EP2588106A2 - Composition pharmaceutique à libération prolongée contenant du pramipexole, ou l'un de ses sels pharmaceutiquement acceptables, présentant une meilleure stabilité - Google Patents

Composition pharmaceutique à libération prolongée contenant du pramipexole, ou l'un de ses sels pharmaceutiquement acceptables, présentant une meilleure stabilité

Info

Publication number
EP2588106A2
EP2588106A2 EP11801051.1A EP11801051A EP2588106A2 EP 2588106 A2 EP2588106 A2 EP 2588106A2 EP 11801051 A EP11801051 A EP 11801051A EP 2588106 A2 EP2588106 A2 EP 2588106A2
Authority
EP
European Patent Office
Prior art keywords
pharmaceutical composition
sustained
release
pramipexole
release pharmaceutical
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP11801051.1A
Other languages
German (de)
English (en)
Other versions
EP2588106A4 (fr
Inventor
Sang-Joon Lee
Kwan-Young Chang
Jae-Soon Ahn
Jae-Min Cho
Sung-Hoon Kam
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bio Pharmartis Co Ltd
Hyundai Pharm Co Ltd
Original Assignee
Bio Pharmartis Co Ltd
Hyundai Pharm Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Bio Pharmartis Co Ltd, Hyundai Pharm Co Ltd filed Critical Bio Pharmartis Co Ltd
Publication of EP2588106A2 publication Critical patent/EP2588106A2/fr
Publication of EP2588106A4 publication Critical patent/EP2588106A4/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • 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
    • A61K31/425—Thiazoles
    • 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
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia

Definitions

  • the present invention relates to a sustained-release pharmaceutical composition containing pramipexole or a pharmaceutically acceptable salt thereof and, more particularly, to a pharmaceutical composition that uses a stabilizer for inhibiting production of related substances caused by additives and greatly enhances stability.
  • Pramipexole is a known agonist for D2 dopamine receptors and used as a treatment for schizophrenia and Parkinson's disease. Pramipexole is structurally different from ergot-derived drugs such as bromocriptine or pergolide and pharmacologically distinctive in that it exhibits selectivity for D2 dopamine receptors and acts as a full agonist.
  • Pramipexole represented by the following formula 1 is (S)-2-amino-4,5,6,7- tetrahydro-6-(propylamino)-benzothiazol (molecular formula: Ci 0 Hi 7 N 3 S; and molecular weight: 21 1.33).
  • Pramipexole or its salts are very stable at the room temperature but unstable in light and moisture. Particularly, pramipexole or its salts are very sensitive to moisture to accelerate production of related substances.
  • Europe EMEA documents specify that regular pramipexole tablets (brand name: Mirapexin tablets) and sustained-release pramipexole tablets (brand name: Mirapexin prolonged-release tablets) are very susceptible to moisture. Those pramipexole tablets are thus specially wrapped to minimize the potential problems occurring on the distribution channels of the drug products.
  • Pharmacopoeia defines the related substances as "ordinary impurities" and, unless not otherwise specified, prescribes the maximum allowable level of the impurities as the sum of the related substances not more than 2.0 %, or specifies the related compounds and the amount of each related substance in terms of chromatographic purity in each drug article; the European Pharmacopoeia and the British Pharmacopoeia define "related substances”; and the Japanese Pharmacopoeia defines "related substances” and the maximum allowable level of the related substances in the regulations on the purity test.
  • the present invention has been made in an effort to solve the above- mentioned problems occurring in the prior arts, and it is an object of the present invention to provide a pharmaceutical composition that inhibits production of related substances and greatly enhances stability.
  • the present invention provides a sustained -release pharmaceutical composition that includes: an active ingredient including an effective amount of pramipexole or its pharmaceutically acceptable salt; a sustained-release agent; and a pharmaceutically acceptable excipient including a stabilizer.
  • a sustained-release pharmaceutical composition that includes: an active ingredient including an effective amount of pramipexole or its pharmaceutically acceptable salt; a sustained-release agent; and a pharmaceutically acceptable excipient including a stabilizer.
  • pramipexole or its pharmaceutically acceptable salt as used herein is intended to include pramipexole, and its racemic body, enantiomer, polymorph, hydrate, or solvate.
  • the pramipexole or its pharmaceutically acceptable salt is (S)-2- amino-4,5,6,7-tetrahydro-6-(propylamino)-benzothiazol that is the S-enantiomer of pramipexole.
  • the pharmaceutically acceptable salt of pramipexole is a salt having middle or high water solubility, including, for example: salts prepared from hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, sulfuric acid, methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-hydroxybenzoic acid, toluenesulfonic acid, formic acid, acetic acid, propionic acid, benzoic acid, anthranilic acid, tartaric acid, maleic acid, malic acid, citric acid, isocitric acid, succinic acid, ascorbic acid, lactic acid, glycolic acid, gluconic acid, glucuronic acid, pyruvic acid, oxaloacetic acid, fumaric acid, aspartic acid, glutamic acid, stearic acid, salicylic acid, phenylacetic acid, mandelic acid
  • an appropriate content for treatment or prevention of diseases means an appropriate content for treatment or prevention of diseases and may be adjusted depending on a variety of factors, including disease type, disease severity, the type and content of active ingredients or other ingredients contained in the composition, dosage form, patient's age, weight, health condition, gender and eating behavior, drug administration time, administration route, secretion rate of composition, duration of treatment, or concomitant medication.
  • an adult may take the pharmaceutical composition of the present invention in a maximum effective amount of 1 to 10 mg/day from once to several times a day through oral or non-oral administration route. It is evident for those skilled in the art that the content of each active ingredient is not so excessive to cause an overdose of the active ingredient and consequently side effects.
  • the pramipexole or its pharmaceutically acceptable salt is contained in an amount of 0.0005 to 0.025 wt.% with respect to the whole pharmaceutical composition.
  • the sustained-release agent includes, but is not limited to: cellulose, such as hydroxypropylmethyl cellulose (HPMC, or hypromellose), hydroxypropyl cellulose (HPC), hydroxyethyl cellulose (HEC), or carboxymethyl cellulose (CMC); xanthan gum; sodium alginate; polyethylene oxide; hydrophilic polymer, such as cross-linked homopolymer or copolymer of acrylic acid; or mixtures of these compounds.
  • HPMC hydroxypropylmethyl cellulose
  • HPC hydroxypropyl cellulose
  • HEC hydroxyethyl cellulose
  • CMC carboxymethyl cellulose
  • xanthan gum sodium alginate
  • polyethylene oxide polyethylene oxide
  • hydrophilic polymer such as cross-linked homopolymer or copolymer of acrylic acid
  • the sustained-release agent includes HPMC (hypromellose), namely HPMC 2910 (E3, E5, E6, E15, E50, E4M, E10M), HPMC 2906 (F50, F4M), or HPMC 2208 (K3, K100, K4M, K15M, K100M), or mixtures of these compounds.
  • HPMC hyperchromlose
  • HPMC 2910 E3, E5, E6, E15, E50, E4M, E10M
  • HPMC 2906 F50, F4M
  • HPMC 2208 K3, K100, K4M, K15M, K100M
  • the HPMC is contained in an amount of 20 to 50 wt.% with respect to the whole pharmaceutical composition.
  • the HPMC content below the preferred range undesirably accelerates the drug release rate to cause side effects pertaining to dose dumping.
  • the HPMC content above the range makes the drug release rate too much slow to reach an optimum Serum drug level, resulting in a failure to provide a sufficient therapeutic effect.
  • the pharmaceutical composition according to an embodiment of the present invention contains a pharmaceutically acceptable excipient including a stabilizer.
  • the stabilizer is hydroxypropyl cellulose having a hydroxypropoxy content of 7.0 to 15.0 %, or a methacryl-based cationic polymer soluble in solution at pH 5.5 or below.
  • hydroxypropyl cellulose having a hydroxypropoxy content of 7.0 to 15.0 % is also called "low-substituted hydroxypropyl cellulose (L-HPC)" and represented by the following formula 2.
  • R is -H, or -CH 2 CH(CH 3 )OH (see Alvarez-Lorenzo et al., 2000).
  • L-HPC is a low-substituted hydroxypropyl ether of cellulose that contains a very small portion of hydroxypropoxy groups in the ⁇ - ⁇ -glucopyranosyl ring of the cellulose.
  • L-HPC is classified as given in Table 1 according to the substitution level and the particle size.
  • LH-1 1 has a middle substitution degree and the greatest particle size and is used as an anti-capping agent and disintegrant in the direct compression method.
  • LH-21 is used as a binder and disintegrant in making tablets through the wet granulation method.
  • LH-31 has a suitable particle size small enough to pass through nets and is used for extrusion molding to form granules.
  • LH-22 and LH-32 are used in the case where there is no need for high binding strength, while LH-20 and LH-30 are used for high binding strength.
  • an appropriate L-HPC is chosen according to the type of applications.
  • the L-HPC has a hydroxypropoxy content of 7.0 to 9.9 %.
  • the L-HPC is normally used as an excipient (disintegrant or binder) having a good disintegrating property but problematic when contained in a sustained-release agent and exposed in vivo, causing pores to form around the sustained-release agent and to make the drug release control difficult. For this reason, the L-HPC has never been used for the sustained-release preparations.
  • composition using an appropriate combination of a sustained-release agent e.g., HPMC
