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WO2018108884A1 - Formulation de comprimés pharmaceutiques - Google Patents

Formulation de comprimés pharmaceutiques Download PDF

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Publication number
WO2018108884A1
WO2018108884A1 PCT/EP2017/082379 EP2017082379W WO2018108884A1 WO 2018108884 A1 WO2018108884 A1 WO 2018108884A1 EP 2017082379 W EP2017082379 W EP 2017082379W WO 2018108884 A1 WO2018108884 A1 WO 2018108884A1
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WO
WIPO (PCT)
Prior art keywords
tablets
magnesium stearate
tablet
hydrochloride
lactose
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.)
Ceased
Application number
PCT/EP2017/082379
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German (de)
English (en)
Inventor
Peter Serno
Katrin IDE
Carmen Lobback
Michael Pfeffer
Christine Schwer
Anke Stroyer
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Bayer Pharma AG
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Bayer Pharma AG
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Publication date
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Publication of WO2018108884A1 publication Critical patent/WO2018108884A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A61K9/20—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
    • 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
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure

Definitions

  • the present invention relates to a stable pharmaceutical tablet formulation containing 2- ⁇ 4- [2- ( ⁇ [2- (4-chlorophenyl) -1,3-thiazol-4-yl] methyl ⁇ sulfanyl) -3,5-dicyano-6 - (pyrrolidin-1-yl) pyryl] phenoxy ⁇ ethyl-L-alanyl-L-alaninate (Neladenoson bialanat) in the form of one of its salts, characterized in that it releases the active ingredient quickly, and processes for their preparation, their use as a medicament, as well as its use for the prophylaxis and / or treatment of cardiovascular diseases such as worsening chronic heart failure, heart failure with impaired or preserved left ventricular ejection fraction (heart failure with reduced or ejection fraction, HFrEF or HFpEF), angina pectoris and ischemic injury during acute coronary syndrome.
  • cardiovascular diseases such as worsening chronic heart failure, heart failure with impaired or preserved left ventricular e
  • Neladenoson bialanate is the compound 2- ⁇ 4- [2 - ( ⁇ [2- (4-chlorophenyl) -1,3-thiazol-4-yl] methyl ⁇ sulfanyl) -3,5-dicyano-6- (pyrrolidine 1-yl) pyridin-4-yl] phenoxy ⁇ ethyl-L-alanyl-L-alaninate of the formula (I)
  • Neladenoson bialanat is used in the form of one of its salts. Preference is given to using the hydrochloride (II), in particular the monohydrochloride (IIa).
  • Neladenosone is the compound 2 - [[2- (4-chlorophenyl) thiazol-4-yl] methylsulfanyl] -4- [4- (2-hydroxyethoxy) phenyl] -6-pyrrolidin-1-ylpyridine-3 , 5-dicarbonitrile of the formula (III)
  • Neladenosone, the bialanate and the hydrochloride or the monohydrochloride of the bialanate are known (see WO 2010/086101 and WO 2016/188711).
  • the compounds of the formulas (I), (II) and (III) act as partial adenosine A1 receptor agonists and can be used, for example, as agents for the prophylaxis and / or treatment of cardiovascular disorders such as, for example, chronic heart failure, heart failure with impaired or preserved left ventricular ejection fraction (HFrEF or HFpEF), angina pectoris, and ischemic injury during acute coronary syndrome.
  • cardiovascular disorders such as, for example, chronic heart failure, heart failure with impaired or preserved left ventricular ejection fraction (HFrEF or HFpEF), angina pectoris, and ischemic injury during acute coronary syndrome.
  • neladenosone III
  • prodrugs of neladenosone such as neladenoson bialanate (I) (ibid., Compare Examples 1 and 44).
  • Prodrugs of pharmaceutical agents are often developed to increase the solubility of the drug, to overcome limited intestinal uptake, or to reduce its metabolism in the gastrointestinal tract.
  • Most of the prodrugs available on the market are esters, which are cleaved in vivo mostly by esterase-mediated hydrolysis into the actual active ingredient, which can then develop its intended pharmacological effect.
  • the chemical lability is a desired property of the biological activity of prodrugs, which, on the other hand, at the same time considerably impairs the stability in the pharmaceutical dosage form.
