WO2015147467A1 - Préparation pharmaceutique comprenant du telmisartan et de la (s)-amlodipine présentant une meilleure stabilité à l'oxydation - Google Patents

Préparation pharmaceutique comprenant du telmisartan et de la (s)-amlodipine présentant une meilleure stabilité à l'oxydation Download PDF

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WO2015147467A1
WO2015147467A1 PCT/KR2015/002461 KR2015002461W WO2015147467A1 WO 2015147467 A1 WO2015147467 A1 WO 2015147467A1 KR 2015002461 W KR2015002461 W KR 2015002461W WO 2015147467 A1 WO2015147467 A1 WO 2015147467A1
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Prior art keywords
amlodipine
pharmaceutical preparation
telmisartan
pharmaceutically acceptable
succinic acid
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PCT/KR2015/002461
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English (en)
Inventor
Ji Ye HAM
Jin A KOO
Hye Jin Seo
Shin Jung Park
Jong Lae Lim
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Chong Kun Dang Pharmaceutical Corp.
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Publication of WO2015147467A1 publication Critical patent/WO2015147467A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4422—1,4-Dihydropyridines, e.g. nifedipine, nicardipine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer

Definitions

  • the present invention relates to a pharmaceutical preparation comprising telmisartan and (S)-amlodipine with improved oxidative stability.
  • Hypertension refers to a condition where blood pressure above normal is maintained continuously. Hypertension causes various complications and may ultimately lead to death. Hypertension is classified into primary hypertension and secondary hypertension depending on the cause of the increase in blood pressure.
  • the primary hypertension is also known as essential hypertension in which the cause of the increase in blood pressure is unknown, and secondary hypertension is a condition where the increase in blood pressure is caused by a particular disease or disorder. Secondary hypertension can be treated by removing the cause of the increase in blood pressure, but the cause of primary hypertension, which accounts for about 95% of the cases of hypertension, is not known clearly, and the patients with primary hypertension is treated with drug therapy based on several blood pressure-lowering mechanisms.
  • vasodilators Drugs commonly used for the treatment of hypertension are generally divided into vasodilators, diuretics, and sympatholytics depending on the mechanism of action of these drugs, and the currently widely used vasodilators are divided again into angiotensin converting enzyme (ACE) inhibitors, angiotensin II receptor blockers, and calcium channel blockers.
  • ACE angiotensin converting enzyme
  • a combination therapy of an angiotensin II receptor blocker (ARB) and a calcium channel blocker (CCB) which has different mechanism of action is first selected in the event of a failure in blood pressure regulation through the single administration.
  • the pharmacological actions of these two drugs for blood pressure lowering are different from each other, and thus the combined administration of these two drugs has an effective blood pressure-lowering effect and reduces the amount of drugs used, thus significantly reducing the side effects of each component.
  • Telmisartan one of the angiotensin II receptor blockers (ARBs), is commercially available in two doses of 40 mg and 80 mg under the trade name of Pritor and has a chemical name of 4’-[2-n-propyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl-methyl]biphenyl-2-carboxylic acid and a structure of the following Formula 1:
  • Telmisartan is prescribed for essential hypertension and is a drug that selectively acts on an angiotensin II receptor, which acts as a potent vasoconstrictor in a renin-angiotensin-aldosterone system and, in particular, selectively acts on an AT1 receptor involved in the main physiological actions such as vasoconstriction, etc.
  • telmisartan has a blood pressure-lowering effect continuously for 24 hours, and thus the drug taken the day before has the effect of regulating blood pressure until the next morning when blood pressure rapidly increases.
  • the renal clearance of telmisartan is less than 2%, and thus it is not necessary to adjust the dose in patients with mild to severe renal impairment.
  • the telmisartan is generally prepared and supplied in the form of a free acid and has very poor solubility in aqueous systems at the physiological pH range (pH 1 to 7) of the gastrointestinal tract, and thus a basic material is used for the formulation.
