WO2022270935A1 - Pharmaceutical combination preparation comprising candesartan, amlodipine and atorvastatin - Google Patents
Pharmaceutical combination preparation comprising candesartan, amlodipine and atorvastatin Download PDFInfo
- Publication number
- WO2022270935A1 WO2022270935A1 PCT/KR2022/008921 KR2022008921W WO2022270935A1 WO 2022270935 A1 WO2022270935 A1 WO 2022270935A1 KR 2022008921 W KR2022008921 W KR 2022008921W WO 2022270935 A1 WO2022270935 A1 WO 2022270935A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- pharmaceutical combination
- atorvastatin
- candesartan
- pharmaceutically acceptable
- acceptable salt
- Prior art date
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- 238000002360 preparation method Methods 0.000 title claims abstract description 137
- XUKUURHRXDUEBC-KAYWLYCHSA-N Atorvastatin Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-KAYWLYCHSA-N 0.000 title claims abstract description 79
- XUKUURHRXDUEBC-UHFFFAOYSA-N Atorvastatin Natural products C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CCC(O)CC(O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-UHFFFAOYSA-N 0.000 title claims abstract description 78
- 229960005370 atorvastatin Drugs 0.000 title claims abstract description 78
- 239000002053 C09CA06 - Candesartan Substances 0.000 title claims abstract description 65
- 229960000932 candesartan Drugs 0.000 title claims abstract description 65
- 229960000528 amlodipine Drugs 0.000 title claims abstract description 52
- HTIQEAQVCYTUBX-UHFFFAOYSA-N amlodipine Chemical compound CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1Cl HTIQEAQVCYTUBX-UHFFFAOYSA-N 0.000 title claims abstract 12
- SGZAIDDFHDDFJU-UHFFFAOYSA-N candesartan Chemical compound CCOC1=NC2=CC=CC(C(O)=O)=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C1=NN=N[N]1 SGZAIDDFHDDFJU-UHFFFAOYSA-N 0.000 title abstract description 4
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Classifications
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- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
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Definitions
- the present invention relates to a pharmaceutical combination preparation comprising candesartan, amlodipine and atorvastatin as active ingredients.
- the pharmaceutical combination preparation according to the present invention which comprises the three active ingredients simultaneously, may exhibit pharmacological effects comparable to those of co-administration of Lipitor ® Tab, which is a single tablet of atorvastatin, and Cantabell ® Tab which is a combination tablet of candesartan and amlodipine, because the dissolution pattern and PK profile of each of the active ingredients are equivalent to those of the co-administration.
- the pharmaceutical combination preparation according to the present invention may significantly improve the convenience of drug administration due to its high stability because the contents of individual and total related substances therein do not significantly increase under long-term and accelerated conditions.
- Hypertension refers to a condition in which blood pressure remains elevated at all times. Hypertension may cause several complications and eventually lead to death. Hypertension is divided into primary hypertension and secondary hypertension depending on the cause of elevated blood pressure. Primary hypertension is essential hypertension in which the cause of elevated blood pressure is unknown, and secondary hypertension is hypertension in which blood pressure is elevated as a result of a specific disease or illness. Secondary hypertension can be treated by identifying the causes of elevated blood pressure. However, since the cause of primary hypertension, which accounts for about 95% of total hypertension, is not clearly known, treatment of primary hypertension patients is performed by drug therapy based on several blood pressure-lowering mechanisms.
- Candesartan is known as an angiotensin II receptor blocker (ARB).
- ARB angiotensin II receptor blocker
- Amlodipine is known as a calcium channel blocker (CCB), and is used for the treatment of hypertension and other medical indications (see WO 2006/059217).
- CB calcium channel blocker
- Atorvastatin is known as an HMG-CoA reductase inhibitor, has the effect of lowering blood lipid levels and cholesterol levels by preventing HMG-CoA from being reduced to mevalonate, and thus is used for hyperlipidemia, hypercholesterolemia and atherosclerosis. (See US Patent No. 4681893).
- a combination preparation comprising all of candesartan, amlodipine and atorvastatin, which have different mechanisms of action as described above, may be considered.
- an alkalizing agent that is used to ensure the stability of atorvastatin may have problems in that it increases the production of related substances of amlodipine and affects the solubility of candesartan.
- Patent Document 1 WO 2006/059217
- Patent Document 2 US Patent No. 4681893
- An object of the present invention is to provide a pharmaceutical combination preparation comprising three active ingredients.
- an object of the present invention is to provide a pharmaceutical combination preparation comprising candesartan or candesartan cilexetil, atorvastatin or a pharmaceutically acceptable salt thereof or a solvate thereof, and amlodipine or a pharmaceutically acceptable salt thereof, the pharmaceutical combination preparation comprising: a first compartment containing the candesartan or candesartan cilexetil; and a second compartment containing the atorvastatin or pharmaceutically acceptable salt thereof or solvate thereof, wherein the amlodipine or pharmaceutically acceptable salt thereof is not contained in the second compartment containing the atorvastatin or pharmaceutically acceptable salt thereof or solvate thereof.
- Another object of the present invention is to provide the pharmaceutical combination preparation which has a pH of 8.0 to 10.0 when dissolved in distilled water.
- Still another object of the present invention is to provide the pharmaceutical combination preparation in which the first and second compartments are formulated in a separate form.
- the present invention provides the following means.
- the present invention provides a pharmaceutical combination preparation comprising candesartan or candesartan cilexetil, atorvastatin or a pharmaceutically acceptable salt thereof or a solvate thereof, and amlodipine or a pharmaceutically acceptable salt thereof, the pharmaceutical combination preparation comprising: a first compartment containing the candesartan or candesartan cilexetil; and a second compartment containing the atorvastatin or pharmaceutically acceptable salt thereof or solvate thereof, wherein the amlodipine or pharmaceutically acceptable salt thereof is not contained in the second compartment containing the atorvastatin or pharmaceutically acceptable salt thereof or solvate thereof.
- the present invention provides a pharmaceutical combination preparation comprising candesartan or candesartan cilexetil, atorvastatin or a pharmaceutically acceptable salt thereof or a solvate thereof, and amlodipine or a pharmaceutically acceptable salt thereof, the pharmaceutical combination preparation comprising: a first compartment containing the candesartan or candesartan cilexetil; and a second compartment containing the atorvastatin or pharmaceutically acceptable salt thereof or solvate thereof, wherein the amlodipine or pharmaceutically acceptable salt thereof is not contained in the second compartment containing the atorvastatin or pharmaceutically acceptable salt thereof or solvate thereof, and the pharmaceutical combination preparation has a pH of 8.0 to 10.0 when dissolved in distilled water.
