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WO2012140604A1 - Formulations stables de chlorhydrate de pramipexole - Google Patents

Formulations stables de chlorhydrate de pramipexole Download PDF

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Publication number
WO2012140604A1
WO2012140604A1 PCT/IB2012/051819 IB2012051819W WO2012140604A1 WO 2012140604 A1 WO2012140604 A1 WO 2012140604A1 IB 2012051819 W IB2012051819 W IB 2012051819W WO 2012140604 A1 WO2012140604 A1 WO 2012140604A1
Authority
WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
pramipexole
stabilizer
pharmaceutically acceptable
sustained release
Prior art date
Application number
PCT/IB2012/051819
Other languages
English (en)
Inventor
Shilpa D. VIBHUTE
Sunil Agarwal
Yogesh JOSHI
Original Assignee
Sandoz Ag
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 Sandoz Ag filed Critical Sandoz Ag
Publication of WO2012140604A1 publication Critical patent/WO2012140604A1/fr

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
    • A61K31/428—Thiazoles condensed with carbocyclic rings
    • 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
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • 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
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • 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
    • 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
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1635—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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin

Definitions

  • the invention encompasses a stable pharmaceutical composition comprising Pramipexole or pharmaceutically acceptable salt thereof and methods for preparing the same.
  • the salt is the hydrochloride salt.
  • the invention encompasses pharmaceutical compositions in the form of compressed tablets or sustained release tablets.
  • Pramipexole dihydrochloride monohydrate 2-amino-6-N-propylamino-4, 5, 6, 7- tetrahydrobenzo-thiazole-dihydrochloride monohydrate, of formula (I), is a dopamine - D 3 /D 2 agonist.
  • Pramipexole dihydrochloride is known primarily for the treatment of schizophrenia, and particularly for the treatment of Parkinson's disease, and is marketed as the dihydrochloride monohydrate under several brand names, such as Mirapex. It has the following structure:
  • Pramipexole dihydrochloride monohydrate molecular formula C1 0 H 2 1C1 2 N 3 OS; relative molecular mass 302.27.
  • Pramipexole dihydrochloride monohydrate is a white to off-white, tasteless, crystalline powder. Melting occurs in the range of 296°C to 301°C, with decomposition.
  • Pramipexole is a chiral compound with one chiral centre. Pure (S)-enantiomer is obtained from the synthetic process by chiral recrystallization of one of the intermediates during synthesis.
  • Pramipexole dihydrochloride monohydrate is a highly soluble compound. Water solubility is more than 20 mg/ml and solubility in buffer media is generally above 10 mg/ml between pH 2 and pH 7.4. Pramipexole dihydrochloride monohydrate is not hygroscopic, and of highly crystalline nature. Under milling the crystal modification (monohydrate) does not change. Pramipexole is very stable in the solid state, yet in solution it is light sensitive. Pramipexole dihydrochloride and other tetrahydrobenzothiazoles were first discovered by Schneider et al. and described in European Patent 0 186 087 (the '087 patent) and U.S. Patent No. 4,886,812 (the '812 patent).
  • Pramipexole dihydrochloride degrades into its corresponding imine during manufacture and /or storage.
  • the imine is a degradation product, which reduces the effective dosage of Pramipexole dihydrochloride when it is administered to a patient.
  • the present invention overcomes the aforesaid problem by providing pharmaceutical composition of Pramipexole dihydrochloride which is stable to aforesaid degradation.
  • the present inventors have surprisingly developed a stable pharmaceutical composition of Pramipexole dihydrochloride which comprises a stabilizer which is capable of inhibiting nucleophilic addition elimination reaction which leads to the formation of Pramipexole dihydrochloride imine impurity i.e degradation product.
  • a stable pharmaceutical composition of Pramipexole dihydrochloride having improved stability can be prepared which overcome the drawback/problem of degradation of Pramipexole or pharmaceutically acceptable salt thereof during manufacture and /or storage.
  • a pharmaceutical composition comprising Pramipexole or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipients selected from at least one of diluent, binder, disintegrant, lubricant, glidant and stabilizer, provided that the stabilizer is the one which can inhibit the reaction of nucleophilic addition/ elimination which leads to the formation of corresponding imine, wherein the Pramipexole contains its corresponding imine and the amount of the corresponding imine has not increased by more than 1% by weight from the initial amount of Pramipexole after storage at about 40°C and about 75% relative humidity for 6 months.
  • Pramipexole dihydrochloride compositions are subject to degradation during manufacture and storage. It is known that the Pramipexole dihydrochloride degrades into its corresponding imine. The corresponding imine is a degradation product, which reduces the effective dosage of Pramipexole dihydrochloride when it is administered to a patient.