  • the authors suggest optimizing the production conditions and, in particular, as dry as possible process conditions for coating the tablet cores and the use of high-density polyethylene (HDPE) bottles with desiccant as primary packaging [Kestur et al., Int. J. Pharm. 476, 93-98 (2014) and Badawy et al., Int. J. Pharm. 469, 1111-120 (2014)].
  • the proposed formulation of the tablet cores consists in addition to the active ingredient of microcrystalline cellulose, hydroxypropyl cellulose, the disintegrant croscarmellose sodium and the lubricant magnesium stearate and contains no lactose.
  • DMP 754 is an ester prodrug of a fibrinogen glycoprotein IIb / IIIa receptor antagonist. It shows as pure active ingredient after storage for 3 months at 40 ° C and 75% relative humidity, a low degradation.
  • preformulation work with respect to a solid oral dosage form it was found that the compound decomposes significantly in the presence of anhydrous lactose and the content of degradation products increases dramatically.
  • the stability problem could be solved by addition of acids such as disodium citrate [SIF Badawy et al., Pharm. Dev. Tech. 4, 325-331 (1999)].
  • the mixtures or tablets did not contain crospovidone.
  • Fesoterodine is an unstable drug that substantially decomposes in a humid environment and at elevated temperature.
  • the stability of this active ingredient in solid oral dosage forms depends on the excipients used.
  • a particularly preferred filler MicroceLac ® has been described in a proportion of 20-40% of the tablet 100 (paragraph [0262] of US 2010/0130606 A1), which is a co-processed mixture of 75% ⁇ -lactose monohydrate and 25% microcrystalline cellulose , This corresponds to a content of ⁇ -lactose monohydrate in the tablet of 15-30%.
  • lactose destabilizes the drug (paragraph [0334] of US 2010/0130606 A1).
  • stabilization was possible by addition of a stabilizer from the group xylitol, sorbitol, polydextrose, isomalt or dextrose.
  • Neladenoson bialanate hydrochloride (II) and the monohydrochloride (IIa) is also an unstable compound, but can not be formulated into a stable tablet with the known methods of formulating prodrugs and other unstable drugs. It decomposes in common tablet formulations even with most extensive exclusion of water. Neladenosone (III) forms as the degradation product. This is undesirable since neladenosone (III) is almost not bioavailable after oral administration and thus the decomposed active ingredient portion for the desired pharmacological effect on the patient is no longer available. Also for regulatory reasons, tablets with partially decomposed active ingredient are undesirable because the permissible amount of degradation products and the decrease in the active ingredient content of tablets are limited. Tablets, whose active substance is already clearly decomposed, are therefore no longer marketable.
  • neladenosone bialanate hydrochloride (II) or the monohydrochloride (IIa) leave something to be desired in the release of the active ingredient.
  • drug release is sometimes slow and variable.
  • the release of active ingredient ie the dissolution of the active ingredient in an aqueous medium, which corresponds to the conditions in the upper gastrointestinal tract, is a prerequisite for the absorption of the drug into the bloodstream and the unfolding of a pharmacological action.
  • Neladenoson bialanate hydrochloride tablets it is desirable that the active ingredient in the aqueous environment of the upper gastrointestinal tract is released as soon as possible.
  • Low-speed tablets of drug release have the risk that the drug dissolves only in deep sections of the gastrointestinal tract where it encounters adverse conditions of stability or absorption or is excreted without absorption into the body.
  • bialanat (I) in particular for Neladenoson bialanate hydrochloride (II) or Neladenoson bialanat monohydrochloride (IIa) to find tablet formulations for salts of Neladenoson, in which the active ingredient is as stable as possible, ie in tablet formulations As slowly as possible to Neladenoson (III) decomposes, and from which the release of the drug takes place as quickly as possible.
  • the monohydrochloride contains the hydrochloride in exactly defined stoichiometric content.
  • monohydrochloride (IIa) represents in the context of this invention is a preferred embodiment, although not always explicitly mentioned in detail.
  • the dosage form of the tablet is generally described in European Pharmacopoeia 9.3 (Chapter 07 Dosage Forms - Tablets).
  • uncoated and coated tablets are preferred.
  • the tablets contain the active ingredient Neladenoson bialanate hydrochloride (II) or the monohydrochloride (IIa). But there are also other salt forms of Neladenoson bialanat (I) possible. Preference is given to dosages of 1 to 100 mg, in particular 2.5 to 60 mg, very particularly preferably 2.5 to 45 mg per tablet [amount stated as neladenosone bialanate (I)].