- the pharmaceutical combination preparation according to the present invention which comprises candesartan, amlodipine and atorvastatin simultaneously, may exhibit pharmacological effects comparable to those of co-administration of Lipitor ® Tab, which is a single tablet of atorvastatin, and Cantabell ® Tab which is a combination tablet of candesartan and amlodipine, because the dissolution pattern and PK profile of each of the active ingredients are equivalent to those of the co-administration.
- the pharmaceutical combination preparation since the contents of individual and total related substances in the pharmaceutical combination preparation according to the present invention do not significantly increase under long-term and accelerated conditions, the pharmaceutical combination preparation is highly stable and may have significantly improve the convenience of drug administration, suggesting that it may be used as a combination preparation useful for the prevention or treatment of hypertension and hyperlipidemia.
- a numerical range includes numerical values defined in the range. Every maximum numerical limitation given throughout the present specification includes every lower numerical limitation, as if such lower numerical limitations were expressly written herein. Every minimum numerical limitation given throughout the present specification will include every higher numerical limitation, as if such higher numerical limitations were expressly written herein. Every numerical range given throughout this specification will include every narrower numerical range that falls within such broader numerical range, as if such narrower numerical ranges were all expressly written herein.
- the present inventors have made efforts to design a dosage form, which minimizes drug-drug interactions (DDI) and increases stability, in order to develop a three-agent combination preparation comprising, as active ingredients, the angiotensin-receptor blocker (ARB) candesartan and the calcium channel blocker (CCB) amlodipine, which are antihypertensive agents, and the statin-based drug atorvastatin which is a hyperlipidemia therapeutic agent.
- DPI drug-drug interactions
- ARB angiotensin-receptor blocker
- CCB calcium channel blocker
- statin-based drug atorvastatin which is a hyperlipidemia therapeutic agent.
- the present inventors have designed as a dosage form of a pharmaceutical combination preparation in order to achieve the above-described objects, and as a result, have found that the pharmaceutical combination preparation may exhibit pharmacological effects comparable to those of co-administration of Lipitor ® , which is a single tablet of atorvastatin, and Cantabell ® which is a combination tablet of candesartan and amlodipine, because the dissolution pattern and PK profile of each of the active ingredients are equivalent to those of the co-administration, and the pharmaceutical combination preparation may have significantly improve the convenience of drug administration due to its high stability under long-term and accelerated conditions, thereby completing the present invention.
- Lipitor ® which is a single tablet of atorvastatin
- Cantabell ® which is a combination tablet of candesartan and amlodipine
- the present invention provides the following means.
- the present invention provides a pharmaceutical combination preparation comprising candesartan or candesartan cilexetil, atorvastatin or a pharmaceutically acceptable salt thereof or a solvate thereof, and amlodipine or a pharmaceutically acceptable salt thereof, the pharmaceutical combination preparation comprising: a first compartment containing the candesartan or candesartan cilexetil; and a second compartment containing the atorvastatin or pharmaceutically acceptable salt thereof or solvate thereof, wherein the amlodipine or pharmaceutically acceptable salt thereof is not contained in the second compartment containing the atorvastatin or pharmaceutically acceptable salt thereof or solvate thereof.
- the present invention provides a pharmaceutical combination preparation comprising candesartan or candesartan cilexetil, atorvastatin or a pharmaceutically acceptable salt thereof or a solvate thereof, and amlodipine or a pharmaceutically acceptable salt thereof, the pharmaceutical combination preparation comprising: a first compartment containing the candesartan or candesartan cilexetil; and a second compartment containing the atorvastatin or pharmaceutically acceptable salt thereof or solvate thereof, wherein the amlodipine or pharmaceutically acceptable salt thereof is not contained in the second compartment containing the atorvastatin or pharmaceutically acceptable salt thereof or solvate thereof, and the pharmaceutical combination preparation has a pH of 8.0 to 10.0 when dissolved in distilled water.
- candesartan refers to a benzimidazole-based drug represented by the following Formula 1, which is an angiotensin II receptor blocker (ARB) and is mainly used for the treatment of hypertension.
- ARB angiotensin II receptor blocker
- the specific chemical name of candesartan is 2-ethoxy-1-[[2'-(4,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylic acid.
- candesartan cilexetil is a prodrug of candesartan, represented by the following Formula 2, which is hydrolyzed to candesartan due to ester hydrolysis upon absorption in the gastrointestinal tract and exhibits activity.
- the specific chemical name of candesartan cilexetil is 1-(cyclohexyloxycarbonyloxy)ethyl-2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate.
- the candesartan or candesartan cilexetil that is used in the present invention may be easily chemically synthesized by synthesis methods known to those skilled in the art, or may be a commercially available product.
- amlodipine refers to a compound represented by the following Formula 3, which is a calcium channel blocker (CCB) mainly used for the treatment of hypertension and angina.
- CB calcium channel blocker
- the specific chemical name of amlodipine is 3-ethyl-5-methyl-2-(2-aminoethoxy-methyl)-4-(2-chlorophenyl)-6-methyl-1,4-dihydro-3,5-pyridine dicarboxylate.
- amlodipine that is used in the present invention may be easily chemically synthesized by synthesis methods known to those skilled in the art, or may be a commercially available product.
- atorvastatin refers to a compound represented by Formula 4 below, which is an HMG-CoA reductase inhibitor mainly used for the treatment of hyperlipidemia, hypercholesterolemia and atherosclerosis.
- the specific chemical name of atorvastatin is [R-(R*,R*)]-2-(4-fluorophenyl)- ⁇ , ⁇ -dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid.
- the atorvastatin that is used in the present invention may be easily chemically synthesized by synthesis methods known to those skilled in the art, or may be a commercially available product.
- the term “pharmaceutically acceptable salt” is meant to include salts derived from pharmaceutically acceptable acids or bases.
- pharmaceutically acceptable salt is meant to include any organic or inorganic addition salt which is used at a concentration that is relatively non-toxic and harmless to patients and in which side effects due to the salt do not deteriorate the beneficial effects of the pharmacologically active ingredient.
- solvate is meant to include hydrate, acetone solvate, methanol solvate, ethanol solvate, and the like.
- the pharmaceutically acceptable salt of amlodipine may be selected from among amlodipine hydrochloride, hydrobromide, sulfate, phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, and besylate, and may preferably be amlodipine besylate, without being limited thereto.