  • Suitable basic materials include: alkali metal hydroxides such as sodium hydroxide or calcium hydroxide; basic amino acids such as arginine, lysine, and meglumine (N-methyl-D-glucamine), and among others, sodium hydroxide and meglumine are mainly used.
  • amlodipine one of the calcium channel blockers (CCBs)
  • CBs calcium channel blockers
  • Norvasc has a chemical name of 3-ethyl-5-methyl-2-(2-aminoethoxymethyl)-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate and a structure of the following Formula 2:
  • Amlodipine has a half-life of 30 to 50 hours and is a very useful calcium channel blocker that exhibits activity continuously over a long period of time. Amlodipine blocks the influx of calcium into the vascular smooth muscle to induce peripheral arterial vasodilation, resulting in a decrease in blood pressure, and is effective in angina pectoris due to vasoconstriction. Moreover, when orally administered, it is absorbed in the small intestine such that more than 40% is metabolized in the liver by cytochrome P450 3A4, a drug-metabolizing enzyme, and the remaining 60% is released into blood to provide an effective blood pressure-lowering effect.
  • amlodipine is a chiral compound with a chiral center, and it is known that the S-(-)-isomer of amlodipine is a potent calcium channel blocker that has higher activity than an isomeric mixture (in racemic form) (Arrowsmith et al., J. Med. Chem., 29, 1696 (1986)), and the (R)-optical isomer has activity 1,000 times lower than the (S)-optical isomer and has a kinin-mediated nitric oxide mechanism that is likely to be associated with side effects (Hintze et al., J. Cardiovasc. Pharmacol., 39(2):208-14 (2002)).
  • a complex composition comprising telmisartan and amlodipine as active ingredients, which are representative ARB and CCB drugs, has the same blood pressure-lowering effect, reduces the amount of drugs to significantly reduce the side effects of each component, and has recently been the subject of research on complex formulations.
  • both the telmisartan and amlodipine are compounds which are difficult to handle, and thus it is necessary to solve various technical problems related to the formulation.
  • Korean Patent Publication No. 10-2007-0085801 discloses a bilayer tableting technology for separating the basic telmisartan formulation from the amlodipine drug, and complex formulations comprising telmisartan and amlodipine using this technology are commercially available at present under the trade name of Twynsta.
  • An object of the present invention is to provide a combination composition comprising telmisartan and amlodipine, in which (S)-amlodipine is used instead of amlodipine racemate so as to reduce the amount of drugs used and to thereby reduce side effects, and the combination composition of the present invention can improve the stability of (S)-amlodipine which has lower stability than the racemate.
  • the inventors of the present invention have conducted studies on preparations that replace amlodipine racemate with (S)-amlodipine so as to improve the drawbacks of the existing combination preparation comprising telmisartan and amlodipine racemate as active ingredients (the composition disclosed in Korean Patent Publication No. 10-2007-0085801).
  • the combination preparation comprising telmisartan and (S)-amlodipine as active ingredients produces much more degradation products during long-term storage, compared to the existing combination preparation, resulting in reduced stability.
  • the inventors of the present invention have conducted extensive studies to ensure the stability of (S)-amlodipine in the combination preparation comprising telmisartan and (S)-amlodipine as active ingredients and found at the end of a long period of study that the addition of succinic acid to a layer comprising (S)-amlodipine improves the stability of (S)-amlodipine, thus completing the present invention.
  • the present invention provides a pharmaceutical preparation comprising telmisartan or a pharmaceutically acceptable salt thereof and (S)-amlodipine or a pharmaceutically acceptable salt thereof as active ingredients, and further comprising succinic acid.
  • the pharmaceutical preparation of the present invention comprising (S)-amlodipine instead of amlodipine racemate can significantly reduce the content of amlodipine (by about 1/2) and reduce or eliminate side effects (such as headache and/or edema) caused by the use of an excess of amlodipine, compared to the preparation of the above literature.