  • the amount of active ingredient is 2-50%, depending on the dosage and size of the tablets.
  • the tablets contain excipients. Amounts of the excipients are understood to mean the proportions by weight of a single excipient of the total mass of excipients of the tablet ("excipient content") of lacquer substance is also an adjuvant and is included in the calculation of the total mass of excipients of the coated tablet.
  • Tablets usually contain a filler.
  • a filler for example, are common: sugars or sugar alcohols such as mannitol, carbohydrates, such as microcrystalline cellulose or maltodextrin, inorganic fillers such as calcium hydrogen phosphate or calcium carbonate, and mixtures or coprocessed excipient mixtures such as MicroceLac ® (eg MicroceLac ® 80 from Meggle consisting of 75% ⁇ -lactose monohydrate and 25% microcrystalline cellulose), or Cellactose ® (for example Cellactose ® 80 from Meggle consisting of 75% ⁇ -lactose monohydrate and 25% Pulvercellu- loose).
  • MicroceLac ® eg MicroceLac ® 80 from Meggle consisting of 75% ⁇ -lactose monohydrate and 25% microcrystalline cellulose
  • Cellactose ® for example Cellactose ® 80 from Meggle consisting of 75% ⁇ -lactose monohydrate and 25% Pulvercell
  • the tablets according to the invention contain as fillers at least 68, preferably at least 75, up to a maximum of 95 percent by weight (based on all excipients of the tablet) lactose in one of its forms, such as anhydrous lactose or lactose monohydrate or mixtures thereof.
  • lactose may be made of different modifications, such as a-lactose monohydrate, beta-lactose or amorphous lactose, or have been prepared by different methods such as the commercial grades SUPERTAB ® 21 is ON or SUPERTAB ® 24an, Pharmatose ®, Supertab ® 1 1 SD or 14SD, Tablettose ® or FlowLac ® 90 or 100th
  • the tablets also contain a disintegrant.
  • a disintegrant Typical examples are: alginic acid, low-substituted hydroxypropylcellulose, corn starch, carboxymethyl starch sodium, carmellose calcium, croscarmellose sodium and other starch or cellulose derivatives.
  • these disintegrants are unsuitable because they adversely affect the stability of the active ingredient (I) in the form of one of its salts in the tablet.
  • the tablets of the invention contain as disintegrants crospovidone.
  • Crospovidone is described in the monograph "Crospovidone" of European Pharmacopoeia 9.0 Particularly preferred are tablet formulations containing 5 to 20% by mass (based on all excipients of the tablet) of crospovidone, in particular Crospovidone of type A.
  • Crospovidone of type A is coarser than that of the type B and has according to the method described in the US Pharmacopoeia USP39 method of wet screening a mass fraction of more than 15% of particles> 63 m.
  • the tablets may contain any of the known lubricants, dry binders, flow control agents or coating materials.
  • lubricant there may be used, for example, magnesium stearate, sodium stearyl fumarate, stearic acid, glycerin monostearate, glycerin monobehenate, calcium behenate, hydrogenated vegetable fats or oils, polyethylene glycols or talc. External lubrication of the tablets is also possible.
  • a flow control agent for example, fumed silica is suitable.
  • Coated tablets As coating materials for coated tablets according to the European Pharmacopoeia 9.0 (monograph "Coated tablets” of the European Pharmacopoeia 9.0) are the known pharmaceutical paints, which polymers such as hypromellose, hydroxypropyl cellulose, macrogol-poly (vinyl alcohol) graft copolymer, polyvinyl alcohol or poly (meth) acrylates, color pigments such as iron oxides, titanium dioxide or indigo carmine lacquer, plasticizers such as macrogols, tributyl citrate, tributyl acetyl citrate, dibutyl sebacate, triacetin or glycerol monostearate, as well as talc, etc.
  • polymers such as hypromellose, hydroxypropyl cellulose, macrogol-poly (vinyl alcohol) graft copolymer, polyvinyl alcohol or poly (meth) acrylates, color pigments such as iron oxides, titanium dioxide or indigo car
  • Coating materials with further functional properties can also be used, such as film formers for modified release of active substances such as ammonium methacrylate copolymers, cellulose acetate, Cellulose acetate butyrate, chitosan, ethyl cellulose, polyacrylates, poly (vinyl acetate) or enteric polymers such as cellulose acetate phthalate, hypromellose acetate succinate, hypromellose phthalate, methacrylic acid-methacrylic at-copolymers, poly (methacrylate-co-methyl-methacrylate-co-methacrylic acid) or polyvinyl acetate phthalate.