- the pharmaceutically acceptable salt of atorvastatin may be selected from among a calcium salt, magnesium salt, sodium salt, potassium salt, and aluminum salt of atorvastatin, and the solvate may be used in the form of a hydrate.
- atorvastatin may be atorvastatin calcium trihydrate (chemical name: (-)-monocalcium bis ⁇ (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-1H-pyrrol-1-yl]-3,5-dihydroxyheptanoate ⁇ trihydrate), but is not limited thereto.
- the first and second compartments may be formulated in a separate form, without being limited thereto.
- the term "separate form” means that the first compartment is separated from the second compartment by one or more additional compartments.
- the pharmaceutical combination preparation may further comprise a third compartment, which is positioned between the first and second compartments and does not contain the atorvastatin or pharmaceutically usable salt or solvate thereof or the candesartan or candesartan cilexetil, but the present invention is not limited thereto.
- third compartment refers to a compartment positioned between the first compartment and the second compartment to separate the first and second compartments from each other.
- the third compartment is composed only of pharmaceutical additives, or comprises pharmaceutical additives and a pharmacologically active substance.
- the third compartment may comprise a binder, a diluent, a disintegrant, and a lubricant, which are pharmaceutical additives, without being limited thereto.
- the binder may be at least one selected from the group consisting of polyvinylpyrrolidone (PVP), methyl cellulose, and hydroxypropylmethyl cellulose (HPMC), without being limited thereto.
- PVP polyvinylpyrrolidone
- HPMC hydroxypropylmethyl cellulose
- the diluent may be at least one selected from the group consisting of anhydrous calcium hydrogen phosphate, microcrystalline cellulose, xylitol, trehalose, sorbitol, maltose, sorbitol, erythritol, glucose, maltitol, mannitol, sucrose, lactose, and hydrates thereof, without being limited thereto.
- the disintegrant may be any one or more selected from the group consisting of crospovidone, sodium starch glycolate, croscarmellose sodium, low-substituted hydroxypropyl cellulose, starch, alginic acid or sodium salt thereof, and mixtures thereof, without being limited thereto.
- the lubricant may be any one or more selected from the group consisting of sodium stearyl fumarate, magnesium stearate, calcium stearate, sucrose, fatty acid stearate, sucrose fatty acid ester, talc, hydrogenated vegetable oil, high-melting-point wax, glyceryl fatty acid esters, glyceryl behenate, and mixtures thereof, without being limited thereto.
- the third compartment may comprise polyvinylpyrrolidone (PVP), anhydrous calcium hydrogen phosphate, microcrystalline cellulose, croscarmellose sodium and magnesium stearate, without being limited thereto.
- PVP polyvinylpyrrolidone
- anhydrous calcium hydrogen phosphate microcrystalline cellulose
- croscarmellose sodium and magnesium stearate without being limited thereto.
- the third compartment may be comprised in an amount of 5 to 40 wt%, specifically 10 to 30 wt%, based on the total weight of the pharmaceutical combination formulation, but the present invention is limited thereto.
- the pharmaceutical combination preparation of the present invention comprises the third compartment as described above, there is an advantage in that the first compartment and the second compartment are formulated in a separate form, so that the increase in absorption of candesartan or candesartan cilexetil by the alkalizing agent included in the second compartment to be described later may be minimized, and thus the alkalizing agent does not affect the solubility of candesartan or candesartan cilexetil, indicating that it is possible to design a pharmaceutical combination preparation.
- the pharmaceutical combination preparation may be a trilayer tablet formulation comprising: a first layer containing candesartan or candesartan cilexetil and amlodipine or a pharmaceutically acceptable salt thereof; a second layer containing atorvastatin or a pharmaceutically acceptable salt or a solvate thereof; and a third layer positioned between the first layer and the second layer and containing additives, but the present invention is not limited thereto.
- a dosage form that minimizes the interaction between candesartan or candesartan cilexetil and an alkalizing agent for atorvastatin or a pharmaceutically acceptable salt thereof or a solvate thereof.
- a dosage form may be designed to comprise an additive layer between the first layer and the second layer, so that the first layer and the second layer may be formulated in a separate form, so that the increase in absorption of candesartan or candesartan cilexetil by the alkalizing agent may be minimized, thus ensuring bioequivalence.
- the pharmaceutical combination preparation may be a trilayer tablet formulation comprising: a first layer containing candesartan or candesartan cilexetil; a second layer containing atorvastatin or a pharmaceutically acceptable salt thereof or a solvate thereof; and a third layer positioned between the first layer and the second layer and containing additives and amlodipine or a pharmaceutically acceptable salt thereof, but the present invention is not limited thereto.
- the pharmaceutical combination preparation may be a bilayer table formulation comprising: a first layer containing candesartan or candesartan cilexetil and amlodipine or a pharmaceutically acceptable salt thereof; and a second layer containing atorvastatin or a pharmaceutically acceptable salt thereof or a solvate thereof, but the present invention is not limited thereto.
- the second compartment containing atorvastatin or a pharmaceutically acceptable salt or solvate thereof may contain an alkalizing agent, but the present invention is not limited thereto.
- alkalizing agent refers to an alkaline compound for stabilizing atorvastatin or a pharmaceutically acceptable salt thereof or a solvate thereof.
- atorvastatin in an acidic environment, is degraded into the corresponding lactone.
- atorvastatin When formulated in a tablet, powder or other dosage form, atorvastatin may be present in contact with pharmaceutical additives such as a binder, a diluent, etc., or may be destabilized by contact with additives.
- the alkalizing agent serves to control the solubility and bioavailability of the active ingredient atorvastatin or a pharmaceutically acceptable salt thereof or a solvate thereof by preventing the degradation thereof, and may be used to modulate the pharmacokinetic parameters of the atorvastatin or pharmaceutically acceptable salt thereof or solvate thereof by affecting the solubility thereof.
- the alkalizing agent may be at least one selected from the group consisting of magnesium hydroxide (Mg(OH) 2 ), magnesium carbonate (MgCO 3 ), calcium carbonate (CaCO 3 ), sodium carbonate (Na 2 CO 3 ), meglumine (C 7 H 17 NO 5 ), arginine (C 6 H 14 N 4 O 2 ) and sodium hydroxide (NaOH), without being limited thereto.
