WO2017048033A1 - Préparation d'un mélange de produits pharmaceutiques - Google Patents

Préparation d'un mélange de produits pharmaceutiques Download PDF

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Publication number
WO2017048033A1
WO2017048033A1 PCT/KR2016/010304 KR2016010304W WO2017048033A1 WO 2017048033 A1 WO2017048033 A1 WO 2017048033A1 KR 2016010304 W KR2016010304 W KR 2016010304W WO 2017048033 A1 WO2017048033 A1 WO 2017048033A1
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WO
WIPO (PCT)
Prior art keywords
amlodipine
telmisartan
pharmaceutical combination
preparation
combination preparation
Prior art date
Application number
PCT/KR2016/010304
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English (en)
Inventor
Hye Mi AHN
Min Kwan Cho
Teak Hwan SHIN
Shin Jung Park
Jong Rae Lim
Original Assignee
Chong Kun Dang Pharmaceutical Corp.
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Publication date
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First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=58289304&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=WO2017048033(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Chong Kun Dang Pharmaceutical Corp. filed Critical Chong Kun Dang Pharmaceutical Corp.
Publication of WO2017048033A1 publication Critical patent/WO2017048033A1/fr
Priority to PH12018500559A priority Critical patent/PH12018500559A1/en

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    • 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
    • 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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds

