WO2018219801A1 - Extrudats à libération immédiate - Google Patents

Extrudats à libération immédiate Download PDF

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Publication number
WO2018219801A1
WO2018219801A1 PCT/EP2018/063775 EP2018063775W WO2018219801A1 WO 2018219801 A1 WO2018219801 A1 WO 2018219801A1 EP 2018063775 W EP2018063775 W EP 2018063775W WO 2018219801 A1 WO2018219801 A1 WO 2018219801A1
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WO
WIPO (PCT)
Prior art keywords
alkyl
group
salts
solvates
formula
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PCT/EP2018/063775
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English (en)
Inventor
Ildiko Terebesi
Peter Serno
Steffen SANDMANN
Julia FREUNDLIEB
Anke Stroyer
Tanja PIES
Original Assignee
Bayer Pharma Aktiengesellschaft
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Publication of WO2018219801A1 publication Critical patent/WO2018219801A1/fr

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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
    • A61K31/435—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
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A61K9/146—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 organic macromolecular compounds

Definitions

  • the present invention relates to stable transparent compositions in form of rapid release melt extrudates that contain selective partial adenosine A1 receptor agonists as active pharmaceutical ingredients, a polymeric compound as excipient and optionally a water-soluble sugar alcohol.
  • This invention also relates to a solvent-free process of preparing said extrudates as well as the use of said extrudates in the production of rapid release preparations.
  • the present invention relates to novel transparent rapid release compositions of selective partial adenosine A1 receptor agonists obtainable by extrusion of a melt comprising
  • Selective partial adenosine A1 receptor agonists are compounds of the formula (A)
  • R 1 represents (Ci-C4)-alkyl
  • R 2 represents (Ci-C4)-alkyl
  • (Ci-C4)-alkyl may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of fluorine, trifluoromethyl, trifluoromethoxy, (C1-C4)- alkoxy, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkoxy and (Ci-C4)-alkylsulphonyl,
  • R 1 and R 2 each represent hydrogen
  • R 1 and R 2 together with the nitrogen atom to which they are attached form a 4- to 7-membered het- erocycle which may contain a further heteroatom from the group consisting of N, O and S, where the 4- to 7-membered heterocycle may be substituted by 1 to 2 substituents independently of one another selected from the group consisting of fluorine, trifluoromethyl, (Ci- C4)-alkyl, trifluoromethyl and (Ci-C4)-alkoxy,
  • the compounds according to the invention may exist in stereoiso- meric forms (enantiomers, diastereomers).
  • the invention therefore encompasses the enantiomers or diastereomers and the respective mixtures thereof. It is possible to isolate the stereoisomerical- ly homogeneous constituents from such mixtures of enantiomers and/or diastereomers in a known manner.
  • the present invention encompasses all the tautomeric forms.
  • Preferred salts in the context of the present invention are physiologically acceptable salts of the compounds according to the invention. Also encompassed are salts which are not themselves suitable for pharmaceutical applications but can be used, for example, for isolation or purification of the compounds of the invention.
  • Physiologically acceptable salts of the compounds according to the invention include acid addition salts of mineral acids, carboxylic acids and sulphonic acids, for example salts of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, ethanesulphonic acid, toluenesulphonic acid, benzenesulphonic acid, naphthalenedisulphonic acid, acetic acid, trifluoro- acetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid and benzoic acid.
  • Physiologically acceptable salts of the compounds of the invention also include salts of conventional bases, by way of example and with preference alkali metal salts (e.g. sodium and potassium salts), alkaline earth metal salts (e.g. calcium and magnesium salts) and ammonium salts de- rived from ammonia or organic amines having 1 to 16 carbon atoms, by way of example and with preference ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzyla- mine, N-methylmorpholine, arginine, lysine, ethylenediamine and N-methylpiperidine.
  • alkali metal salts e.g. sodium and potassium salts
  • alkaline earth metal salts e.g. calcium and magnesium salts
  • solvates in the context of the invention are those forms of the compounds accord- ing to the invention which form a complex in the solid or liquid state by coordination with solvent molecules. Hydrates are a specific form of the solvates in which the coordination is with water. Solvates preferred in the context of the present invention are hydrates.
  • Alkyl in the context of the invention is a linear or branched alkyl radical having 1 to 4 carbon atoms. Preferred examples include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl.