  • film formers for modified release of active substances such as ammonium methacrylate copolymers, cellulose acetate, Cellulose acetate butyrate, chitosan, ethyl cellulose, polyacrylates, poly (vinyl acetate) or enteric polymers such as cellulose acetate phthalate,
  • the tablets consist of active ingredient such as Neladenoson bialanat hydrochloride (II) or another salt of Neladenoson bialanat (I) and excipients.
  • active ingredient such as Neladenoson bialanat hydrochloride (II) or another salt of Neladenoson bialanat (I) and excipients.
  • the stated percentage of active ingredient refers to the mass of the tablet.
  • lactose monohydrate or anhydrous lactose, as well as crospovidone and optionally further excipients are based on the sum of the masses of all adjuvants of the tablet, without the active ingredient.
  • the tablets are produced by mixing, sieving and compressing the powder components (direct tabletting method). Alternatively, the powder mixture or parts thereof may be first dry granulated and then compressed into tablets. The tablets may be coated by spraying on an aqueous or organic solvent based lacquer suspension.
  • the achievable stability of the tablets according to the invention depends on the type of packaging and, associated therewith, the residual moisture during storage and the storage temperature.
  • Packaging forms with desiccants remove moisture from the tablets and lead to a particularly low rate of degradation of the salts of active ingredient (I) to neladenosone (III).
  • the achievable stability of the tablets according to the invention depends on the residual moisture of the tablets at the time of packaging. Furthermore, the degradation rate of the salts of active ingredient (I) to neladenosone (III) at low storage temperature is lower than at higher storage temperature.
  • the tablets of the invention have a very good chemical stability.
  • a synthetic zeolite is in this case with a pore size of 3A used (Tri-Sorb ® from Clariant) as a molecular sieve.
  • the tablets of the invention have a rapid release of active ingredient. Under the conditions described in the Experimental Section, at least 90%, preferably 95%, of the active ingredient is released within 15 minutes.
  • the subject of the invention is thus a pharmaceutical tablet formulation containing 2- ⁇ 4- [2- ( ⁇ [2- (4-chlorophenyl) -1,3-thiazol-4-yl] methyl ⁇ sulfanyl) -3,5- dicyano-6- (pyrrolidin-1-yl) -pyridin-4-yl] phenoxy ⁇ ethyl-L-alanyl-L-alaninate [neladenoson bialanate (I)] in the form of one of its salts, characterized in that the excipient moiety
  • the invention further provides a pharmaceutical tablet formulation comprising 2- ⁇ 4- [2- ( ⁇ [2- (4-chlorophenyl) -1,3-thiazol-4-yl] methyl ⁇ sulfanyl) -3,5- dicyano-6- (pyrrolidined-1-yl) pyridin-4-yl] phenoxy ⁇ ethyl-L-alanyl-L-alaninate [neladenoson bialanate (I)] in the form of one of its salts, characterized in that the increase in the Decomposition product 2- [[2- (4-chlorophenyl) thiazol-4-yl] methylsulfanyl] -4- [4- (2-hydroxyethoxy) phenyl] -6-pyrrolidin-1-ylpyridine-3,5-dicarbonitrile [ Neladenosone (III)] when stored for 3 months at 40 ° C and a relative humidity of 75%, measured after packaging of 10 tablets in a 45
  • the invention also provides a pharmaceutical tablet formulation comprising 2- ⁇ 4- [2- ( ⁇ [2- (4-chlorophenyl) -1,3-thiazol-4-yl] methyl ⁇ sulfanyl) -3,5- dicyano-6- (pyrrolidined-1-yl) pyridin-4-yl] phenoxy ⁇ ethyl-L-alanyl-L-alaninate [neladenoson bialanate (I)] in the form of one of its salts, characterized in that the increase in the Decomposition product 2- [[2- (4-chlorophenyl) thiazol-4-yl] methylsulfanyl] -4- [4- (2-hydroxyethoxy) phenyl] -6-pyrrolidin-1-ylpyridine-3,5-dicarbonitrile [ Neladenosone (III)] when stored for 3 months at 40 ° C and a relative humidity of 75%, measured after packaging in blister films containing an aluminum layer as
  • the invention furthermore relates to pharmaceutical tablet formulations as described in embodiments (A), (B) or (C), which are each characterized in that the excipient fraction
  • the invention furthermore relates to pharmaceutical tablet formulations as described in embodiments (A), (B), (C) or (D), which are each additionally characterized in that the active ingredient (I) is at least 90% effective after 15 minutes. is released.