  • the pharmaceutical preparation of the present invention comprising succinic acid as a stabilizing agent can solve the problems of low stability of (S)-amlodipine.
  • the succinic acid may preferably be contained in an amount of 0.36 to 10.8 wt% with respect to the total weight of the pharmaceutical preparation, more preferably, in an amount of 0.72 to 3.6 wt%, most preferably in an amount of about 1.0 wt%.
  • the succinic acid is contained in the above-described numerical range, the production of (S)-amlodipine related compounds is minimized, which make it possible to obtain a desired level of stability.
  • the pharmaceutical preparation of the present invention may preferably comprise a first layer comprising the telmisartan or a pharmaceutically acceptable salt thereof as an active ingredient and a second layer comprising the (S)-amlodipine or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the purpose of this preparation is to physically separate the first layer and the second layer to block the interaction between the active ingredients and excipients contained in the respective layers.
  • the succinic acid is contained in the second layer to stabilize the (S)-amlodipine or a pharmaceutically acceptable salt thereof.
  • the pharmaceutically acceptable salt of telmisartan may be selected from the group consisting of a sodium salt, a potassium salt, a magnesium salt, and a calcium salt of telmisartan.
  • telmisartan or a pharmaceutically acceptable salt thereof may preferably be a free acid of telmisartan.
  • the first layer may preferably comprise an alkalizing agent to solve the problem of low solubility of telmisartan.
  • the alkalizing agent may preferably be selected from the group consisting of an alkali metal hydroxide (e.g., sodium hydroxide or calcium hydroxide), a basic amino acids (e.g., arginine or glycine), meglumine (N-methyl-D-glucamine), and mixtures thereof, and sodium hydroxide and meglumine may preferably be used.
  • the pharmaceutically acceptable salt of (S)-amlodipine may preferably be selected from the group consisting of besylate, maleate, orotate, camsylate, adipate, and mesylate, and the most preferred is besylate.
  • the pharmaceutical composition of the present invention comprises 0.5% or less of (S)-amlodipine related compound D, 0.5% or less of other individual related compounds, and 1.0% or less of total related compounds other than related compound D after being stored under accelerated conditions (40 °C, 75% relative humidity, and sealed) for 2 months, thus providing a pharmaceutical preparation comprising telmisartan and (S)-amlodipine with improved stability of (S)-amlodipine.
  • the pharmaceutical preparation of the present invention can be effectively used for the purpose of preventing or treating a cardiovascular disease selected from the group consisting of hypertension, angina pectoris, arterial spasm, cardiac arrhythmia, cerebral infarction, heart hypertrophy, congestive heart failure, and myocardial infarction, and in particular can be used to prevent or treat essential hypertension.
  • a cardiovascular disease selected from the group consisting of hypertension, angina pectoris, arterial spasm, cardiac arrhythmia, cerebral infarction, heart hypertrophy, congestive heart failure, and myocardial infarction, and in particular can be used to prevent or treat essential hypertension.
  • the pharmaceutical preparation of the present invention may further comprise pharmaceutically acceptable additives.
  • the additives may be contained in an amount of 5 to 90 wt% with respect to the total weight of the pharmaceutical preparation of the present invention.
  • Examples of the additives may include those commonly used in formulations as long as they are pharmaceutically acceptable, such as fillers, binders, disintegrants, lubricants, etc.
  • the filler may preferably be selected from the group consisting of pregelatinized starch, microcrystalline cellulose, cellulose, mannitol, erythritol, lactose monohydrate, anhydrous dibasic calcium phosphate, sorbitol, and xylitol, more preferably pregelatinized starch, microcrystalline cellulose, anhydrous dibasic calcium phosphate, or lactose monohydrate.
  • the binder may preferably be selected from the group consisting of polyvinylpyrrolidone (povidone), copolymers of vinylpyrrolidone with other vinyl derivatives (copovidone), microcrystalline cellulose, hydroxypropyl methylcellulose, methylcellulose, hydroxypropyl cellulose, and pregelatinized starch, more preferably hydroxypropyl methylcellulose or povidone.