  • Cvcloalkyl in the context of the invention is a monocyclic saturated carbocycle having 3 to 7 ring carbon atoms.
  • Preferred examples include: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • Alkoxy in the context of the invention is a straight-chain or branched alkoxy radical having 1 to 4 carbon atoms.
  • Preferred examples include: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy and tert-butoxy.
  • Cvcloalkoxy in the context of the invention is a monocyclic saturated carbocycle which has 3 to 7 carbon atoms and is bonded via an oxygen atom.
  • Preferred examples include: cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and cycloheptyloxy.
  • Alkylsulphonyl in the context of the invention is a straight-chain or branched alkyl radical which has 1 to 4 carbon atoms and is attached via a sulphonyl group.
  • Preferred examples include: me- thylsulphonyl, ethylsulphonyl, n-propylsulphonyl, isopropylsulphonyl, n-butylsulphonyl and tert- butylsulphonyl.
  • Heterocycle in the context of the invention is a saturated heterocycle which has a total of 4 to 7 ring atoms, contains one or two ring heteroatoms from the group consisting of N, O and S and is attached via a ring carbon atom or optionally a ring nitrogen atom.
  • Examples include: azetidinyl, pyrrolidinyl, pyrazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpho- linyl, thiomorpholinyl and azepanyl. Preference is given to azetidinyl, pyrrolidinyl, piperidinyl and morpholinyl.
  • the selective partial adenosine A1 receptor agonists are compounds of the formula (A), in which
  • R 1 represents (Ci-C3)-alkyl
  • R 2 represents (Ci-C3)-alkyl
  • (Ci-C3)-alkyl may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of fluorine, trifluoromethyl, methoxy, ethoxy, cyclopropyl and cyclobutyl,
  • R 1 and R 2 each represent hydrogen
  • R 1 and R 2 together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocycle which may contain a further heteroatom from the group consisting of N, O and S, where the 4- to 6-membered heterocycle may be substituted by 1 or 2 substituents inde- pendently of one another selected from the group consisting of fluorine, trifluoromethoxyl,
  • the selective partial adenosine A1 receptor agonists are compounds of the formula (A), in which
  • R 1 represents ethyl
  • R 2 represents ethyl
  • R 1 and R 2 each represent hydrogen
  • R 1 and R 2 together with the nitrogen atom to which they are attached form an azetidinyl, pyrrolidinyl or piperidinyl ring,
  • azetidinyl ring may be substituted by a methoxy substituent
  • the selective partial adenosine A1 receptor agonists are se- lected from the group consisting of 2-amino-6-( ⁇ [2-(4-chlorophenyl)-1 ,3-thiazol-4-yl]methyl ⁇ sulphanyl)-4-[4 ⁇
  • compositions according to the present invention are in particular selected from the following list:
  • the selective partial adenosine A1 receptor agonists are present in the compositions according to the invention in the range of 0.1 to 10 % by weight, preferably in the range of 1 to 7.5 %, further preferred in the range of 1.5 to 5 %.
  • the selective partial adenosine A1 receptor agonists are poorly soluble in water.
  • a surprisingly higher relative bioavailability can be reached.
  • cardiovascular disorders like e.g. coronary heart disease, ischemic injury during acute coronary syndrome, angina pectoris, heart failure, worsening chronic heart failure, heart failure with reduced ejection fraction (HFrEF), heart failure with preserved ejection fraction (HFpEF), myocardial infarction and atrial fibrillation
  • HPC hydroxypropylcellulose
  • HPMC AS hydroxypropyl methylcellulose acetate succinate
  • HPC AS hydroxypropyl methylcellulose acetate succinate
  • HPC AS polyvinyl caprolac- tam-polyvinyl acetate-polyethylene glycol graft co-polymer
  • Preferred for the present invention is HPC with low or medium viscosity.
  • the low viscosity hydroxypropylcellulose preferably has an average molecular weight of from
  • the medium viscosity hydroxypropylcellulose preferably has a viscosity in the range of 150 to 400 mPa ⁇ s (at 20 °C/2% aq.) and an average molecular weight of about 620 000 g/mol (see e.g. Technical Data Sheet Nisso, HPC, TDS-01 , Version 1.7, 2015, Type M).
  • the molar degree of substitution refers to the average number of moles of propylene oxide per glucose unit in the cellulose.
  • composition according to the invention comprises preferably 50 to 80 % or 60 to 90 %, more preferably 60 to 80 % and even more preferred 80 % by weight of HPC of low or medium viscosity.
  • Soluplus® has the following structure
  • Soluplus ® has an average molecular weight of 90 000 to 140 000 g/mol.
  • composition according to the invention comprises preferably 50 to 80 % or 60 to 95 %, more preferably 70 to 95 % and even more preferred 95 % by weight of Soluplus®.
  • HPMC AS Hydroxypropyl methylcellulose acetate succinate
  • HPMC AS is a mixture of acetic acid and mono- succinic acid esters of hydroxypropyl methylcellulose as described in the monograph of the US Pharmacopeia (USP 39-NF 34, 2016).
  • different types may be used, e.g. AffinisolTM products from Dow (grades 716G, 912G and 126G) or AQOAT ® products from ShinEtsu (grades AS-LG/LF, AS-MG/MF, AS_HG/HF).