  • the invention also relates to pharmaceutical tablet formulations as described in embodiments (A), (B), (C) or (D), which are each further characterized in that the active ingredient (I) after 15 minutes to at least 95 % is released.
  • the invention also relates to pharmaceutical tablet formulations as described in the embodiments (A), (B), (C), (D), (E) or (F), each of which is additionally characterized in that the active ingredient in Form of the hydrochloride (II) is present.
  • the invention also relates to pharmaceutical tablet formulations as described in the embodiments (A), (B), (C), (D), (E), (F) or (G), which are each further characterized in that a type A crospovidone is chosen as the disintegrant.
  • the invention also relates to pharmaceutical tablet formulations as described in the embodiments (A), (B), (C), (D), (E), (F), (G) or (H), each of which additionally characterized in that they contain 5-25% (w / w) 2- ⁇ 4- [2- ( ⁇ [2- (4-chlorophenyl) -1,3-thiazol-4-yl] methyl ⁇ sulfanyl) - 3,5-dicyano-6- (pyrrolidin-1-yl) pyridin-4-yl] -phenoxy ⁇ ethyl-L-alanyl-L-alaninate hydrochloride [neladenoson bialanate hydrochloride (II)].
  • the invention also relates to pharmaceutical tablet formulations as described in the embodiments (A), (B), (C), (D), (E), (F), (G), (H) or (I) , which are each further characterized in that the tablet has a film coating.
  • the invention further provides a process for preparing a pharmaceutical tablet formulation comprising 2- ⁇ 4- [2- ( ⁇ [2- (4-chlorophenyl) -1,3-thiazol-4-yl] methyl ⁇ sulfanyl) -3,5-dicyano-6- (pyrrolidin-1-yl) pyridin-4-yl] phenoxy ⁇ ethyl-L-alanyl-L-alaninate
  • the invention further relates to the method mentioned above under (K), characterized in that the powder mixture or parts thereof are first dry granulated and then pressed into tablets.
  • the invention further relates to the method mentioned above under (K) or (L), characterized in that it is carried out in the absence of moisture.
  • lactose monohydrate due to the water content of this adjuvant for the Formulation of a moisture-sensitive agent is less suitable, as well as the use of lactose types such as Flowlac ® 90, which contains a proportion of amorphous lactose (see Example 14).
  • lactose types such as Flowlac ® 90, which contains a proportion of amorphous lactose (see Example 14).
  • Flowlac ® 90 which contains a proportion of amorphous lactose (see Example 14).
  • the free mobility of the molecules is not limited by binding into a solid crystal lattice, which generally reduces the stability of co-processed active ingredients.
  • Comparative Examples 37 to 39 show the poor stability of neladenosone bialanate hydrochloride (II) tablets with xylitol or pregelatinized cornstarch as a bulking agent. Even with the application of Cho et al. [Int. J. Pharm. 400, 145-152 (2010)] and Mika et al.
  • the stability of tablets with Neladenoson bialanat hydrochloride (II) in comparative stability tests at the same moisture content of the tablets, the same packaging and the same storage temperature of 40 ° C was also tested.
  • the stability of the tablets depends on the one hand on the lactose content of the tablets, even if the disintegrating agent has already been selected according to the findings of the invention.
  • the breakdown product increases by 0.13 percentage points in the case of a lactose content of the tablet excipients of about 85% in the measurement period (see Example 15).
  • the rate of degradation is 2.7 times higher with an increase of 0.35 percentage points over the same period (see Comparative Example 19).
  • the stability of the tablets depends on the disintegrant, even if the filler has already been selected according to the findings of the invention.
  • the examples and comparative examples 20, 21, 12 and 22 show a significantly reduced rate of formation of the degradation product under otherwise identical conditions when the disintegrant crospovidone according to the invention is used.