Definitions

  • the present disclosure relates to a pharmaceutical combination preparation comprising telmisartan and (S)-amlodipine with improved hygroscopic properties.
  • 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. 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 thus the patients with primary hypertension are 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
  • Telmisartan is one of the angiotensin II receptor blockers (ARBs) and is commercially available in two doses of 40 mg and 80 mg under the trade name of Pritor. 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 the renin-angiotensin-aldosterone system and, in particular, selectively acts on an AT1 receptor involved in the main physiological actions such as vasoconstriction, etc.
  • ARBs angiotensin II receptor blockers
  • Amlodipine is one of the calcium channel blockers (CCBs) and is commercially available in doses of 5 mg and 10 mg under the trade name of Norvasc.
  • CBs calcium channel blockers
  • S-amlodipine a pure optical isomer
  • a complex composition comprising telmisartan and (S)-amlodipine as active ingredients, which are representative ARB and CCB drugs, has an effective blood pressure-lowering effect and reduces the amount of drugs used, which significantly reduces the side effects of each component.
  • An object of the present disclosure is to provide a pharmaceutical combination preparation comprising a first layer comprising telmisartan or a pharmaceutically acceptable salt thereof, microcrystalline cellulose, and calcium silicate; and a second layer comprising (S)-amlodipine or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides a pharmaceutical combination preparation comprising a first layer comprising telmisartan or a pharmaceutically acceptable salt thereof, microcrystalline cellulose, and calcium silicate; and a second layer comprising (S)-amlodipine or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical combination preparation of the present disclosure comprises microcrystalline cellulose and calcium silicate in the first layer to improve the hygroscopic properties of the first layer comprising telmisartan and, at the same time, not to influence the stability of (S)-amlodipine contained in the second layer.
  • telmisartan is a compound with the chemical name of 2-(4- ⁇ [4-methyl-6-(1-methyl-1H-1,3-benzothiazol-2-yl)-2-propyl-1H-1,3-benzothiazol-1-yl]methyl ⁇ phenyl)benzoic acid and is represented by the following Formula 1:
  • telmisartan may be commercially available or synthesized by any method known in the art, but not limited thereto.
  • Telmisartan of the present disclosure may be used in various forms such as a free acid of telmisartan or a pharmaceutically acceptable salt thereof, an isomer, a racemate, a hydrate, a solvate, etc. as long as the same pharmacological activity is maintained.
  • the pharmaceutically acceptable salt comprises a salt derived from a pharmaceutically acceptable acid or base.
  • pharmaceutically acceptable salt refers to any organic or inorganic addition salt whose concentration has effective action because it is relatively non-toxic and harmless to the patients and whose side effects do not degrade the beneficial efficacy of the active ingredient.
  • the pharmaceutically acceptable salt of telmisartan of the present disclosure may be a sodium salt, a potassium salt, a magnesium salt, or a calcium salt of telmisartan, but not limited thereto.
  • the pharmaceutical combination preparation of the present disclosure comprises a free acid of telmisartan.
  • 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 the 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. Furthermore, 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.
  • Telmisartan has very poor solubility in aqueous systems at the physiological pH range (pH 1 to 7) of the gastrointestinal tract, and thus it is preferred to use an alkalizing agent to improve the solubility and solubilization of telmisartan for the formulation.
  • the first layer of the pharmaceutical combination preparation according to the present disclosure preferably comprises an alkalizing agent.
  • alkalizing agents that can be used include metal hydrates, basic amino acids, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, sodium hydrogen phosphate, and mixtures thereof.
  • the metal hydrate may include sodium hydroxide, calcium hydroxide, etc.
  • the basic amino acid may include arginine, ricin, meglumine (N-methyl-D-glucamine), etc.
  • the pharmaceutical combination preparation of the present disclosure comprises dried sodium carbonate.
  • the alkalizing agent has deliquescence and hygroscopic properties, and thus when a preparation comprising an alkalizing agent is exposed to water or moisture, the preparation is sticky or melted, which is very problematic.
  • the second layer of the pharmaceutical combination preparation according to the present disclosure preferably comprises (S)-amlodipine as an active ingredient.
  • (S)-amlodipine is a compound with the chemical name of 3-ethyl-5-methyl-2-(2-aminoethoxymethyl)-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate and is represented by the following Formula 2:
  • (S)-amlodipine of the present disclosure may be used in various forms such as a free base of (S)-amlodipine or a pharmaceutically acceptable salt thereof, an isomer, a racemate, a hydrate, a solvate, etc. as long as the same pharmacological activity is maintained.
  • the pharmaceutically acceptable salt comprises a salt derived from a pharmaceutically acceptable acid or base.
  • pharmaceutically acceptable salt refers to any organic or inorganic addition salt whose concentration has effective action because it is relatively non-toxic and harmless to the patients and whose side effects do not degrade the beneficial efficacy of the active ingredient.
  • Amlodipine is one of the calcium channel blockers (CCBs) and is a very useful calcium channel blocker that has a half-life of 30 to 50 hours and 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. Amlodipine is a chiral compound with a chiral center, and it is known that the (S)-optical 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.
  • the (S)-amlodipine is easily hydrolyzed by the alkalizing agent used for the solubility and solubilization of telmisartan, resulting in reduced stability of amlodipine.
  • the pharmaceutical combination preparation of the present disclosure has the advantage of improving both the hygroscopic properties of telmisartan and the reduced stability of (S)-amlodipine.
  • the present disclosure provides the improvement of the hygroscopic properties in the first layer of pharmaceutical combination preparation that comprises microcrystalline cellulose as an excipient and calcium silicate as an adsorbent.
  • the addition of microcrystalline cellulose and calcium silicate in the first layer does not influence the stability of the (S)-amlodipine contained in the second layer.
  • the weight ratio of telmisartan or a pharmaceutically acceptable salt thereof to microcrystalline cellulose is 10:25 to 10:35.
  • the pharmaceutical combination preparation of the present disclosure may comprise microcrystalline cellulose in an amount of 50 to 60 wt% with respect to the total weight of the first layer.
  • microcrystalline cellulose contained in the preparation was determined and, as a result, it was found that when the weight ratio of telmisartan to microcrystalline cellulose was 10:25 and 10:30, the friability of tablets was small, and the maximum hardness of tablets was high; in particular, when the amount of microcrystalline cellulose contained in the preparation was higher, the maximum hardness of tablets increased, and the friability of tablets decreased.
  • the weight ratio of telmisartan or a pharmaceutically acceptable salt thereof to calcium silicate is 10:1 to 10:6.
  • the weight ratio of telmisartan or a pharmaceutically acceptable salt thereof to microcrystalline cellulose is 10:25 to 10:30, and the weight ratio of telmisartan or a pharmaceutically acceptable salt thereof to calcium silicate is 10:1 to 10:5.
  • the weight ratio of telmisartan or a pharmaceutically acceptable salt thereof to calcium silicate is 10:2 to 10:3.
  • an appropriate content of calcium silicate contained in the preparation which improves the hygroscopic properties of the telmisartan layer and does not significantly degrade the stability of the (S)-amlodipine layer, that is, the weight ratio of telmisartan or a pharmaceutically acceptable salt thereof to calcium silicate was preferably 10:1 to 10:5, more preferably, 10:2 to 10:3.
  • the pharmaceutical combination preparation of the present disclosure may further comprise at least one pharmaceutically acceptable additive.
  • Any additives that are well known in the art may be used as long as they do not cause an interaction with telmisartan or a pharmaceutically acceptable salt thereof and (S)-amlodipine or a pharmaceutically acceptable salt thereof and does not disturb the efficacy.
  • the pharmaceutically acceptable additive may be at least one selected from the group consisting of diluents, binders, disintegrants, lubricants, and coating agents, but not limited thereto.
  • excipient refers to a substance that is added to give appropriate hardness and shape to the medicinal preparation or give certain volume and weight to the medicinal preparation to have a size that is easy to handle when the amount of the main ingredient is small.
  • examples of the excipient may include sugar derivatives such as mannitol, sorbitol, etc.; starches such as corn starch, potato starch, etc.; cellulose derivatives such as low substituted hydroxypropylcellulose, methylcellulose etc.; inorganic excipients such as calcium carbonate, etc., but not limited thereto.
  • binder refers to a substance that can impart elasticity and adhesion to increase the strength of the resulting preparation, particularly, the strength of the resulting tablets.
  • examples of the binder may include carboxymethylcellulose-sodium (CMC-Na), starch solutions, polyvinylpyrrolidone (PVP), gum arabic, hydroxypropylcellulose (HPC), etc., but not limited thereto.
  • disintegrant refers to a substance that is used to accelerate the disintegration of solid preparations such that an activator that shows efficacy in the preparation is released within a short period of time.
  • examples of the disintegrant may include carboxymethylcellulose-calcium (CMC-Ca), crospovidone, sodium starch glycolate, sodium croscarmellose, low substituted hydroxypropylcellulose, etc., but not limited thereto.
  • lubricant refers to a substance that offers improved flow characteristics.
  • examples of the lubricant may include colloidal silica, magnesium stearate, stearic acid, talk, sodium stearyl fumarate, etc., but not limited thereto.
  • the pharmaceutical combination preparation of the present disclosure may be, for example, an oral solid preparation, preferably a bilayer tablet.
  • the present disclosure provides a method for preparing a pharmaceutical combination preparation comprising telmisartan and (S)-amlodipine.
  • the pharmaceutical combination preparation of the present disclosure may be prepared by any method known to those skilled in the art such as wet granulation method, direct compression, dry granulation, etc.
  • the method of preparing a pharmaceutical combination preparation of the present disclosure by the wet granulation comprises the steps of preparing a binder solution; preparing a mixture by mixing a main ingredient with a diluent (or excipient); combining the binder solution with the mixture; and compressing the combination by drying, sieving, and lubrication.
  • the method of preparing a pharmaceutical combination preparation of the present disclosure by the direct compression comprises the steps of preparing a mixture by mixing a main ingredient with an excipient; and adding a disintegrant and a lubricant to the mixture, followed by lubrication and compression.
  • the pharmaceutical combination preparation of the present disclosure may be prepared as follows: in order to provide a telmisartan layer, for example, a solution prepared by dissolving alkaline components such as dried sodium carbonate in an appropriate solvent is sprayed onto an inert excipient and then dried to prepare an amorphous telmisartan granule composition, a granule composition of a layer comprising (S)-amlodipine is prepared, and then the two granule compositions are compressed to prepare the pharmaceutical combination preparation of the present disclosure.
  • the pharmaceutical combination preparation of the present disclosure 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.
  • Calcium silicate was added to water and completely dissolved by stirring.
  • Total related compounds The sum of related compounds other than related compound D

