WO2015189778A1 - Adsorbats et compositions d'agomélatine en solution - Google Patents

Adsorbats et compositions d'agomélatine en solution Download PDF

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Publication number
WO2015189778A1
WO2015189778A1 PCT/IB2015/054374 IB2015054374W WO2015189778A1 WO 2015189778 A1 WO2015189778 A1 WO 2015189778A1 IB 2015054374 W IB2015054374 W IB 2015054374W WO 2015189778 A1 WO2015189778 A1 WO 2015189778A1
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WO
WIPO (PCT)
Prior art keywords
agomelatine
adsorbate
peg
composition according
pharmaceutically acceptable
Prior art date
Application number
PCT/IB2015/054374
Other languages
English (en)
Inventor
Giorgio Bertolini
Cinzia BIAGGI
Ilaria FERRANDO
Dieter Ruchatz
Hendrik Schlehahn
Original Assignee
Laboratorio Chimico Internazionale S.P.A.
Alfred E. Tiefenbacher (Gmbh & Co. Kg)
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 Laboratorio Chimico Internazionale S.P.A., Alfred E. Tiefenbacher (Gmbh & Co. Kg) filed Critical Laboratorio Chimico Internazionale S.P.A.
Priority to EP15731717.3A priority Critical patent/EP3154522A1/fr
Publication of WO2015189778A1 publication Critical patent/WO2015189778A1/fr

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Classifications

    • 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
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/143—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with inorganic compounds
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/485—Inorganic compounds
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds
    • 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
    • A61P25/24—Antidepressants