  • a stabilizer e.g., L-HPC
  • the L-HPC is preferably contained in an amount of 10 to 80 wt.%, more preferably 20 to 60 wt.% with respect to the whole pharmaceutical composition.
  • the sustained-release agent and the L-HPC are contained at a weight ratio of the sustained-release agent to the L-HPC in the range of 1 :0.2 - 4.
  • the weight ratio below the preferred range undesirably reduces the expansion of the sustained-release agent to lower the drug release rate, while the weight ratio above the range causes minute pores to form on the surface of the sustained-release agent or increases the expansion of the sustained-release agent upon in vivo exposure, imparting an unexpected release profile.
  • the stabilizer may also be a methacryl-based cationic polymer soluble in solution at pH 5.5 or below.
  • Anionic acryl-based polymer such as carbomer, or carbopol® such as carbomer 941 (carbopol®71G, carbopol®971P) and carbomer 934P (carbopol®974P, carbopol®934P) causes a variance of the release rate of the sustained-release agent according to the diet-based stomach circumstances through pH-dependent drug release, and cannot consistently maintain the rigid matrix form at pH 4.5 or above, causing "dose dumping", rapidly releasing an excess of drug in a short period of time. Accordingly, a methacryl-based cationic polymer soluble in solution at pH 5.5 or below is preferred as the stabilizer.
  • the methacryl-based cationic polymer includes, but is not limited to, a poly(butyl methacrylate, (2-dimethylaminoethyl)methacrylate, methyl methacrylate) 1 :2:1 copolymer (brand name: Eudragit E, Rohm GmbH) represented by the following formula 3.
  • R 1 and R 3 are CH 3 ;
  • R 2 is CH 2 CH 2 N(CH 3 ) 2 ; and
  • R 4 is CH 3 or C 4 H 9 .
  • Eudragit E is a pH-dependent cationic polymer based on dimethylaminoethyl methacrylate and other neutral methacrylic acid esters. Eudragit E is soluble at pH 5.5 or below and hence used as a gastric soluble coating agent that is a solubilizing agent for drugs having a low solubility inside the stomach. The inventors of the present invention have found out that the use of Eudragit E not only realizes efficient release control of sustained-release pramipexole preparations but also remarkably improves the stability.
  • the methacryl-based cationic polymer is contained in an amount of 1 to 8 wt.%, more preferably 1 to 5 wt.% with respect to the whole pharmaceutical composition.
  • the content of the methacryl-based cationic polymer below the preferred range hardly secures the sustained-release property in an in vivo solution at pH 5.0 or above, completing the drug release too early and deteriorating the inhibitory effect on the formation of related substances.
  • the content of the methacryl-based cationic polymer above the range excessively retards the drug dissolution rate.
  • the content of the methacryl-based cationic polymer can be controlled in accordance with the range not only to change the dissolution profile according to a desired purpose but also to much more enhance the stability of the pharmaceutical composition of the present invention.
  • the stabilizer may include both the L-HPC and the methacryl-based cationic polymer to much more enhance the stability of the pharmaceutical composition of the present invention.
  • the stabilizer contains the L-HPC and the methacryl-based cationic polymer at a weight ratio of the L-HPC to the methacryl-based cationic polymer in the range of 1.25: 1 to 40: 1.
  • the pharmaceutical composition of the present invention optionally contains other typical excipients, including diluents, such as microcrystalline cellulose, lactose, glucose, mannitol, alginate, alkaline earth metal salts, clay, polyethylene glycol or dicalcium phosphate; lubricants, such as magnesium stearate or silicon dioxide; or binders, such as microcrystalline cellulose or starch.
  • diluents such as microcrystalline cellulose, lactose, glucose, mannitol, alginate, alkaline earth metal salts, clay, polyethylene glycol or dicalcium phosphate
  • lubricants such as magnesium stearate or silicon dioxide
  • binders such as microcrystalline cellulose or starch.
  • the pharmaceutical composition of the present invention shows an effectively controlled dissolution profile, realizing its usefulness in the manufacture of pramipexole-containing sustained-release preparations in various dosage forms easy for drug release control; includes a stabilizer to minimize impurity production of the drug- containing products during drug storage, remarkably improving chemical stability; and thereby eliminates a need for separate studies on the physical chemical structure analysis and/or on the toxicological effects of the corresponding impurities.
  • FIG. 1 shows the results of the stability assessment according to the use of L- HPC in Experimental Example 1 of the present invention.
  • FIG. 2 shows the results of the stability assessment according to the use of Eudragit E in Experimental Example 2 of the present invention.
  • FIG. 3 shows the results of the dissolution control assessment in Experimental Example 3 of the present invention.
  • Pramipexole-containing sustained-release pharmaceutical compositions were prepared in the form of tablets according to the composition and content in Table 2. More specifically, pramipexole was mixed with all the respective components other than magnesium stearate. To the mixture was finally added magnesium stearate, and the resulting mixture was compressed into tablets on a rotary type tablet making machine.
  • Comparative Example 1 used the composition of pramipexole sustained-release tablets (brand name: Mirapexin Prolonged-release tablets) commercially available in Europe as disclosed in laid-open publication No. KR10-2007-7005700.
  • Pramipexole-containing sustained-release pharmaceutical compositions were prepared in the form of tablets according to the composition and content in Table 3. More specifically, pramipexole was diluted geometrically by blending with HPMC and mixed with all the respective components other than magnesium stearate. To the mixture was finally added magnesium stearate, and the resulting mixture was compressed into tablets on a rotary type tablet making machine.
  • Eudragit E (Eudragit EPO) 14 -
  • pramipexole-containing sustained-release pharmaceutical composition in the form of tablets according to the composition and content in Table 4. More specifically, pramipexole was diluted geometrically by blending with HPMC and mixed with all the respective components other than magnesium stearate. To the mixture was finally added magnesium stearate, and the resulting mixture was compressed into tablets on a rotary type tablet making machine.
  • Example 1 and Comparative Examples 1 , 2 and 3 were subjected to a stress testing during open storage (completely exposed without separate packaging) at 40 ° C and 75 % RH and to an analysis on the impurity content by high performance liquid chromatography every week. The results are presented in FIG. 1.
  • the novel pharmaceutical composition of Example 1 had the least rise in the impurity content.
  • the results show that in the sustained-release pharmaceutical composition containing pramipexole or its salt, the use of a stabilizer such as L-HPC inhibits production of related substances, greatly improving the storage stability of the pramipexole-containing sustained-release pharmaceutical composition.
  • the novel pharmaceutical composition of Example 2 had a considerably lower yield of the related substances, extremely lower than the impurity content of the pharmaceutical composition of Example 1 shown in FIG. 1.
  • the result shows that the stability can be more improved according to the ionic characteristic of the methacryl-based polymer and much more improved by using Eudragit E in combination with the L-HPC.
  • the dissolution profile of the pramipexole-containing sustained-release pharmaceutical composition prepared in Example 4 was assessed according to the dissolution test in the Korean Pharmacopoeia.
  • the results are presented in FIG. 3. More specifically, the test solution (900 mL of 0.05 M phosphate buffer solution (pH 6.8)) was stirred at 50 rpm and 37 ° C in accordance with the paddle method in the dissolution test of the Korean Pharmacopoeia.
  • the drug release rate of the pramipexole-containing sustained-release tablets shows a good sustained-release profile because of the Eudragit E content.