  • the present invention overcomes this problem by providing compositions of Pramipexole dihydrochloride that are stable to this degradation.
  • corresponding imine refers to Pramipexole or a pharmaceutically acceptable salt thereof, wherein the imine impurity is as shown below.
  • the term “pharmaceutically acceptable salt” refers to Pramipexole dihydrochloride.
  • the term “stable” means that the amount of the corresponding imine within the Pramipexole dihydrochloride in the packaged pharmaceutical composition has not increased by more than 1% by weight from the initial amount of Pramipexole dihydrochloride after storage at about 40°C and about 75% relative humidity for 6 months.
  • the corresponding imine content has not increased by more than 0.5% by weight of the initial amount of Pramipexole dihydrochloride after storage at about 40°C at about 75% relative humidity for 6 month.
  • accelerated storage conditions refers to storage of Pramipexole dihydrochloride at about 40°C at about 75% relative humidity for 6 months.
  • Comparative testing with Pramipexole dihydrochloride was performed to determine the conditions which cause the degradation of Pramipexole dihydrochloride into the corresponding imine.
  • Compositions of Pramipexole dihydrochloride and each of the excipients of the prior art tablets were prepared and subjected to stressed storage conditions.
  • the amount of the corresponding imine present in each of the compositions was measured by high performance liquid chromatography ("HPLC") both before and after storage. It was found that the amount of the corresponding imine in the composition increased by over 10 times in the presence of excipients which generate formaldehyde over the storage period.
  • HPLC high performance liquid chromatography
  • a pharmaceutical composition comprising Pramipexole or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipients selected from at least one of diluent, binder, disintegrant, lubricant, glidant and stabilizer, provided that the stabilizer is the one which can inhibit the reaction of nucleophilic addition/ elimination which leads to the formation of corresponding imine, wherein the Pramipexole contains its corresponding imine and the amount of the corresponding imine has not increased by more than 1% by weight from the initial amount of Pramipexole after storage at about 40°C and about 75% relative humidity for 6 months.
  • the corresponding imine content has not increased by more than 0.5% by weight of the initial amount of Pramipexole dihydrochloride after storage at about 40°C at about 75% relative humidity for 6 month.
  • a pharmaceutical composition comprising Pramipexole or its pharmaceutically acceptable salt and pharmaceutically acceptable excipients selected from at least one of diluents, binder, polymers, disintegrant, stabilizer or lubricant.
  • the corresponding imine immediately after preparation of the pharmaceutical composition, is present in an amount of not more than 0.5% by weight of the initial amount of Pramipexole dihydrochloride in the pharmaceutical composition.
  • the stable compositions of the invention encompass solid pharmaceutical dosage forms.
  • the solid pharmaceutical dosage forms are compressed tablets or sustained release tablets.
  • the compressed tablets comprise Pramipexole dihydrochloride, mannitol, microcrystalline cellulose, starch, colloidal silicon dioxide, stabilizer and magnesium stearate.
  • the stabilizer added to the formulation is such that it can inhibit the nucleophilic addition/ elimination reaction which may be effected in the microenvironment of the tablet thereby causing the formation of imine impurity.
  • the sustained release tablets comprise Pramipexole dihydrochloride, sustained release polymer, microcrystalline cellulose, colloidal silicon dioxide, stabilizer and magnesium stearate.
  • Diluents increase the bulk of a solid pharmaceutical composition, and may make a pharmaceutical dosage form containing the composition easier for the patient and care giver to handle.
  • Diluents used in the composition include diluents commonly used in solid pharmaceutical compositions.
  • Diluents include, but are not limited to, calcium carbonate, calcium phosphate (dibasic or tribasic), calcium sulfate, dextrates, dextrin, dextrose excipients, fructose, kaolin, lactitol, anhydrous lactose, lactose monohydrate, maltose, mannitol, sorbitol, sucrose, starch, pregelatinized starch, talc.
  • Binders help to bind the active ingredient and other excipients together. Binders used in the composition include binders commonly used in solid pharmaceutical compositions. Binders include, but are not limited to, acacia, alginic acid, carbomer, hydrochloride carboxymethylcellulose, dextrin, ethylcellulose, gelatin, glucose, guar gum, hydroxypropylcellulose, maltose, methylcellulose, povidone, starch, methylcellulose, polyethylene oxide.
  • Disintegrants increase the dissolution rate of a solid pharmaceutical composition in the patient's body.
  • Disintegrants used in the composition include disintegrants commonly used in solid pharmaceutical compositions.