- Mg(OH) 2 magnesium hydroxide
- MgCO 3 magnesium carbonate
- CaCO 3 calcium carbonate
- Na 2 CO 3 sodium carbonate
- meglumine C 7 H 17 NO 5
- arginine C 6 H 14 N 4 O 2
- NaOH sodium hydroxide
- the density of the alkalizing agent may be 0.2 to 1.5 g/cm 3 , specifically 0.5 to 1.3 g/cm 3 , and the optimum density within the above range may be 0.8 to 1.3 g/cm 3 or 0.5 to 0.7 g/cm 3 , but the present invention is not limited thereto.
- the alkalizing agent may be contained in an amount of 10 to 50 wt%, specifically 20 to 45 wt%, based on the total weight of the second compartment containing the atorvastatin or pharmaceutically acceptable salt thereof or solvate thereof, but the present invention is not limited thereto. That is, when the alkalizing agent satisfies the above-described particle size, surface area and density conditions, it may exhibit a dissolution rate equivalent to that of atorvastatin calcium trihydrate of Lipitor ® tablet.
- the pharmaceutical combination preparation may have a pH in the range of 8.0 to 10.0 when dissolved in distilled water.
- the alkalizing agent when used in the second compartment containing atorvastatin or a pharmaceutically acceptable salt thereof or a solvate thereof, it may affect the in vivo absorption of candesartan or candesartan cilexetil contained in the first compartment, and thus it is necessary to adjust the pH of the pharmaceutical combination preparation.
- the pH of the pharmaceutical combination preparation when dissolved in distilled water is adjusted within the range of 8.0 to 10.0, specifically 8.5 to 9.5, the candesartan or candesartan cilexetil may exhibit a dissolution rate equivalent to that of candesartan of Cantabell ® tablet.
- candesartan or candesartan cilexetil, atorvastatin or a pharmaceutically acceptable salt thereof or solvate thereof, and amlodipine or a pharmaceutically acceptable salt thereof may be in the form of granules.
- the candesartan or candesartan cilexetil and amlodipine or pharmaceutically acceptable salt thereof contained in the first compartment, and atorvastatin or pharmaceutically acceptable salt thereof or solvate thereof contained in the second compartment may be in the form of granules, without being limited thereto.
- the third compartment that contains only additives or does not contain the atorvastatin or pharmaceutically usable salt thereof or solvate thereof or the candesartan or candesartan cilexetil may be in the form of granules, without being limited thereto.
- the granules may be prepared through conventional granulation methods, including dry granulation method and wet granulation method, and preferably may be prepared by wet granulation method.
- the granules of the present invention may further contain a binder, and a binder commonly used may be used as the binder.
- the candesartan or candesartan cilexetil may be 8 to 16 mg per unit preparation, without being limited thereto.
- the content of the amlodipine or pharmaceutically acceptable salt thereof may be 5 to 10 mg per unit preparation, without being limited thereto.
- the content of the atorvastatin or pharmaceutically acceptable salt thereof or solvate thereof may be 10 to 40 mg per unit preparation, without being limited thereto.
- the pharmaceutical combination preparation may comprise candesartan or candesartan cilexetil, amlodipine or a pharmaceutically acceptable salt thereof and atorvastatin or a pharmaceutically acceptable salt thereof or a solvate thereof in the following amounts per unit preparation, without being limited thereto.
- the pharmaceutical combination preparation may be for the prevention or treatment of hypertension and hyperlipidemia, without being limited thereto.
- the dissolution rate of candesartan or candesartan cilexetil in the pharmaceutical combination preparation may be equivalent to the dissolution rate of candesartan cilexetil of Cantabell ® Tab.
- the dissolution rate of amlodipine or a pharmaceutically acceptable salt thereof in the pharmaceutical combination preparation may be equivalent to the dissolution rate of amlodipine besylate of Cantabell ® Tab.
- the dissolution rate of atorvastatin or a pharmaceutically acceptable salt thereof or a solvate thereof in the pharmaceutical combination preparation may be equivalent to the dissolution rate of atorvastatin calcium trihydrate of Lipitor ® Tab.
- each of candesartan or candesartan cilexetil and amlodipine or a pharmaceutically acceptable salt thereof in the pharmaceutical combination preparation may exhibit a serum drug concentration-time area under curve (hereinafter referred to as "AUC") bioequivalent to that of Cantabell ® Tab containing the same amounts of the active ingredients.
- AUC serum drug concentration-time area under curve
- atorvastatin or a pharmaceutically acceptable salt thereof or a solvate thereof in the pharmaceutical composition may exhibit a serum drug concentration-time area under curve (AUC) bioequivalent to that of Lipitor ® Tab containing the same amount of the active ingredient.
- AUC serum drug concentration-time area under curve
- the present invention provides a method for preventing or treating hypertension and hyperlipidemia comprising a step of administering a therapeutically effective amount of the pharmaceutical combination preparation to a subject in need thereof.
- the prevention or treatment method according to the present invention comprises not only dealing with the disease itself before the onset of symptoms, but also inhibiting or avoiding the symptoms thereof by administering the pharmaceutical combination preparation.
- the prophylactic or therapeutic dose of a particular active ingredient will vary depending on the nature and severity of the disease or condition, and the route along which the active ingredient is administered.
- the dose and the dosing frequency will vary depending on the age, weight and response of the individual patient.
- a suitable dosage regimen may be readily selected by one of ordinary skill in the art while taking these factors into account.
- the treatment method according to the present disclosure may further include administration of a therapeutically effective amount of an additional active agent useful for disease treatment together with the pharmaceutical combination preparation.
- the additional active agent may exhibit a synergistic effect or an auxiliary effect with the pharmaceutical combination preparation.
- the present invention provides the use of the pharmaceutical combination preparation for the manufacture of a medicament having a preventive or therapeutic effect on hypertension and hyperlipidemia.
- the pharmaceutical combination preparation for the manufacture of the medicament may be mixed with acceptable adjuvants, diluents, carriers, and the like, and may be prepared into a complex preparation along with other active agents, thus having a synergy action of active ingredients.
- the present invention provides the use of the pharmaceutical combination preparation for the manufacture of a medicament having a preventive or therapeutic effect on hypertension and hyperlipidemia.