  • Suitable sugar alcohols are mannitol, xylitol, sorbitol, adonitol, dulcitol and generally pentitols and hexitols. Preferred for the present invention is maltitol.
  • composition according to the invention may comprise water-soluble sugar alcohol or mixtures thereof.
  • the composition comprises preferably 5-25 %, more preferably 10-20 % and even more preferred 15 % by weight of a water-soluble sugar alcohol or mixtures thereof.
  • the present invention relates to novel transparent rapid release compositions of selective partial adenosine A1 receptor agonists obtainable by extrusion of a melt comprising a) at least one selective artial adenosine A1 receptor agonist of the formula (A)
  • R 1 represents (Ci-C4)-alkyl
  • R 2 represents (Ci-C4)-alkyl
  • (Ci-C4)-alkyl may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of fluorine, trifluoromethyl, trifluorometh- oxy, (Ci-C4)-alkoxy, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkoxy and (Ci-C4)-alkylsulphonyl, or
  • R 1 and R 2 each represent hydrogen
  • R 1 and R 2 together with the nitrogen atom to which they are attached form a 4- to 7- membered heterocycle which may contain a further heteroatom from the group consisting of N, O and S,
  • 4- to 7-membered heterocycle may be substituted by 1 to 2 substituents independently of one another selected from the group consisting of fluorine, trifluorome- thyl, (Ci-C4)-alkyl, trifluoromethyl and (Ci-C4)-alkoxy,
  • a polymeric compound selected from the group consisting of hydroxy- propylcellulose (HPC) with low or medium viscosity, hydroxypropyl methylcellulose acetate succinate (HPMC AS) or a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft co-polymer,
  • the low viscosity HPC has a viscosity in the range of 3.0 to 10.0 mPa ⁇ s (at 20 °C/2% aq.) and the medium viscosity HPC has a viscosity in the range of 150 to 400 mPa ⁇ s (at 20 °C/2% aq.)
  • the present invention relates to novel transparent rapid release compositions of selective partial adenosine A1 receptor agonists obtainable by extrusion of a melt comprising
  • R 1 represents (Ci-C4)-alkyl
  • R 2 represents (Ci-C4)-alkyl, where (Ci-C4)-alkyl may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of fluorine, trifluoromethyl, trifluorometh- oxy, (Ci-C4)-alkoxy, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkoxy and (Ci-C4)-alkylsulphonyl, or
  • R 1 and R 2 each represent hydrogen
  • R 1 and R 2 together with the nitrogen atom to which they are attached form a 4- to 7- membered heterocycle which may contain a further heteroatom from the group consisting of N, O and S,
  • 4- to 7-membered heterocycle may be substituted by 1 to 2 substituents independently of one another selected from the group consisting of fluorine, trifluoromethyl, (Ci-C4)-alkyl, trifluoromethyl and (Ci-C4)-alkoxy,
  • a polymeric compound selected from the group consisting of hydroxy- propylcellulose (HPC) with low or medium viscosity, hydroxypropyl methylcellulose acetate succinate (HPMC AS) or a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft co-polymer,
  • the low viscosity HPC has a viscosity in the range of 3.0 to 10.0 mPa ⁇ s (at 20 °C/2% aq.) and the medium viscosity HPC has a viscosity in the range of 150 to 400 mPa ⁇ s (at 20 °C/2% aq.)
  • the invention furthermore relates to a solvent-free process for producing such compositions (cf. US 6,569,455).
  • Transparent melt extrudates with the desired fast release and high stability can be obtained in a simple manner with the specifically selected polymer hydroxypropylcellulose of low or medium viscosity with an average molecular weight from 1 10 000 to 300 000 or about 620 000 g/mol, respectively, and with a molecular degree of substitution of at least 3 in an amount of 50-99 % by weight, preferably 50-80 % or 60-90 %, more preferably 60-80 % and even more preferred 80 % by weight, based on the active ingredient/polymer mixture in conjunction with selective partial adenosine A1 receptor agonists and, where appropriate, excipients.
  • the present application also relates to preparations produced with the use of the extrudates of the invention.
  • Fast-release extrudates or preparations mean for the purposes of the invention those which release 80 % of the active ingredient(s) within 60 min in the USP paddle method (see USP 39, Chapter 724 - Drug Release).
  • the extrudates or preparations of the invention display very rapid release and show significant super-saturation. They are therefore particularly well suited for fast reaching of high plasma concentrations of active pharmaceutical ingredient.
  • the release of active ingredient is influenced, for example, by the concentration of active ingredient in the final product or by extrusion process parameters such as the screw geometry, the extrusion rate, the extrusion temperature, the diameter and surface area of the extrudate etc.
  • the release rate is influenced in particular by the particle size of the extrudate.
  • the release is influenced in particular by the content of disintegrant in the final formulation.
  • the extrudate or the preparation is administered orally.