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  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Epidemiology (AREA)
  • Neurology (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Psychiatry (AREA)
  • Psychology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne une composition pharmaceutique à libération prolongée contenant du pramipexole, ou l'un de ses sels pharmaceutiquement acceptables, et plus particulièrement une composition pharmaceutique contenant un agent de stabilisation servant à inhiber la production de substances apparentées en raison de la présence d'additifs et améliorant grandement la stabilité. La dissolution de la composition pharmaceutique est efficacement régulée, ce qui permet de préparer facilement des préparations à libération prolongée contenant du pramipexole sous diverses formes galéniques. En outre, la composition pharmaceutique contient un agent de stabilisation servant à minimiser la production des impuretés issues des produits médicamenteux pendant son stockage et améliorant grandement la stabilité chimique, ce qui permet d'éviter de mettre en œuvre des études séparées portant sur l'analyse de la structure physico-chimique et/ou sur les effets toxicologiques des impuretés correspondantes.
EP11801051.1A 2010-07-02 2011-05-12 Composition pharmaceutique à libération prolongée contenant du pramipexole, ou l'un de ses sels pharmaceutiquement acceptables, présentant une meilleure stabilité Withdrawn EP2588106A4 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR1020100064044A KR101307334B1 (ko) 2010-07-02 2010-07-02 프라미펙솔 또는 이의 약학적으로 허용되는 염을 포함하는 안정성이 개선된 서방형 약학 조성물
PCT/KR2011/003515 WO2012002644A2 (fr) 2010-07-02 2011-05-12 Composition pharmaceutique à libération prolongée contenant du pramipexole, ou l'un de ses sels pharmaceutiquement acceptables, présentant une meilleure stabilité