  • povidone polyvinylpyrrolidone
  • microcrystalline cellulose hydroxypropyl methylcellulose, methylcellulose, hydroxypropyl cellulose, and pregelatinized starch, more preferably hydroxypropyl methylcellulose or povidone.
  • the disintegrant may preferably be selected from the group consisting of croscarmellose sodium (cross-linked sodium carboxymethylcellulose), sodium starch glycolate, crospovidone (cross-linked polyvinylpyrrolidone), corn starch, pregelatinized starch, low-substituted hydroxypropyl cellulose, and microcrystalline cellulose, more preferably sodium starch glycolate or crospovidone.
  • the lubricant may preferably be sodium stearyl fumarate or magnesium stearate, more preferably magnesium stearate.
  • the pharmaceutical preparation of the present invention may be prepared by any method well known to those skilled in the art.
  • direct compression is used to provide a composition of a layer comprising (s)-amlodipine.
  • the pharmaceutical preparation of the present invention comprises (S)-amlodipine as an active ingredient, which significantly reduces the amount of drugs used and reduces or eliminates side effects caused by the use of an excess of amlodipine, and further comprises succinic acid as an stabilizer, which ensures the stability of (S)-amlodipine.
  • FIG. 1 is a graph showing the contents of (S)-amlodipine related compound D measured in Example 1 and Comparative Example 1 after being stored under accelerated conditions (40 °C, 75% relative humidity, and sealed) for 2 months.
  • FIG. 2 is a graph showing the contents of other individual related compounds of (S)-amlodipine measured in Example 1 and Comparative Example 1 after being stored under accelerated conditions (40 °C, 75% relative humidity, and sealed) for 3 months.
  • FIG. 3 is a graph showing the results of total related compounds other than (S)-amlodipine related compound D measured in Example 1 and Comparative Example 1 after being stored under accelerated conditions (40 °C, 75% relative humidity, and sealed) for 3 months.
  • FIG. 4 is a graph showing the results of (S)-amlodipine related compound D, other individual related compounds, and total related compounds other than related compound D measured in Examples 1 to 5 after being stored under accelerated conditions (40 °C, 75% relative humidity, and open) for 2 weeks.
  • Telmisartan granule mixture was prepared using the ingredients shown in the following Table 1 by the following method:
  • Anhydrous ethanol was heated at about 50 °C to completely dissolve sodium hydroxide, meglumine, and povidone. Telmisartan was completely dissolved in this mixture and used as a binding solution or spray.
  • D-sorbitol was fed into a fluid bed granulator, and the binding solution or spray of step 1) was sprayed thereon. Upon completion of the spray, drying and screening steps were sequentially performed.
  • Primary mixing was performed by placing the dried granules of step 2) in a mixer and adding D-sorbitol thereto. Upon completion of the primary mixing, secondary mixing was performed by adding sieved magnesium stearate to the primary mixture, thus preparing the final mixture.
  • Anhydrous dibasic calcium phosphate and blue dye No. 2 were mixed and sieved.
  • (S)-amlodipine besylate and anhydrous dibasic calcium phosphate were added thereto and sieved.
  • Microcrystalline cellulose, colloidal silicon dioxide, and sodium starch glycolate were added thereto and sieved.
  • Microcrystalline cellulose, sodium hydrogen carbonate, and magnesium stearate were mixed with the trituration of step 1).
  • Granules were prepared by compacting and crushing the granules of step 2) using a compactor equipped with a 16 mesh sieve. Sieved magnesium stearate was added to the granules and finally mixed to prepare the final mixture.
  • (S)-amlodipine granule mixture was prepared using the ingredients shown in the following Table 3, in which the preparation method was the same as in Preparation Example 2, except that crushed succinic acid was added during the trituration of the granules:
  • (S)-amlodipine granule mixtures were prepared by the same method as in Example 3, except that citric acid (Preparation Example 4), ascorbic acid (Preparation Example 5), tartaric acid (Preparation Example 6), erythorbic acid (Preparation Example 7), lactic acid (Preparation Example 8), formic acid (Preparation Example 9), acetic acid (Preparation Example 10), oxalic acid (Preparation Example 11), malic acid (Preparation Example 12), fumaric acid (Preparation Example 13), BHA (Preparation Example 14), and BHT (Preparation Example 15) were used in the same content instead of succinic acid.