  • the extrudate of the invention is comminuted, for example, ground to an average particle diameter of less than 1 mm, sieved using 600 ⁇ sieve mm and packed e.g. as sachet.
  • the extrudate of the invention is, where appropriate in comminuted form, mixed with a disintegrant and, where appropriate, further excipients and processed to a single-unit dosage form.
  • Disintegrants are substances which ensure rapid disintegration of dosage forms in aqueous solution, such as, for example, crosslinked poylvinylpyrrolidone (e.g. polyvinylpolypyrrol- idone, PVPP, or crospovidone).
  • crosslinked poylvinylpyrrolidone e.g. polyvinylpolypyrrol- idone, PVPP, or crospovidone
  • it is preferred to use large amounts of disintegrant that is to say more than 0.1 part by weight of disintegrant per 1 part of extrudate (active ingredi- ent(s), HPC and optionally water-soluble sugar alcohol).
  • Single-unit dosage forms mean preparations which are administered as single dose, for example tablets, coated tablets or capsules.
  • a mixture of at least one selective partial adenosine A1 receptor agonists and a polymeric compound an amount of at least 50 % by weight and optionally a water-soluble sugar alcohol or mixtures thereof is produced, and the mixture is passed through an extruder which has at the place where the product enters a temperature of from 20 to 40°C, and at the exit die or dies a temperature of ⁇ 225°C, where the exit dies have a diameter of from 0.5 to 5 mm, preferably from 1 to 3 mm, and the extruded strands are comminuted after their emergence.
  • the residence time of the mixture in the extruder depends on technical aspects of the process and may vary to a large degree. It is generally less than 60 min, preferably less than 30 min.
  • the ingredients can be mixed before entry into the extruder or inside the extruder. Premixing, that is to say mixing before entry, is preferred, inter alia for reasons of the content uniformity.
  • extrudates obtained in this way may be formulated as granulates by adding common pharmaceutical excipients such as flavours, glidants and other processing agents, if needed.
  • the ex- trudates may also be packed into sachets or sticks. It is also possible to process the extrudates into immediate-release tablets or orally-dispersible tablets or chewable tablets.
  • 1 part by weight of compound of formula (I) is mixed with low-viscosity HPC (average MW about 11 1 000 to 150 000 g/mol), so that an average amount of HPC of 50-80 %, preferably 80 %, is included in the mixture.
  • HPC low-viscosity HPC
  • Maltitol is added with an average amount of 0-30 %, preferably 15 %.
  • the mixture is processed in a twin screw extruder with an exit die having a diameter of 1 mm.
  • the mate- rial is extruded at a die temperature of 178 °C.
  • the transparent extrudates are comminuted, and the fraction ( ⁇ 250 ⁇ ) is mixed with common pharmaceutical excipients to gain oral dosage forms.
  • 0.5 g of compound of formula (II) is mixed with 8 g medium-viscosity HPC (average MW about 620 000 g/mol, 150 to 400 mPa ⁇ s at 20 °C/2% aq.), and 1.5 g Maltitol in a mixer for 10 min.
  • the powder blend is processed in a twin screw extruder with an exit die having a diameter of 1 mm.
  • the material is extruded for 7 to 20 min at a die temperature of 160 to 175°C.
  • the transparent ex- trudates are comminuted and the fraction ( ⁇ 600 ⁇ ) was further used. Yield after extrusion: 5.8 to 7.2 g, yield after milling and sieving: 4.7 to 5.9 g.
  • the extrudate powder after milling was dispersed in water and administered in 5 mL/kg to the animals. Since the compound of formula (II) has a very low solubility in water for the purpose of comparison with the formulations according to the invention the hydrochloride salt of the prodrug (i.e. 2- ⁇ 4-[2-( ⁇ [2-(4-chlorophenyl)-1 ,3-tN
  • the administered doses are related to the compound of formula (II). Plasma samples were collected at predefined time points up to 96 h post dosing.
  • the calculated pharmacokinetic parameters refer to the compound of formula (II) (analyte) and are summarized in the table below.
  • the exposure of the compound of formula (II) in terms of AU Cnorm was 0.794 kg ⁇ h/L when administered as prodrug in solution.
  • the exposure of the Soluplus extrudate was 0.200 kg ⁇ h/L and of the H PC Type M extrudate was 0.413 kg ⁇ h/L.
  • the relative bioavailability (F re i, prodrug solution set to 100 %) was about 25 % for the Soluplus extrudate and about 52 % for the H PC Type M extrudate. Since the compound of formula (II) has a very low solubility in water it is thus surprising that such a high relative bioavailability can be reached using the extrudate formulations according to the invention.
  • the maximum concentration of the compound of formula (II) in rat plasma was reached 3 h (tmax) after administration of the three formulations.
  • the dose-normalized C ma x was 0.0716 kg/L after dosing as prodrug in solution and was 0.0180 kg/L for the Soluplus extrudate and 0.0366 kg/L for the H PC Type M extrudate.
  • the elimination half-life of the compound of formula (II) was long for the three tested formulations and ranged between 17.5 h and 22.9 h determined in the interval up to 96 h post dosing.