- Example 1 Content (mg) Candesartan cilexetil and amlodipine besylate granules Candesartan cilexetil 16.00 Amlodipine besylate (as amlodipine) 13.88 (10.00) Mannitol 148.32 Microcrystalline cellulose 50.00 Copovidone 12.00 Hydroxypropyl cellulose 12.00 Triethyl citrate 2.60 Sodium stearyl fumarate 2.60 Magnesium stearate 2.60 Total weight of candesartan/amlodipine besylate granules 260.00 Atorvastatin calcium trihydrate granules Atorvastatin calcium trihydrate (as atorvastatin) 43.40 (40.00) Lactose hydrate 58.04 Microcrystalline cellulose 39.16 Croscarmellose sodium 25.00 Hydroxypropyl cellulose 6.00 Precipitated magnesium carbonate 80.00 Polysorbate 80 2.40 Magnesium stearate 2.00 Total weight of
- a binder solution was prepared by dissolving hydroxypropyl cellulose and triethyl citrate in purified water. Then, amlodipine besylate and mannitol were mixed together and sieved, and then candesartan cilexetil, microcrystalline cellulose and mannitol were added thereto. The resulting mixture was kneaded with the binding solution.
- the kneaded product was granulated, dried in a cabinet dryer, and milled in a co-mill, and then mannitol, copovidone, magnesium stearate and sodium stearyl fumarate were added thereto and finally mixed, thereby preparing candesartan cilexetil and amlodipine besylate granules.
- a binder solution was prepared by dissolving hydroxypropyl cellulose and polysorbate 80 in purified water. Then, a mixture of precipitated magnesium carbonate as an alkalizing, croscarmellose sodium, atorvastatin calcium trihydrate, lactose hydrate, and microcrystalline cellulose was kneaded with the binder solution.
- the kneaded product was granulated, dried in a fluidized bed granulator, and milled in a co-mill, and then croscarmellose sodium and magnesium stearate were added thereto, thereby preparing atorvastatin calcium trihydrate granules.
- the candesartan cilexetil and amlodipine besylate granules and the atorvastatin calcium trihydrate granules were compressed into a tablet.
- a colorant was suspended in purified water, and then the tablet was coated with the suspension by means of a coating machine, thereby preparing a coated tablet.
- a pharmaceutical combination preparation in a bilayer form was prepared in the same manner as in Example 1, except that 8 mg candesartan cilexetil, 6.94 mg amlodipine besylate (5 mg as amlodipine) and 10.85 mg atorvastatin calcium trihydrate (10 mg as atorvastatin) were used as active ingredients, 12 mg magnesium carbonate was used, and the amounts of the pharmaceutical additives contained in the candesartan cilexetil and amlodipine besylate granules and the atorvastatin calcium trihydrate granules were adjusted according to the reduced ratios of the main ingredients.
- a pharmaceutical combination preparation in a bilayer form was prepared in the same manner as in Example 1, except that 8 mg candesartan cilexetil, 6.94 mg amlodipine besylate (5 mg as amlodipine) and 10.85 mg atorvastatin calcium trihydrate (10 mg as atorvastatin) were used as active ingredients, 33 mg ground calcium carbonate (particle size: 0.5 to 45 ⁇ m, surface area: 3,500 cm 2 /g, and density: 0.8 to 1.3 g/cm 3 ) was used instead of magnesium carbonate, and the amounts of the pharmaceutical additives contained in the candesartan cilexetil and amlodipine besylate granules and the atorvastatin calcium trihydrate granules were adjusted according to the reduced ratios of the main ingredients.
- a pharmaceutical combination preparation in a trilayer form was prepared in the same manner as in Example 1, except that 33 mg ground calcium carbonate (particle size: 0.5 to 45 ⁇ m, surface area: 3,500 cm 2 /g, and density: 0.8 to 1.3 g/cm 3 ) was used instead of magnesium carbonate, the following step of preparing an additive layer granules was performed between step 2) of preparing atorvastatin calcium trihydrate granules and step 3) of tableting, and in the tableting step, the candesartan cilexetil granules, the additive layer granules, and the atorvastatin calcium trihydrate granules were sequentially placed and compressed into a tablet.
- Microcrystalline cellulose (82 mg), anhydrous calcium hydrogen phosphate (76 mg), copovidone (30 mg), croscarmellose sodium (10 mg) and magnesium stearate (2 mg) were added and mixed together, thus preparing additive layer granules.
- a pharmaceutical combination preparation in a trilayer form was prepared in the same manner as in Example 4, except that 33 mg precipitated calcium carbonate (particle size: 0.5 to 15 ⁇ m, surface area: 15,600 cm 2 /g, and density: 0.5 to 0.7 g/cm 3 ) was used instead of ground calcium carbonate.
- a pharmaceutical combination preparation in a trilayer form was prepared in the same manner as in Example 5, except that the active ingredient amlodipine besylate contained in the candesartan cilexetil and amlodipine besylate granules was applied to additive layer granules, so that candesartan cilexetil granules, additive layer granules containing amlodipine besylate, and atorvastatin calcium trihydrate granules were used.
- Lipitor ® Tab 40 mg (Comparative Example 1), Cantabell ® Tab 16/10 mg (Comparative Example 2), Lipitor ® Tab 10 mg (Comparative Example 3), and Cantabell ® Tab 8/5 mg (Comparative Example 4) were selected as reference drugs.
- the pharmaceutical combination preparation (high dose) according to Example 1 was orally administered to a healthy adult male, or Comparative Example 1 (Lipitor ® Tab 40 mg) and Comparative Example 2 (Cantabell ® Tab 16/10 mg) were co-administered, and then bioequivalence was evaluated.
- candesartan cilexetil (8 mg) and each type and amount of alkalizing agent were added to 900 mL of distilled water, and then dissolved for 3 hours with stirring at 200 rpm, and the solubility of the candesartan cilexetil was examined.
- magnesium carbonate (MgCO 3 ) and calcium carbonate (CaCO 3 ) were used as an alkalizing agent contained in the atorvastatin calcium trihydrate layer, the in vivo absorption of candesartan cilexetil was examined in a clinical trial at a low dose (8/5/10 mg).
- each of the pharmaceutical combination preparations according to Examples 2 and 3 was administered once to healthy adult males, and then the blood was collected at the same time points, and the blood concentration of each of atorvastatin calcium trihydrate, amlodipine besylate and candesartan cilexetil was quantified using LC-MS/MS.
- the AUC values of atorvastatin calcium trihydrate, amlodipine besylate and candesartan cilexetil upon oral administration of each of the pharmaceutical combination preparations according to Examples 2 and 3 were log-transformed, and then the geometric mean was calculated and the 90% confidence interval for the ratio of the geometric mean was calculated.