Publications (2)

Publication Number Publication Date
EP2588106A2 true EP2588106A2 (fr) 2013-05-08
EP2588106A4 EP2588106A4 (fr) 2014-01-01

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EP11801051.1A Withdrawn EP2588106A4 (fr) 2010-07-02 2011-05-12 Composition pharmaceutique à libération prolongée contenant du pramipexole, ou l'un de ses sels pharmaceutiquement acceptables, présentant une meilleure stabilité

Country Status (4)

Country Link
EP (1) EP2588106A4 (fr)
JP (1) JP2013530212A (fr)
KR (1) KR101307334B1 (fr)
WO (1) WO2012002644A2 (fr)

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US10624858B2 (en) 2004-08-23 2020-04-21 Intellipharmaceutics Corp Controlled release composition using transition coating, and method of preparing same
US10064828B1 (en) 2005-12-23 2018-09-04 Intellipharmaceutics Corp. Pulsed extended-pulsed and extended-pulsed pulsed drug delivery systems
CN104825397A (zh) 2006-04-03 2015-08-12 伊萨·奥迪迪 含有机溶胶涂层的受控释放递送物件
US10960077B2 (en) 2006-05-12 2021-03-30 Intellipharmaceutics Corp. Abuse and alcohol resistant drug composition
EP2906202A4 (fr) * 2012-10-15 2016-04-27 Isa Odidi Formulations de médicament pour administration par voie orale
CN105456216B (zh) * 2014-08-18 2019-11-05 江苏神龙药业股份有限公司 盐酸普拉克索缓释片剂组合物及其制备方法
CN106474084B (zh) * 2015-08-28 2020-12-11 江苏先声药业有限公司 一种盐酸普拉克索缓释制剂及其制备方法
CN107951853B (zh) * 2016-10-17 2022-04-08 海思科制药(眉山)有限公司 一种盐酸普拉克索缓释药物组合物及其制备方法
CN108785263B (zh) * 2017-04-26 2021-06-29 江苏恒瑞医药股份有限公司 普拉克索或其药用盐的固体药物组合物及其制备方法
CN114939112B (zh) * 2017-12-28 2024-03-01 北京北大维信生物科技有限公司 普拉克索缓释药物组合物、其制备方法及用途

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Also Published As

Publication number Publication date
KR101307334B1 (ko) 2013-09-12
WO2012002644A2 (fr) 2012-01-05
KR20120003278A (ko) 2012-01-10
WO2012002644A3 (fr) 2012-04-12
EP2588106A4 (fr) 2014-01-01
JP2013530212A (ja) 2013-07-25

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