  • Disintegrants include, but are not limited to, alginic acid, croscarmellose hydrochloride, crospovidone, potassium polacrilin, sodium starch glycolate, starch.
  • Lubricants are added to a pharmaceutical composition for ease in processing, to prevent adhesion to the equipment used during processing.
  • Lubricants used in the composition include lubricants commonly used in solid pharmaceutical compositions.
  • Lubricants used in the composition include, but are not limited to, calcium stearate, glyceryl behenate, magnesium stearate, mineral oil, polyethylene glycol, hydrochloride stearyl fumarate, stearic acid, talc, vegetable oil, hydrochloride lauryl sulfate, zinc stearate.
  • Glidants improve the flowability of a non-compacted solid composition and improve the accuracy of dosing.
  • Glidants used in the composition include glidants commonly used in solid pharmaceutical compositions.
  • Glidants used in the composition include, but are not limited to, colloidal silicon dioxide, magnesium trisilicate, starch, talc, tribasic calcium phosphate.
  • Stabilizers used in this composition which would stabilize the formulation include but not limited to Butylated Hydroxytoluene (BHT), Butylated Hydroxyanisole (BHA), Sodium- metabisulphite, Meglumine, Sodium citrate, Povidone, Glycine, Arginine.
  • BHT Butylated Hydroxytoluene
  • BHA Butylated Hydroxyanisole
  • Sodium- metabisulphite Meglumine
  • Sodium citrate Sodium citrate
  • Povidone Glycine
  • Glycine Arginine.
  • the solid pharmaceutical dosage forms of the invention may be prepared by conventional processes known to those of ordinary skill in the art, including, but not limited to, wet granulation, dry granulation such as slugging or compaction, or direct compression of the formulation into tablets or filling into capsules.
  • Pramipexole or a pharmaceutically acceptable salt thereof is blended with diluents and binders to form a blend.
  • Disintegrant is then added to the blend and blended.
  • Lubricant is then added to the blend and blended. The blend is compressed into a tablet.
  • the sustained release tablets are prepared by wet granulation.
  • Pramipexole or a pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients in powder form are blended and then further mixed in the presence of a liquid, typically water or organic solvents like isopropyl alcohol, ethanol, which causes the powders to clump into granules.
  • the granulate can be screened and/or milled, dried and then screened and/or milled to the desired particle size.
  • the dried granulate is compressed into a sustained release tablet or other excipients optionally be added prior to tabletting.
  • Pramipexole or a pharmaceutically acceptable salt thereof, sustained release polymer, binder, disintegrant, diluent and stabilizer is blended and mixed with a lubricant to form a blend.
  • the blend is then compressed into a sustained release tablet.
  • Pramipexole dihydrochloride containing a stabilizer was subjected to stress conditions in an open pertidish for 7 days at 50°C/ 75%RH , and the percentage of imine impurity was measured using HPLC as described in example 1.
  • Pramipexole Dihydrochloride Monohydrate hypromellose, hydrogenated castor oil, meglumine, microcrystalline cellulose and colloidal silicon dioxide, were blended and mixed. The final blend was lubricated with magnesium stearate and the tablets were compressed.
  • Pramipexole Dihydrochloride Monohydrate hypromellose, glyceryl monostearte, meglumine, microcrystalline cellulose and colloidal silicon dioxide, were blended and mixed. The final blend was lubricated with magnesium stearate and the tablets were compressed.
  • Example 6 Pramipexole Dihydrochloride Monohydrate, hypromellose, PVP, meglumine, microcrystalline cellulose, were blended and mixed and were granulated using Isopropyl alcohol. The granules were lubricated with magnesium stearate and colloidal silicon dioxide was added as a glidants and the tablets were compressed.
  • Example 6 Example 6:
  • Pramipexole Dihydrochloride Monohydrate hypromellose, meglumine, mannitol, corn starch, microcrystalline cellulose and colloidal silicon dioxide, were blended and mixed. The final blend was lubricated with magnesium stearate and the tablets were compressed.
  • Pramipexole Dihydrochloride Monohydrate hypromellose, glyceryl monostearte, sodium metabisulphite, microcrystalline cellulose and colloidal silicon dioxide, were blended and mixed. The final blend was lubricated with magnesium stearate and the tablets were compressed.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention porte sur une composition pharmaceutique stable comprenant du pramipexole ou un sel pharmaceutiquement acceptable de celui-ci et un stabilisant qui permet d'inhiber la réaction d'addition/élimination nucléophile qui conduit à la formation de l'impureté imine correspondante. L'invention porte en outre sur des procédés pour sa préparation. En particulier, la présente invention porte sur des compositions pharmaceutiques sous la forme de comprimés ou de comprimés à libération prolongée comprenant la composition pharmaceutique de la présente invention.
PCT/IB2012/051819 2011-04-15 2012-04-13 Formulations stables de chlorhydrate de pramipexole WO2012140604A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN1246/MUM/2011 2011-04-15
IN1246MU2011 2011-04-15