- each of the pharmaceutical combination preparations according to Examples 2 and 3 and the pharmaceutical combination preparations according to Comparative Examples 3 and 4 was added to 900 mL of distilled water and dissolved for 3 hours while stirring at 200 rpm, and the solubility of the candesartan cilexetil was examined.
- Table 4 shows the pharmacokinetic behaviors of the pharmaceutical combination preparations at a low dose (8/5/10 mg) depending on the type of alkalizing agent.
- Example 2 (MgCO 3 )
- Example 3 (CaCO 3 )
- Amlodipine besylate AUC 0.99 0.97
- Candesartan cilexetil AUC 0.93 0.93
- Table 5 below shows the pH environments and the absorption behaviors of candesartan at high and low doses depending on the weight of the alkalizing agent.
- Example 2 (MgCO 3 )
- Example 3 (CaCO 3 ) CaCO 3 pH Solubility (Can) MgCO 3 pH Solubility (Can) CaCO 3 pH Solubility (Can)
- High dose (16/10/40) 132mg 9.0 38.7% 48mg 10.0 50.2% 132mg 8.7 36.2%
- Medium dose (16/5/20) 66mg 8.9 58.2% 24mg 8.8 58.7% 66mg 8.9 49.3%
- Low dose (8/5/10) 33mg 8.8 72.3% 12mg 8.7 67.8% 33mg 8.6 73.3%
- the dosage form was designed with calcium carbonate (CaCO 3 ) showing a pH and solubility of candesartan cilexetil similar to those of Comparative Examples 3 and 4 regardless of doses (low dose, medium dose, and high dose), and in particular, the dosage form was designed with the high dose on which the effect of the alkalizing agent was great.
- CaCO 3 calcium carbonate
- Example 3 is a bilayer tablet obtained by formulating granules containing candesartan cilexetil and amlodipine besylate and granules containing atorvastatin calcium trihydrate; and the pharmaceutical combination preparation of Example 4, which is a trilayer tablet obtained by adding an additive granule layer between the two layers in order to minimize the increase in absorption of candesartan cilexetil by the alkalizing agent of the atorvastatin layer.
- the pharmaceutical combination preparations according to Examples 3 and 4 were administered once to healthy adult males, and then the blood was collected at the same time points, and the blood concentration of each of atorvastatin calcium trihydrate, amlodipine besylate and candesartan cilexetil was quantified using LC-MS/MS. After quantification, the AUC values of atorvastatin calcium trihydrate, amlodipine besylate and candesartan cilexetil upon administration of each of each of the pharmaceutical combination preparations according to Examples 3 and 4 were log-transformed, and then the geometric mean was calculated and the 90% confidence interval for the ratio of the geometric mean was calculated.
- Example 3 (bilayer tablet)
- Example 4 (trilayer tablet) Atorvastatin calcium trihydrate AUC 0.95 1.05 Amlodipine besylate AUC 1.00 1.04 Candesartan cilexetil AUC 0.84 0.91
- dissolution rate measurement was performed based on method 1 (rotating basket method) prescribed in the Korean Pharmacopoeia. 900 mL of DW was used as a dissolution medium, the dissolution temperature was 37 ⁇ 0.5°C, and the rotation speed was 50 rpm. At 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes, 60 minutes and 90 minutes after the start of dissolution, the dissolution medium was taken and filtered to obtain a sample solution, and the dissolution rate was measured by analyzing the sample solution together with a standard solution by liquid chromatography.
- Table 8 shows the results of measuring the dissolution profiles of Lipitor ® Tab 40 mg according to Comparative Example 1 and the pharmaceutical combination preparations according to Examples 4 and 5.
- dissolution rate measurement was performed based on method 1 (rotating basket method) prescribed in the Korean Pharmacopoeia. 900 mL of DW was used as a dissolution medium, the dissolution temperature was 37 ⁇ 0.5°C, and the rotation speed was 50 rpm. At 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes and 60 minutes after the start of dissolution, the dissolution medium was taken and filtered to obtain a sample solution, and the dissolution rate was measured by analyzing the sample solution together with a standard solution by liquid chromatography.
- Table 9 below shows the results of measuring the dissolution profiles of the pharmaceutical combination preparations according to Examples 5 and 6.
- Candesartan cilexetil Example 5 0.1 0.3 1.2 3.0 4.5
- Atorvastatin calcium trihydrate Example 5 30.5 58.2 67.4 78.1 83.5 84.1
- the pharmaceutical combination preparation according to Example 5 was orally administered to healthy adult males, or Comparative Example 1 (Lipitor ® Tab 40 mg) and Comparative Example 2 (Cantabell ® Tab 16/10 mg) were co-administered, and then bioequivalence was evaluated.
- the blood was collected at the same time points, and the blood concentration of each of atorvastatin calcium trihydrate, amlodipine besylate and candesartan cilexetil was quantified using LC-MS/MS.
- the AUC values of atorvastatin calcium trihydrate, amlodipine besylate and candesartan cilexetil upon oral administration of the pharmaceutical combination preparation according to Example 5 and a combination of Comparative Example 1 (Lipitor ® Tab 40 mg) and Comparative Example 2 (Cantabell ® Tab 16/10 mg) were log-transformed, and then the geometric mean was calculated and the 90% confidence interval for the ratio of the geometric mean was calculated. When the 90% confidence interval is 0.8 to 1.25, the two formulations are recognized as bioequivalent.
- Table 10 shows the results of evaluating bioequivalence as described above.
- the 90% confidence interval for the ratio of the geometric mean of the AUC value of each of atorvastatin calcium trihydrate, amlodipine besylate and candesartan cilexetil in the pharmaceutical combination preparation of Example 5 was within the range of 0.8 to 1.25, indicating that oral administration of the pharmaceutical combination preparation according to Example 5 of the present invention exhibited PK profiles equivalent to those of oral administration of a combination of Comparative Examples 1 and 2.