  • Bilayer tablets having a total weight of 680 mg were prepared by compressing the telmisartan granule mixture prepared in Preparation Example 1 and the (S)-amlodipine granule mixture prepared in Preparation Example 3 using a bilayer tablet press (Sejong Pharmatech, Model: MSP).
  • the prepared tablets comprise 80 mg of telmisartan and 2.5 mg of (S)-amlodipine in each layer, and 7.00 mg of succinic acid (1.00 wt% with respect to the total weight).
  • Bilayer tablets were prepared by the same method in Example 1 using the telmisartan granule mixture prepared in Preparation Example 1 and the (S)-amlodipine granule mixtures prepared in Preparation Examples 16 to 19.
  • the contents of telmisartan and (S)-amlodipine were the same, and the content of succinic acid was 2.45 mg (0.36 wt%), 24.5 mg (3.6 wt%), 49.0 mg (7.2 wt%), and 73.5 mg (10.8 wt%), respectively.
  • Bilayer tablets having a total weight of 680 mg were prepared by compressing the telmisartan granule mixture prepared in Preparation Example 1 and the (S)-amlodipine granule mixture prepared in Preparation Example 2 using a bilayer tablet press (Sejong Pharmatech, Model: MSP).
  • the prepared tablets comprise 80 mg of telmisartan and 2.5 mg of (S)-amlodipine in each layer, and 7.00 mg of succinic acid.
  • Bilayer tablets having a total weight of 680 mg were prepared by compressing the telmisartan granule mixture prepared in Preparation Example 1 and the (S)-amlodipine granule mixtures prepared in Preparation Examples 4 to 15 using a bilayer tablet press (Sejong Pharmatech, Model: MSP).
  • the prepared tablets comprise 80 mg of telmisartan and 2.5 mg of (S)-amlodipine in each layer.
  • Example 1 The amounts of degradation products produced under accelerated conditions in Example 1 with succinic acid and Comparative Example 1 without succinic acid were compared, and the results are shown in the following Table 5 to 7 and FIGS. 1 to 3:
  • Total related compounds The sum of related compounds other than related compound D
  • Example 1 it can be seen from Example 1, in which succinic acid was added, that the production of degradation products including related compound D was suppressed, compared to Comparative Example 1 in which no succinic acid was added.
  • Comparative Example 1 in which no succinic acid was added, the content of related compound D exceeded 0.5% after 1 month, and the contents of other individual related compounds and total related compounds exceeded 2% after 3 months.
  • the related compound D was stable until 2 months, and other individual related compounds and total related were less than 0.5% and less than 1.0%, respectively, measured for 3 months, indicating significantly improved stability.
  • dehydro amlodipine is known as a representative oxidation related compound of amlodipine and has a structure of the following Formula 3:
  • the related compound D is the main product of the oxidation and thus can be interpreted as a parameter indicating the oxidative stability. According to the standards and the experimental method, the standards of related compound D and other individual related compounds are less than 0.5%, and the standard of total related compounds is less than 1.0%.
  • succinic acid to the pharmaceutical preparation comprising telmisartan and (S)-amlodipine as active ingredients allows to ensure the stability during storage and distribution of (S)-amlodipine.
  • Total related compounds The sum of related compounds other than related compound D
  • the bilayer tablets containing 1.0 wt% of succinic acid showed the most significant effect of reducing the degradation products, and the tablets containing 0.36 wt% of succinic acid (Example 2) and 10.8 wt% of succinic acid (Example 5) showed similar results. Therefore, it can be seen that the effect of improving the stability is obtained for a particular numerical range (0.36 wt% to 10.8 wt%, preferably 0.72 wt% to 3.6 wt%, most preferably about 1.0 wt%) in the pharmaceutical preparation containing telmisartan and (S)-amlodipine as active ingredients.
  • the pharmaceutical preparation of the present invention comprises (S)-amlodipine as an active ingredient, which significantly reduces the amount of drugs used and reduces or eliminates side effects caused by the use of an excess of amlodipine, and further comprises succinic acid as an stabilizer, which ensures the stability of (S)-amlodipine.