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Inorganic Chemistry (AREA)

Abstract

La présente invention concerne une préparation d'un mélange de produits pharmaceutiques comprenant du telmisartan et de la (S)-amlodipine ayant des propriétés hygroscopiques améliorées.
PCT/KR2016/010304 2015-09-15 2016-09-13 Préparation d'un mélange de produits pharmaceutiques WO2017048033A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PH12018500559A PH12018500559A1 (en) 2015-09-15 2018-03-14 Pharmaceutical combination preparation

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KR1020150130317A KR101750689B1 (ko) 2015-09-15 2015-09-15 약제학적 복합제제
KR10-2015-0130317 2015-09-15

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TWI734046B (zh) * 2017-11-15 2021-07-21 韓商鍾根堂股份有限公司 包含替米沙坦或其藥學上可接受鹽類之具有改良的吸濕性質和溶解速率之製劑

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20070085801A (ko) * 2004-11-05 2007-08-27 베링거 인겔하임 인터내셔날 게엠베하 텔미사르탄 및 암로디핀을 포함하는 2층 정제
WO2008069612A1 (fr) * 2006-12-08 2008-06-12 Hanmi Pharm. Co., Ltd. Composition pharmaceutique comprenant de l'amlodipine et du losartan
WO2010008244A2 (fr) * 2008-07-18 2010-01-21 한올제약주식회사 Préparation pharmaceutique
KR20100128247A (ko) * 2009-05-27 2010-12-07 (주)다산메디켐 발포성 층을 포함하는 다층 정제
EP2391365B1 (fr) * 2009-01-23 2014-11-26 Hanmi Science Co., Ltd. Composition pharmaceutique solide comprenant de l'amlodipine et du losartan

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20070085801A (ko) * 2004-11-05 2007-08-27 베링거 인겔하임 인터내셔날 게엠베하 텔미사르탄 및 암로디핀을 포함하는 2층 정제
WO2008069612A1 (fr) * 2006-12-08 2008-06-12 Hanmi Pharm. Co., Ltd. Composition pharmaceutique comprenant de l'amlodipine et du losartan
WO2010008244A2 (fr) * 2008-07-18 2010-01-21 한올제약주식회사 Préparation pharmaceutique
EP2391365B1 (fr) * 2009-01-23 2014-11-26 Hanmi Science Co., Ltd. Composition pharmaceutique solide comprenant de l'amlodipine et du losartan
KR20100128247A (ko) * 2009-05-27 2010-12-07 (주)다산메디켐 발포성 층을 포함하는 다층 정제

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TWI734046B (zh) * 2017-11-15 2021-07-21 韓商鍾根堂股份有限公司 包含替米沙坦或其藥學上可接受鹽類之具有改良的吸濕性質和溶解速率之製劑

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KR101750689B1 (ko) 2017-06-26
KR20170032681A (ko) 2017-03-23
PH12018500559A1 (en) 2018-09-17

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