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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)

Abstract

La présente invention concerne des compositions transparentes stables sous la forme d'extrudats fondus à libération rapide qui contiennent des agonistes partiels sélectifs du récepteur A1 de l'adénosine en tant qu'ingrédients pharmaceutiques actifs, un composé polymère en tant qu'excipient et éventuellement un alcool de sucre soluble dans l'eau. La présente invention concerne également un procédé sans solvant de préparation desdits extrudats ainsi que l'utilisation desdits extrudats dans la production de préparations à libération rapide.
PCT/EP2018/063775 2017-06-02 2018-05-25 Extrudats à libération immédiate WO2018219801A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP17174136.6 2017-06-02
EP17174136 2017-06-02

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WO2018219801A1 true WO2018219801A1 (fr) 2018-12-06

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996025149A1 (fr) 1995-02-14 1996-08-22 Basf Aktiengesellschaft Preparations solides de principes actifs, contenant de l'hydroxypropylcellulose
US6569455B1 (en) 1999-07-23 2003-05-27 Bayer Aktiengesellschaft Quick-release extrudates, method for preparing the same and compositions obtained from said extrudates
WO2003053441A1 (fr) 2001-12-11 2003-07-03 Bayer Healthcare Ag 2-thio-3,5-dicyano-4-phenyl-6-aminopyridine substituees et leur utilisation
WO2010086101A1 (fr) 2009-01-29 2010-08-05 Bayer Schering Pharma Aktiengesellschaft Dicyanopyridine à substitution alkylamino et ses promédicaments d'ester d'acide aminé

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996025149A1 (fr) 1995-02-14 1996-08-22 Basf Aktiengesellschaft Preparations solides de principes actifs, contenant de l'hydroxypropylcellulose
US6569455B1 (en) 1999-07-23 2003-05-27 Bayer Aktiengesellschaft Quick-release extrudates, method for preparing the same and compositions obtained from said extrudates
WO2003053441A1 (fr) 2001-12-11 2003-07-03 Bayer Healthcare Ag 2-thio-3,5-dicyano-4-phenyl-6-aminopyridine substituees et leur utilisation
WO2010086101A1 (fr) 2009-01-29 2010-08-05 Bayer Schering Pharma Aktiengesellschaft Dicyanopyridine à substitution alkylamino et ses promédicaments d'ester d'acide aminé

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
ANONYMOUS: "Clinical Study Synopsis (Capadenoson)", INTERNET, February 2010 (2010-02-01), pages 1 - 5, XP055408199, Retrieved from the Internet <URL:http://trialfinder.bayerscheringpharma.de/html/pdf/12679_Study_Synopsis_CTP.pdf> [retrieved on 20170920] *
MEIBOM DANIEL ET AL: "Neladenoson Bialanate Hydrochloride: A Prodrug of a Partial Adenosine A 1 Receptor Agonist for the Chronic Treatment of Heart Diseases", CHEMMEDCHEM, vol. 12, no. 10, 10 May 2017 (2017-05-10), pages 728 - 737, XP055408313, ISSN: 1860-7179, DOI: 10.1002/cmdc.201700151 *
TENDERA MICHAL ET AL: "The new oral adenosine A1 receptor agonist capadenoson in male patients with stable angina", CLINICAL RESEARCH IN CARDIOLOGY, STEINKOPFF-VERLAG, DA, vol. 101, no. 7, 28 February 2012 (2012-02-28), pages 585 - 591, XP035074061, ISSN: 1861-0692, DOI: 10.1007/S00392-012-0430-8 *

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