  • it is not enough to formulate tablets that are stable because of a low rate of formation of neladenosone (III).
  • III neladenosone
  • the rate of onset may be disadvantageously slow in slowly releasing tablets.
  • the tablets according to the invention have the advantage of very rapid and complete release. This is in the examples 1 1, 12, 13, 14, 22 and 24-31 each at 97% to 100%, in Example 23 at 93.0%. In contrast, conventional tablets have partially lower (Comparative Examples 1, 2, 21) or significantly lower release rates (Comparative Examples 5, 8 and 10). This advantage is surprising, since the tablets each contained active ingredient of the same particle size and would not be predictable or explainable due to the disintegration times of tablets according to the invention and conventional tablets. Thus, the tablets of Comparative Example 10 show a very rapid disintegration within 0.17 minutes and yet an unsatisfactory slow release of the active ingredient of only 55.1% in 15 minutes.
  • the disintegration time is 0.58 minutes and the release rate is 99.8% in 15 minutes.
  • a particularly slow release rate has the tablet composition proposed in WO 2010/086101 (ibid., Page 187). As shown in Comparative Example 43, these tablets release only 7.1% of the active ingredient within 15 minutes.
  • the release of the active ingredient from the tablets is determined by the method of US Pharmacopoeia USP 39 (Chapter ⁇ 71 1> Dissolution) using the apparatus 2 (Paddle Test).
  • a tablet is introduced into each beaker of the USP apparatus 2 and the amount of neladenoson bialanate (I) which has gone into solution is determined after filtering off the undissolved constituents by means of HPLC.
  • the release medium used is acetate buffer pH 4.5 with addition of 0.1% Brij 35 and the blade stirrer of USP Apparatus 2 has a rotational speed of 50 revolutions per minute. Unless otherwise stated, the rate of release of six specimens is determined. In each case, the mean value of the amount of active ingredient released after 15 minutes is given.
  • the disintegration time of the tablets is determined by the method of the European Pharmacopoeia 9.0 (Chapter 2.9.1 Disintegration of Tablets and Capsules) with disk to 6 tablets and the median of the disintegration times of the individual tablets is given.
  • the breaking strength of the tablets is determined by the method of European Pharmacopoeia 9.0 (Chapter 2.9.8 Resistance to crushing of tablets) and the mean of the individual determinations is stated.
  • the flexural strength of oval tablets is determined with a commercial tablet break strength tester containing two inserts with a total of three break mandrels. The measurement principle is described in [Bauer KH, Frömming KH and Guide C, Textbook of Pharmaceutical Technology, Stuttgart 1999 on page 352, Figure 14.54c].
  • the tablet to be tested is placed on the bridge side, so that the top and bottom of the tablet points to the test jaws.
  • the fracture mandrels of the test jaws are adjusted so that they roughly triple the top of the tablet. It determines the force necessary to break the tablet when the test jaws move together and gives the mean of the individual determinations.
  • neladenosone (III) is determined by high pressure liquid chromatography.
  • the tablets are prepared as follows: 5 tablets are used e.g. with 25 ml of 10 mmolar aqueous phosphoric acid. After disintegration of the tablets, 60-70 ml of acetonitrile are added and sonicated for 10 minutes. The suspension is shaken overnight, treated with ultrasound for a further 10 min, brought to room temperature and made up to 100 ml. After shaking, an aliquot is centrifuged and, depending on the tablet thickness, diluted with a mixture of 1 part by volume phosphoric acid (10 mmol / L) and 3 parts by volume acetonitrile and finally chromatographed.
  • neladenosone bilanate (I)
  • possible synthesis secondary components and the degradation products, in particular of neladenosone (III) a highly selective analytical method was developed.
  • the stationary phase used is a commercially available Triart C18 HPLC column (1, 9 ⁇ particles, column dimensions 50 mm 2.0 mm).
  • the mobile phase used is a solvent mixture which
  • B consists of acetonitrile with 5% (v / v) methanol (B).
  • the solvent mixture of A and B is changed with a gradient during the chromatographic run according to the following time scheme.
  • the column temperature is 20 ° C and the chromatographic run time 40 minutes.
  • the degradation product neladenosone (III) appears at a relative retention time of approximately 1.48. Since the separation capacity of HPLC columns can vary, there are small deviations possible.