Publications (1)

Publication Number Publication Date
WO2012140604A1 true WO2012140604A1 (fr) 2012-10-18

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Country Status (1)

Country Link
WO (1) WO2012140604A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2870965A1 (fr) * 2013-11-06 2015-05-13 Sanovel Ilac Sanayi ve Ticaret A.S. Formulations pharmaceutiques liquides orales de pramipexole
US20160113908A1 (en) * 2013-05-20 2016-04-28 Mylan, Inc. Transdermal Therapeutic System for Extended Dosing of Pramipexole in Treating Neurological Disorders
CN107951853A (zh) * 2016-10-17 2018-04-24 四川海思科制药有限公司 一种盐酸普拉克索缓释药物组合物及其制备方法
WO2018191160A1 (fr) 2017-04-10 2018-10-18 Chase Therapeutics Corporation Association comprenant un antagoniste de nk1 et méthode de traitement de synucléinopathies
WO2019006050A1 (fr) 2017-06-30 2019-01-03 Chase Therapeutics Corporation Compositions d'antagoniste de nk-1 et méthodes destinées à être utilisées dans le traitement de la dépression

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0186087A1 (fr) 1984-12-22 1986-07-02 Dr. Karl Thomae GmbH Tétrahydro-benzothiazoles, leur procédé de préparation et leur utilisation comme intermédiaires ou médicaments
WO2007002518A1 (fr) * 2005-06-23 2007-01-04 Spherics, Inc. Formes de dosage de pramipexole a liberation retardee ou a liberation prolongee/retardee
US20070129329A1 (en) * 2005-12-02 2007-06-07 Alembic Limited Stabilized pharmaceutical composition of pramipexole and method of preparation thereof
WO2008122638A2 (fr) * 2007-04-10 2008-10-16 Boehringer Ingelheim International Gmbh Procédé d'élaboration de pastilles de dihydrochlorure de pramipexole
EP2308464A1 (fr) * 2009-10-06 2011-04-13 Sanovel Ilac Sanayi ve Ticaret A.S. Compositions orales désintégrables de pramipexole

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0186087A1 (fr) 1984-12-22 1986-07-02 Dr. Karl Thomae GmbH Tétrahydro-benzothiazoles, leur procédé de préparation et leur utilisation comme intermédiaires ou médicaments
US4886812A (en) 1984-12-22 1989-12-12 Dr. Karl Thomae Gmbh Tetrahydro-benzthiazoles, the preparation thereof and their use as intermediate products or as pharmaceuticals
WO2007002518A1 (fr) * 2005-06-23 2007-01-04 Spherics, Inc. Formes de dosage de pramipexole a liberation retardee ou a liberation prolongee/retardee
US20070129329A1 (en) * 2005-12-02 2007-06-07 Alembic Limited Stabilized pharmaceutical composition of pramipexole and method of preparation thereof
WO2008122638A2 (fr) * 2007-04-10 2008-10-16 Boehringer Ingelheim International Gmbh Procédé d'élaboration de pastilles de dihydrochlorure de pramipexole
EP2308464A1 (fr) * 2009-10-06 2011-04-13 Sanovel Ilac Sanayi ve Ticaret A.S. Compositions orales désintégrables de pramipexole

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20160113908A1 (en) * 2013-05-20 2016-04-28 Mylan, Inc. Transdermal Therapeutic System for Extended Dosing of Pramipexole in Treating Neurological Disorders
US9682068B2 (en) * 2013-05-20 2017-06-20 Mylan Inc. Transdermal therapeutic system for extended dosing of pramipexole in treating neurological disorders
EP2870965A1 (fr) * 2013-11-06 2015-05-13 Sanovel Ilac Sanayi ve Ticaret A.S. Formulations pharmaceutiques liquides orales de pramipexole
CN107951853A (zh) * 2016-10-17 2018-04-24 四川海思科制药有限公司 一种盐酸普拉克索缓释药物组合物及其制备方法
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
WO2018191160A1 (fr) 2017-04-10 2018-10-18 Chase Therapeutics Corporation Association comprenant un antagoniste de nk1 et méthode de traitement de synucléinopathies
WO2019006050A1 (fr) 2017-06-30 2019-01-03 Chase Therapeutics Corporation Compositions d'antagoniste de nk-1 et méthodes destinées à être utilisées dans le traitement de la dépression

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