Definitions

  • the present invention relates to a new agomelatine composition, particularly agomelatine in solution which is adsorbed on an inert carrier or directly formulated.
  • Another subject-matter of the invention is a solid form made of an agomelatine in solution adsorbate and a process for the preparation of said solid form as well as the use of the adsorbate and of the composition in therapy, and pharmaceutical compositions comprising the same.
  • Agomelatine is an antidepressant drug having the following formula (I)
  • Agomelatine is currently commercially available only in solid form.
  • the solubility does not represent a limiting factor for bioavailability.
  • An object of the invention is to provide a new solid form of agomelatine in solution which can be absorbed in an effective and very fast way.
  • Another object of the invention is to provide a new solid form of agomelatine in solution, in which said agomelatine is dissolved in a solvent and adsorbed on an inert carrier.
  • Another object of the invention is to provide a process for the preparation of said new solid form of agomelatine.
  • Another object of the invention is to provide a new solid form of agomelatine which can be easily processed and formulated into pharmaceutical compositions.
  • a further object of the invention is to provide pharmaceutical compositions comprising the adsorbates of agomelatine in solution.
  • Another object of the invention is to provide pharmaceutical compositions comprising the agomelatine in solution.
  • Figure 1 shows the dissolution profiles of presently marketed agomelatine and of representative compositions according to the invention.
  • an object of the invention is a new solid form which consists of an adsorbate of agomelatine in solution on one or more pharmaceutically acceptable inert solid carriers, particularly an adsorbate of agomelatine, characterized in that it is agomelatine in solution in a pharmaceutically acceptable solvent which is adsorbed on at least one pharmaceutically acceptable inert solid carrier.
  • solid form means a pharmaceutical formulation, in the specific case of agomelatine, which occurs as a stable solid which is suitable either to be used as such or to be formulated into a pharmaceutical composition.
  • the term “adsorbate(s)” refers to solid mixtures in which a solution of agomelatine in a pharmaceutically acceptable solvent is supported on one or more pharmaceutically acceptable inert solid carriers.
  • the term “agomelatine in solution” is meant to refer to a solution of agomelatine in one or more pharmaceutically acceptable solvents.
  • Suitable solvents according to the invention are, for example, polyethylene glycols (PEGs); polysorbates, for example polysorbate 20, polysorbate 40, polysorbate 60 and polysorbate 80; triglycerides, for example the triglycerides sold under the trade name Miglyol ® or 1,2,3-triacetoxypropane (Triacetin); coconut oil, castor oil; cotton seed oil; corn seed oil; etc., and mixtures thereof.
  • PEGs polyethylene glycols
  • polysorbates for example polysorbate 20, polysorbate 40, polysorbate 60 and polysorbate 80
  • triglycerides for example the triglycerides sold under the trade name Miglyol ® or 1,2,3-triacetoxypropane (Triacetin)
  • Miglyol ® 1,2,3-triacetoxypropane
  • Triacetin 1,2,3-triacetoxypropane
  • suitable solvents according to the invention are selected from Transcutol (diethyleneglycol monoethyl ether), Labrasol (caprylocaproyl macrogol-8 glycerides), Kolliphor EL (Polyoxyl castor oil), Kollisolv P 124 (poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol)) and mixture therof.
  • the above solvents may be mixed together or with other solvents, such as for instance, lower alcohols, such as methanol or ethanol.
  • One of the preferred solvent according to the invention is PEG, advantageously a PEG having a molecular weight from 200 to 800, for example of 200, 400, 600 and 800.
  • the solvent is PEG 400.
  • Transcutol diethyleneglycol monoethyl ether
  • Labrasol caprylocaproyl macrogol-8 glycerides
  • Kolliphor EL Polyoxyl castor oil
  • Kollisolv P 124 poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol) or Poloxamer 124.
  • an "inert solid carrier” is meant to refer to any pharmaceutically acceptable “filler” agent which is used in the pharmaceutical arts.
  • suitable inert solid carriers include, for example, silica, advantageously colloidal silica, saccharides, polysaccharides such as cyclodextrins, starches, maltodextrins, cellulose and derivatives thereof, lactose, mannitol; salts or minerals such as magnesium and aluminum silicates, kaolin, talc, calcium phosphates; certain solid polyalcohols such as sorbitol; magnesium salts of fatty acids; zeolites; and pharmaceutically acceptable water-soluble polymers, such as solid high molecular weight PEGs (polyethylene glycols), PVP (polyvinylpyrrolidone) and the like.
  • PEGs polyethylene glycols
  • PVP polyvinylpyrrolidone
  • the inert solid carriers are selected from colloidal silicas, advantageously anhydrous and amorphous colloidal silicas such as the silica currently marketed under the trade name
  • the inert solid carriers are selected from cellulose and derivatives thereof, such as microcrystalline cellulose, carboxymethyl cellulose and hydroxypropyl methylcellulose.
  • the inert solid carriers are selected from cyclodextrins, for example beta- or gamma-cyclodextrin, starch, lactose and maltodextrins.
  • the adsorbates of the invention may include agomelatine solutions and one or more pharmaceutically acceptable inert solid carriers.
  • Representative solid carrier which can be mixed up to are preferably selected from colloidal silica, microcrystalline cellulose, dicalcium phosphate anhydrous magnesium aluminum silicate and magnesium stearate.
  • the formation of the solid is carried out by mixing the agomelatine solution with the carrier, or carriers, at room temperature.
  • an object of the invention is a new process for the preparation of adsorbates of agomelatine solutions, which comprises:
  • step (a) b. adding one or more pharmaceutically acceptable inert solid carriers to the solution obtained in step (a); c. stirring the thus obtained suspension until a powder is obtained.
  • the invention relates to a process for the preparation of adsorbates of agomelatine solutions, which consists of steps (a) to (c) above.
  • step (a) The entire procedure can be carried out at room temperature. However, if necessary, during step (a), it is possible to heat or sonicate in order to promote the dissolution of agomelatine. There is no need to add acids or any other liquid or solid ingredient to achieve the solution of step (a).
  • step (c) The mixture obtained in step (c) is initially a fine suspension which is then properly stirred in order to transform it into a powder.
  • the powder obtained by the process of the invention can be sieved in order to obtain a more homogeneous particle size.
  • the formation of the agomelatine adsorbate occurs without the need of any intervention, i.e. no particular technique must be carried out, such as for instance, freeze-drying or granulation.
  • adsorbates of the invention which are advantageously but not necessarily prepared according to the process described herein, occur as a powder which is perfectly stable and processable.
  • agomelatine stays in solution in the adsorbates and in the compositions and does not convert into any crystalline form. This is an excellent result, as it does not tend to crystallize over the time. Indeed, the dissolved and absorbed agomelatine does not precipitate, neither into a crystalline, amorphous, or any other solid form. Agomelatine remains completely in solution after absorption onto the solid carrier (sponge effect).