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Abstract
Description
Compartment | Components | Example 1 |
Content (mg) | ||
Candesartan cilexetil and amlodipine besylate granules |
Candesartan cilexetil | 16.00 |
Amlodipine besylate (as amlodipine) | 13.88 (10.00) |
|
Mannitol | 148.32 | |
Microcrystalline cellulose | 50.00 | |
Copovidone | 12.00 | |
Hydroxypropyl cellulose | 12.00 | |
Triethyl citrate | 2.60 | |
Sodium stearyl fumarate | 2.60 | |
Magnesium stearate | 2.60 | |
Total weight of candesartan/amlodipine besylate granules | 260.00 | |
Atorvastatin calcium trihydrate granules | Atorvastatin calcium trihydrate (as atorvastatin) | 43.40 (40.00) |
Lactose hydrate | 58.04 | |
Microcrystalline cellulose | 39.16 | |
Croscarmellose sodium | 25.00 | |
Hydroxypropyl cellulose | 6.00 | |
Precipitated magnesium carbonate | 80.00 | |
Polysorbate 80 | 2.40 | |
Magnesium stearate | 2.00 | |
Total weight of atorvastatin calcium trihydrate granules | 256.00 |
T/R | Example 1 (MgCO3) | |
Atorvastatin calcium trihydrate | AUC | 1.02 |
Amlodipine besylate | AUC | 1.05 |
Candesartan cilexetil | AUC | 1.20 |
Alkalizing agent | pH | Candesartan content | |
Magnesium carbonate (MgCO3) | 20 mg (Example 1) |
9.6 | 82.6% |
16 mg | 9.3 | 82.4% | |
12 mg(Example 2) | 8.9 | 75.3% | |
10 mg | 8.5 | 72.5% | |
Calcium carbonate (CaCO3) | Lipitor® Tab 10 mg (Comparative Example 3) |
8.8 | 72.3% |
33 mg (Example 3) |
8.6 | 73.3% |
T/R | Example 2 (MgCO3) | Example 3 (CaCO3) | |
Atorvastatin calcium trihydrate | AUC | 0.98 | 1.01 |
Amlodipine besylate | AUC | 0.99 | 0.97 |
Candesartan cilexetil | AUC | 0.93 | 0.93 |
Can/Aml/Ato | Comparative Examples 3 and 4 | Example 2 (MgCO3) | Example 3 (CaCO3) | ||||||
CaCO3 | pH | Solubility (Can) | MgCO3 | pH | Solubility (Can) | CaCO3 | pH | Solubility (Can) | |
High dose (16/10/40) | 132mg | 9.0 | 38.7% | 48mg | 10.0 | 50.2% | 132mg | 8.7 | 36.2% |
Medium dose (16/5/20) | 66mg | 8.9 | 58.2% | 24mg | 8.8 | 58.7% | 66mg | 8.9 | 49.3% |
Low dose (8/5/10) |
33mg | 8.8 | 72.3% | 12mg | 8.7 | 67.8% | 33mg | 8.6 | 73.3% |
T/R | Example 3 (bilayer tablet) |
Example 4 (trilayer tablet) |
|
Atorvastatin calcium trihydrate | AUC | 0.95 | 1.05 |
Amlodipine besylate | AUC | 1.00 | 1.04 |
Candesartan cilexetil | AUC | 0.84 | 0.91 |
Calcium carbonate (ground) | Calcium carbonate (precipitated) | |
Particle size (μm) | 0.5 to 45 | 0.5 to 15 |
Surface area (cm2/g) | 3,500 | 15,600 |
Density (g/cm3) | 0.8 to 1.3 | 0.5 to 0.7 |
Component | Example | D.W. dissolution rate (%) | ||||||
5 min | 10 min | 15 min | 30 min | 45 min | 60 min | 90 min | ||
Atorvastatin calcium trihydrate |
Comparative Example 1 | 61.9 | 67.4 | 70.7 | 75.0 | 78.0 | 79.3 | 95.9 |
Example 4 (ground) |
8.1 | 34.7 | 48.8 | 64.1 | 68.4 | 71.0 | 84.8 | |
Example 5 (precipitated) |
30.5 | 58.2 | 67.4 | 78.1 | 83.5 | 84.1 | 91.6 |
Component | Example | D.W. dissolution rate (%) | |||||
5 min | 10 min | 15 min | 30 min | 45 min | 60 min | ||
Amlodipine besylate | Example 5 | 0.1 | 1.4 | 6.4 | 21.1 | 29.1 | 32.5 |
Example 6 | 17.2 | 35.4 | 48.2 | 62.2 | 71.8 | 76.7 | |
Candesartan cilexetil | Example 5 | 0.1 | 0.3 | 1.2 | 3.0 | 4.5 | 6.2 |
Example 6 | 0.2 | 0.4 | 1.6 | 3.5 | 5.0 | 7.3 | |
Atorvastatin calcium trihydrate | Example 5 | 30.5 | 58.2 | 67.4 | 78.1 | 83.5 | 84.1 |
Example 6 | 32.7 | 60.3 | 69.6 | 80.2 | 85.8 | 87.3 |
T/R | Example 5 | |
Atorvastatin calcium trihydrate | AUC | 1.05 |
Amlodipine besylate | AUC | 1.00 |
Candesartan cilexetil | AUC | 0.96 |
Claims (17)
- A pharmaceutical combination preparation comprising candesartan or candesartan cilexetil, atorvastatin or a pharmaceutically acceptable salt thereof or a solvate thereof, and amlodipine or a pharmaceutically acceptable salt thereof,the pharmaceutical combination preparation comprising: a first compartment containing the candesartan or candesartan cilexetil; and a second compartment containing the atorvastatin or pharmaceutically acceptable salt thereof or solvate thereof,wherein the amlodipine or pharmaceutically acceptable salt thereof is not contained in the second compartment containing the atorvastatin or pharmaceutically acceptable salt thereof or solvate thereof.
- The pharmaceutical combination preparation of claim 1, wherein the first and second compartments are formulated in a separate form.
- The pharmaceutical combination preparation of claim 1, further comprising a third compartment which is positioned between the first and second compartments and does not contain the atorvastatin or pharmaceutically usable salt thereof or solvate thereof or the candesartan or candesartan cilexetil.
- The pharmaceutical combination preparation of claim 3, wherein the third compartment contains a binder, a diluent, a disintegrant, and a lubricant.
- The pharmaceutical combination preparation of claim 3, wherein the third compartment is comprised in an amount of 5 to 40 wt% based on the total weight of the pharmaceutical combination preparation.
- The pharmaceutical combination preparation of claim 3, which is a trilayer tablet formulation consisting of:a first layer containing the candesartan or candesartan cilexetil and the amlodipine or pharmaceutically acceptable salt thereof;a second layer containing the atorvastatin or pharmaceutically acceptable salt or solvate thereof; anda third layer positioned between the first layer and the second layer and containing additives.
- The pharmaceutical combination preparation of claim 3, which is a trilayer tablet formulation consisting of:a first layer containing the candesartan or candesartan cilexetil;a second layer containing the atorvastatin or pharmaceutically acceptable salt thereof or solvate thereof; anda third layer positioned between the first layer and the second layer and containing additives and the amlodipine or pharmaceutically acceptable salt thereof.