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Abstract

La présente invention concerne une composition pharmaceutique comprenant du telmisartan ou un sel pharmaceutiquement acceptable de celui-ci et de la (S)-amlodipine ou un sel pharmaceutiquement acceptable de celle-ci et de l'acide succinique. La préparation de la présente invention a pour effet d'améliorer la stabilité de la (S)-amlodipine par l'intermédiaire de l'acide succinique.
PCT/KR2015/002461 2014-03-26 2015-03-13 Préparation pharmaceutique comprenant du telmisartan et de la (s)-amlodipine présentant une meilleure stabilité à l'oxydation WO2015147467A1 (fr)

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CN112294771A (zh) * 2019-07-29 2021-02-02 生达化学制药股份有限公司 速放医药组合物

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KR101883664B1 (ko) 2016-11-29 2018-07-31 안국약품 주식회사 텔미사르탄과 암로디핀을 포함하는 단층 복합정제 및 이의 제조방법
KR102066832B1 (ko) * 2017-11-15 2020-01-16 주식회사 종근당 텔미사르탄 또는 그의 약제학적으로 허용가능한 염을 포함하는 인습성 및 용출률이 향상된 제제

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US20020072532A1 (en) * 1998-11-04 2002-06-13 Foster Robert T. Methods of pharmacological treatment using S (-) amlodipine
US20060110450A1 (en) * 2004-11-05 2006-05-25 Boehringer Ingelheim International Gmbh Bilayer tablet of telmisartan and amlodipine
US20120114753A1 (en) * 2009-05-27 2012-05-10 Dasan Medichem Co., Ltd. Multi-layer tablet comprising effervescent layer

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US20020072532A1 (en) * 1998-11-04 2002-06-13 Foster Robert T. Methods of pharmacological treatment using S (-) amlodipine
US20060110450A1 (en) * 2004-11-05 2006-05-25 Boehringer Ingelheim International Gmbh Bilayer tablet of telmisartan and amlodipine
US20120114753A1 (en) * 2009-05-27 2012-05-10 Dasan Medichem Co., Ltd. Multi-layer tablet comprising effervescent layer

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Title
PARK, J.-Y. ET AL.: "Pharmacokinetic and pharmacodynamic characteristics of a new S-amlodipine formulation in healthy Korean male subjects: a randomized, open-label, two-period, comparative, crossover study.", CLINICAL THERAPEUTICS, vol. 28, no. 11, 2006, pages 1837 - 1847, XP027906877 *
SHARMA, A. ET AL.: "Results of a comparative, phase III, 12-week, multicenter, prospective, randomized, double-blind assessment of the efficacy and tolerability of a fixed-dose combination of telmisartan and amlodipine versus amlodipine monotherapy in Indian adults with stage II hypertension.", CLINICAL THERAPEUTICS, vol. 29, no. 12, 2007, pages 2667 - 2676, XP022420228 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112294771A (zh) * 2019-07-29 2021-02-02 生达化学制药股份有限公司 速放医药组合物
TWI745725B (zh) * 2019-07-29 2021-11-11 生達化學製藥股份有限公司 速放醫藥組成物

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