  • the agomelatine/carrier/solvent ratios vary depending on the carriers and solvents selected for use.
  • the ratios may be in the range from 1/10/10 to 1/1/1, preferably from 1/8/8 to 1/3/5, for example 1/2,5/4, 1/2,3/3,75, 1/2/3,5, etc.
  • the weight amount of agomelatine in the adsorbate will depend on the above ratio.
  • the weight amount of agomelatine in the adsorbate could vary from 5 to 40%, preferably from 10 to 30%, for example 15-25%.
  • Adsorbates in which PEG 400 is used as the solvent and a colloidal silica is used as the carrier are preferred according to the invention, advantageously in the ratios indicated above.
  • adsobates wherein Transcutol (diethyleneglycol monoethyl ether) is used as a solvent and the carrier is a mixture of carriers, for instance such as those selected from colloidal silica, microcrystalline cellulose, dicalcium phosphate anhydrous magnesium aluminum silicate and magnesium stearate.
  • Transcutol diethyleneglycol monoethyl ether
  • the carrier is a mixture of carriers, for instance such as those selected from colloidal silica, microcrystalline cellulose, dicalcium phosphate anhydrous magnesium aluminum silicate and magnesium stearate.
  • the adsorbates of the invention allow to obtain a powder of agomelatine in solution which is perfectly stable and processable and which can be used, for example, for the preparation of solid pharmaceutical compositions, such as tablets or capsules, but also suspensions and suppositories as well as patches for buccal delivery (“buccal patches”) or even patches for transdermal delivery (“transdermal patches”), preferably with the addition of one or more conventional pharmaceutically acceptable excipients or carriers.
  • said adsorbates are only made of agomelatine, one or more solvents and one or more inert carriers as defined above, i.e. they are prepared in the absence of any further substance, such as for instance acidic and or alkalizing agents.
  • agomelatine existing in the new form of the invention is already in solution, it has the advantage of being absorbed faster because it does not require to pass from the solid state to a state of solution in a body fluid, which is an important and significant technical advancement.
  • agomelatine stays in solution in the adsorbates of the invention.
  • the compositions prepared with the adsorbates of the invention does not show any crystalline form by XRD, even after accelerated condition assays (40°C/75 RH, in HDPE containers).
  • compositions comprising the adsorbates of the invention are a further subject-matter of the invention, especially in the form of tablets or capsules as well as the use of the adsorbates and of the pharmaceutical compositions comprising them in therapy, in particular for the treatment of depression.
  • the invention also encompasses a method for treating depression, which comprises administering an effective amount of an adsorbate of the invention, advantageously in the form of a pharmaceutical composition, preferably as a tablet or a capsule, optionally in combination with other active ingredients and with conventional excipients and carriers, to a subject in need thereof.
  • compositions of the invention are particularly suitable for oral administration although, as already mentioned, other forms of administration may be used as well.
  • compositions can be in the form of tablets, capsules or granules, and they are prepared according to conventional methods with the use of pharmaceutically acceptable excipients such as binding agents, filler agents, lubricants, disintegrants, wetting agents, flavouring agents, etc.
  • the tablets can also be coated by methods well known in the art.
  • Capsules and tablets are preferred pharmaceutical compositions and the skilled in the art is perfectly able to select conventional carriers and excipients which can be included in the compositions of the invention.
  • compositions and adsorbates of the invention are also particularly suitable for buccal administration, by which agomelatine can be rapidly absorbed through the mucosa of the mouth because it is already in solution.
  • the adsorbates of the invention are suitable for the preparation of transdermal and transmucosal compositions in virtue of the immediate availability of the active ingredient in solution.
  • each dosage unit according to the invention comprises an amount of agomelatine from 1 to 100 mg, for example from 5 to 80 mg, advantageously from 30 to 50 mg, for example of about 25 mg and, if desired or necessary, conventional excipients and additives well known to one skilled in the art.
  • the adsorbate can be formulated in combination with other active ingredients.
  • the adsorbate of agomelatine solution is formulated as the sole active ingredient.
  • the invention allows to formulate agomelatine in a simple and industrially convenient manner, obtaining compositions from which agomelatine is rapidly absorbed by the body.
  • the adsorbates of the invention represent a new, original alternative to the known compositions of agomelatine.
  • agomelatine An unpredictably very rapid release of agomelatine was observed with respect of the conventional tablets, which are however already quickly dissolved.
  • agomelatine in Valdoxan tablets shows an immediate drug release profile, this means that 75% of the agomelatine is dissolved within 45 minutes.
  • agomelatine adsorbates compositions show a dramatic improved dissolution rate compared to agomelatine Valdoxan reference.
  • Figure 1 shows the dissolution rates of Valdoxan, and of compositions comprising agomelatine adsorbates manufactured according to the invention.
  • the process of the invention here especially directed to obtaining adsorbates of agomelatine in solution, can be applied to any other drug which is dissolved in a suitable solvent or mixture of solvents, thus providing new solid forms consisting of adsorbates of drugs in solution.
  • adsorbates as well as the process for their preparation, the pharmaceutical compositions containing them and the use thereof in therapy, represent a further aspect of the invention.
  • agomelatine 1 g was dissolved in 7.52 g of PEG 400 at room temperature under magnetic stirring. 3.76 g of colloidal silica (Aerosil ® 200) was then added, and the mixture was kept under stirring until a fine powder was formed. The powder was then sieved through a steel sieve of 500 micron to obtain the title adsorbate.
  • the weight content of agomelatine in the adsorbate is approx. 8.4%.
  • Example 1 is repeated using 1 g of agomelatine, 7.52 g of PEG 400 and 7.52 g of g of colloidal silica (Aerosil ® 200).
  • the weight content of agomelatine in the adsorbate is approx. 6.2%.
  • Example 1 is repeated using 1 g of agomelatine, 3.76 g of PEG 400 and 2.3 g of colloidal silica (Aerosil ® 200).
  • the weight content of agomelatine in the adsorbate is about 12.8%.
  • Example 1 is repeated using 25 mg of agomelatine, 125 mg of diethyleneglycol monoethyl ether (Transcutol HP), 50 mg od colloidal silica (Aerosil ® 200), 100 mg of microcrystalline cellulose, 100 mg dicalcium phosphate anhydrous and 6 mg of magnesium stearate.
  • Lubricated blend was filled in Size "1" white opaque/opaque empty hard gelatin capsules by using Pam-manual capsules filling machine.
  • Average Weight of filled capsule (mg) 516.5 519.2 515.8
  • Example 7 The compositions of Example 7 were also compressed to obtain tablets.
  • Lubricated material was compressed into tablets using 9.0 mm