- The pharmaceutical combination preparation of claim 1, which is a bilayer table formulation consisting of:a first layer containing the candesartan or candesartan cilexetil and the amlodipine or pharmaceutically acceptable salt thereof; anda second layer containing the atorvastatin or pharmaceutically acceptable salt thereof or solvate thereof.
- The pharmaceutical combination preparation of claim 1, wherein the second compartment containing the atorvastatin or pharmaceutically acceptable salt thereof or solvate thereof contains an alkalizing agent.
- The pharmaceutical combination preparation of claim 9, wherein the alkalizing agent is at least one selected from the group consisting of magnesium oxide (Mg(OH)2), magnesium carbonate (MgCO3), calcium carbonate (CaCO3), sodium carbonate (Na2CO3), meglumine (C7H17NO5), arginine (C6H14N4O2) and sodium hydroxide (NaOH).
- The pharmaceutical combination preparation of claim 9, wherein the alkalizing agent has a density of 0.2 to 1.5 g/cm3.
- The pharmaceutical combination preparation of claim 9, wherein the alkalizing agent is contained in an amount of 10 to 50 wt% based on the total weight of the second compartment containing the atorvastatin or pharmaceutically acceptable salt thereof or solvate thereof.
- The pharmaceutical combination preparation of claim 1, wherein the candesartan or candesartan cilexetil, the atorvastatin or pharmaceutically acceptable salt thereof, and the amlodipine or pharmaceutically acceptable salt thereof are in the form of granules.
- The pharmaceutical combination preparation of claim 1, wherein the candesartan or candesartan cilexetil is contained in an amount of 8 to 16 mg per unit preparation.
- The pharmaceutical combination preparation of claim 1, wherein the amlodipine or pharmaceutically acceptable salt thereof is contained in an amount of 5 to 10 mg per unit preparation.
- The pharmaceutical combination preparation of claim 1, wherein the atorvastatin or pharmaceutically acceptable salt thereof or solvate thereof is contained in an amount of 10 to 40 mg per unit preparation.
- A pharmaceutical combination preparation comprising candesartan or candesartan cilexetil, atorvastatin or a pharmaceutically acceptable salt thereof or a solvate thereof, and amlodipine or a pharmaceutically acceptable salt thereof,the pharmaceutical combination preparation comprising: a first compartment containing the candesartan or candesartan cilexetil; and a second compartment containing the atorvastatin or pharmaceutically acceptable salt thereof or solvate thereof,wherein the amlodipine or pharmaceutically acceptable salt thereof is not contained in the second compartment containing the atorvastatin or pharmaceutically acceptable salt thereof or solvate thereof, andthe pharmaceutical combination preparation has a pH of 8.0 to 10.0 when dissolved in distilled water.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
MX2023015116A MX2023015116A (en) | 2021-06-24 | 2022-06-23 | Pharmaceutical combination preparation comprising candesartan, amlodipine and atorvastatin. |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR1020210082309A KR20230000506A (en) | 2021-06-24 | 2021-06-24 | Pharmaceutical combination preparation comprising candesartan, amlodipine and atorvastatin |
KR10-2021-0082309 | 2021-06-24 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2022270935A1 true WO2022270935A1 (en) | 2022-12-29 |
Family
ID=84545782
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/KR2022/008921 WO2022270935A1 (en) | 2021-06-24 | 2022-06-23 | Pharmaceutical combination preparation comprising candesartan, amlodipine and atorvastatin |
Country Status (3)
Country | Link |
---|---|
KR (1) | KR20230000506A (en) |
MX (1) | MX2023015116A (en) |
WO (1) | WO2022270935A1 (en) |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20050119270A1 (en) * | 2000-08-04 | 2005-06-02 | Mason R. P. | Synergistic effect of amlodipine and atorvastatin on aortic endothelial cell nitric oxide release |
US20060177504A1 (en) * | 2005-02-08 | 2006-08-10 | Renjit Sundharadas | Combination pain medication |
EP2165702A1 (en) * | 2008-09-17 | 2010-03-24 | Helm AG | Stable and readily dissolved compositions of candesartan cilexetil prepared with wet granulation |
US20100267679A1 (en) * | 2009-04-15 | 2010-10-21 | Jacques Benoit | Pharmaceutical combination of medication to be used by patients for the purpose of preventing or reducing the evolution of atherosclerosis and thus preventing coronary heart disease and cerebro-vascular accidents. |
US10588859B2 (en) * | 2007-03-22 | 2020-03-17 | Berg Llc | Topical formulations having enhanced bioavailability |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4681893A (en) | 1986-05-30 | 1987-07-21 | Warner-Lambert Company | Trans-6-[2-(3- or 4-carboxamido-substituted pyrrol-1-yl)alkyl]-4-hydroxypyran-2-one inhibitors of cholesterol synthesis |
WO2006059217A1 (en) | 2004-12-01 | 2006-06-08 | Ranbaxy Laboratories Limited | Stable solid dosage forms of amlodipine besylate and processes for their preparation |
-
2021
- 2021-06-24 KR KR1020210082309A patent/KR20230000506A/en not_active Application Discontinuation
-
2022
- 2022-06-23 WO PCT/KR2022/008921 patent/WO2022270935A1/en active Application Filing
- 2022-06-23 MX MX2023015116A patent/MX2023015116A/en unknown
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20050119270A1 (en) * | 2000-08-04 | 2005-06-02 | Mason R. P. | Synergistic effect of amlodipine and atorvastatin on aortic endothelial cell nitric oxide release |
US20060177504A1 (en) * | 2005-02-08 | 2006-08-10 | Renjit Sundharadas | Combination pain medication |
US10588859B2 (en) * | 2007-03-22 | 2020-03-17 | Berg Llc | Topical formulations having enhanced bioavailability |
EP2165702A1 (en) * | 2008-09-17 | 2010-03-24 | Helm AG | Stable and readily dissolved compositions of candesartan cilexetil prepared with wet granulation |
US20100267679A1 (en) * | 2009-04-15 | 2010-10-21 | Jacques Benoit | Pharmaceutical combination of medication to be used by patients for the purpose of preventing or reducing the evolution of atherosclerosis and thus preventing coronary heart disease and cerebro-vascular accidents. |
Also Published As
Publication number | Publication date |
---|---|
MX2023015116A (en) | 2024-01-22 |
KR20230000506A (en) | 2023-01-03 |
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