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
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  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Inorganic Chemistry (AREA)
  • Neurology (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Psychiatry (AREA)
  • Pain & Pain Management (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
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Abstract

La présente invention concerne une nouvelle composition d'agomélatine, en particulier de l'agomélatine en solution, qui est adsorbée sur un porteur inerte ou directement formulée. Un autre objet de l'invention concerne une forme solide constituée d'un adsorbat d'agomélatine en solution, et un procédé pour la préparation de ladite forme solide, ainsi que l'utilisation de l'adsorbat et de la composition en thérapie, et des compositions pharmaceutiques les comprenant.
PCT/IB2015/054374 2014-06-10 2015-06-10 Adsorbats et compositions d'agomélatine en solution WO2015189778A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP15731717.3A EP3154522A1 (fr) 2014-06-10 2015-06-10 Adsorbats et compositions d'agomélatine en solution

Applications Claiming Priority (2)

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ITMI20141057 2014-06-10
ITMI2014A001057 2014-06-10

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WO2015189778A1 true WO2015189778A1 (fr) 2015-12-17

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017059877A1 (fr) * 2015-10-07 2017-04-13 Rontis Hellas S.A. Composition pharmaceutique contenant l'agomélatine et son procédé de préparation
CN108785373A (zh) * 2018-07-04 2018-11-13 河南省济源市济世药业有限公司 一种冬凌草超微粉及其制备方法
CN109069437A (zh) * 2016-06-01 2018-12-21 浙江华海药业股份有限公司 一种阿戈美拉汀软胶囊制剂
WO2020260725A1 (fr) * 2019-12-20 2020-12-30 Lts Lohmann Therapie-Systeme Ag Système thérapeutique transmuqueux contenant de l'agomélatine
WO2020260726A1 (fr) * 2019-12-20 2020-12-30 Lts Lohmann Therapie-Systeme Ag Système thérapeutique transmuqueux contenant de l'agomélatine

Citations (4)

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Publication number Priority date Publication date Assignee Title
EP2474522A1 (fr) * 2009-12-23 2012-07-11 Tianjin Taipu Pharmaceutical Science & Technology Development Co., Ltd. Agomélatine et compositions pharmaceutiques la contenant
WO2012093402A1 (fr) * 2011-01-04 2012-07-12 Symed Labs Limited Procédés pour la préparation de n-[2-(7-méthoxy-1-naphtyléthyl]acétamide
US20120322753A1 (en) * 2009-12-29 2012-12-20 Shanghai Zhongxi Sunve Pharmaceutical Co., Ltd. Production method of solid preparation and the solid preparations produced by the method
WO2013063263A1 (fr) * 2011-10-25 2013-05-02 Lycus Llc Compositions pharmaceutiques pour le traitement de la douleur

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2474522A1 (fr) * 2009-12-23 2012-07-11 Tianjin Taipu Pharmaceutical Science & Technology Development Co., Ltd. Agomélatine et compositions pharmaceutiques la contenant
US20120322753A1 (en) * 2009-12-29 2012-12-20 Shanghai Zhongxi Sunve Pharmaceutical Co., Ltd. Production method of solid preparation and the solid preparations produced by the method
WO2012093402A1 (fr) * 2011-01-04 2012-07-12 Symed Labs Limited Procédés pour la préparation de n-[2-(7-méthoxy-1-naphtyléthyl]acétamide
WO2013063263A1 (fr) * 2011-10-25 2013-05-02 Lycus Llc Compositions pharmaceutiques pour le traitement de la douleur

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Title
FRIEDRICH H ET AL: "Dissolution rate improvement of poorly water-soluble drugs obtained by adsorbing solutions of drugs in hydrophilic solvents onto high surface area carriers", EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS, ELSEVIER SCIENCE PUBLISHERS B.V., AMSTERDAM, NL, vol. 62, no. 2, 1 February 2006 (2006-02-01), pages 171 - 177, XP027998056, ISSN: 0939-6411, [retrieved on 20060201], DOI: 10.1016/J.EJPB.2005.08.013 *
KOYUTURK SEMA ET AL: "A novel dilute and shoot HPLC assay method for quantification of irbesartan and hydrochlorothiazide in combination tablets and urine using second generation C18-bonded monolithic silica column with double gradient elution", JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS, vol. 97, 2 May 2014 (2014-05-02), pages 103 - 110, XP028848835, ISSN: 0731-7085, DOI: 10.1016/J.JPBA.2014.04.026 *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017059877A1 (fr) * 2015-10-07 2017-04-13 Rontis Hellas S.A. Composition pharmaceutique contenant l'agomélatine et son procédé de préparation
CN109069437A (zh) * 2016-06-01 2018-12-21 浙江华海药业股份有限公司 一种阿戈美拉汀软胶囊制剂
CN108785373A (zh) * 2018-07-04 2018-11-13 河南省济源市济世药业有限公司 一种冬凌草超微粉及其制备方法
CN108785373B (zh) * 2018-07-04 2022-08-09 河南济世药业有限公司 一种冬凌草超微粉及其制备方法
WO2020260725A1 (fr) * 2019-12-20 2020-12-30 Lts Lohmann Therapie-Systeme Ag Système thérapeutique transmuqueux contenant de l'agomélatine
WO2020260726A1 (fr) * 2019-12-20 2020-12-30 Lts Lohmann Therapie-Systeme Ag Système thérapeutique transmuqueux contenant de l'agomélatine
CN113597303A (zh) * 2019-12-20 2021-11-02 罗曼治疗系统股份公司 含有阿戈美拉汀的经粘膜治疗系统
EP4378527A3 (fr) * 2019-12-20 2024-09-11 LTS Lohmann Therapie-Systeme AG Système thérapeutique transmucosal contenant de l'agomélatine

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