  • the content of neladenosone (III) is related in area percent to the sum of the peak areas of neladenoson bialanate (I) and the by-products and degradation products present.
  • the increase in the content of the degradation product neladenosone (III) is expressed as the difference between the percentage content at the start of storage and at the end of storage in percentage points. For example, when the level of neladenosone (III) is increased from, for example, 0.1% to 0.3%, the increase is 0.2 percentage points.
  • each Tri-Sorb ® Clariant contained 3 g desiccant of molecular sieve.
  • the molecular sieve used here is a synthetic zeolite having a pore size of 3 ⁇ .
  • Each 20 of these tablets were packaged in a HDPE bottle with desiccant of molecular sieve and subjected to 40 ° C and 75% humidity a durability test.
  • the content of the decomposition product neladenosone (III) increased from initially 0.5% to 3.4%, ie by 2.90 percentage points and thus by 580%. After 6 months, the content of this decomposition product was 9.8% and thus increased by 1860%. The active ingredient was thus unstable in the tablet formulation.
  • the release rate of the tablets was 86.0% in 15 minutes.
  • the tablets thus contained only 2.7% of type B crospovidones in the excipient portion.
  • the release rate of the tablets was 74.8% in 15 minutes.
  • neladenosone (III) After storage for 2 months, the content of the decomposition product neladenosone (III) increased from 0.963% to 18.8%, or 17.84 percentage points. This corresponds to an increase of the initial level of neladenosone (III) by 1852%. The active ingredient was thus unstable in the tablet formulation.
  • neladenosone (III) After storage for 2 months, the content of the decomposition product neladenosone (III) increased from 1.77% to 12.26% and thus by 10.49 percentage points. This corresponds to an increase of the initial content of neladenosone (III) by 593%.
  • the active ingredient was thus unstable in the tablet formulation.
  • the release rate of the tablets was 63.6% in 15 minutes (mean of three tablets studied). Composition of the tablets
  • Comparative Examples 6-10 show that even using the optimal disintegrants found in this invention, crospovidone tablet formulations using conventional bulking agents are either unstable or too slow to release.
  • unpainted tablets were prepared containing per tablet 10.51 mg of micronized Neladenoson bialanate hydrochloride (II), 150.23 mg of bulking agent, 18.00 mg of crospovidone and 1.26 mg of magnesium stearate.
  • the ingredients corresponding to a batch size of 150 g were first mixed without magnesium stearate and sieved, mixed with magnesium stearate and pressed into round tablets of 180 mg mass and a diameter of 8 mm and a breaking strength of about 80 N.
  • Each 10 tablets were packaged in a HDPE bottle with desiccant from molecular sieve and stored for 3 months at 40 ° C and 75% relative humidity.
  • Active ingredient (II) in mg per tablet 10.51 10.51 10.51 10.51 10.51 10.51 10.51
  • Crospovidone Polyplasdone ®
  • the paint components were sprayed as a 15% dispersion in water in a paint spray on the tablet cores.
  • 10 film-coated tablets each were packed in a HDPE bottle with molecular sieve desiccant and stored for 3 months at 40 ° C. and 75% relative humidity.
  • the stability of the active ingredient (II) in the tablet core can be increased so far by the excipient combination according to the invention that a short-term exposure of the cores to an aqueous coating suspension is possible.
  • Examples 15-18 further show that the best results of the stability test are found in the preferred use of only lactose as the filler. Small amounts of other fillers are still tolerable, but already worsen the stability of the tablets.
  • the tablets were coated with 5 mg of lacquer solids per tablet, which consisted of 2.528 mg hypromellose 5 cP, 0.506 mg talc, 1.958 mg titanium dioxide and 0.008 mg red iron oxide.
  • the paint components were sprayed as a 15% dispersion in water in a paint spray on the tablet cores.
  • 10 film-coated tablets each were packed in a HDPE bottle with molecular sieve desiccant and stored for 3 months at 40 ° C. and 75% relative humidity.
  • Crospovidone (Polyplasdone ® XL)
  • Uncoated tablets were prepared, which bialanat Noson per tablet 10.51 mg of micronized Nelade- hydrochloride (II), 150.23 mg of anhydrous .beta.-l - Lactose (Supertab ® 24an), 18.00 mg disintegrating agent and 1, 26 mg of magnesium stearate contained.
  • the ingredients corresponding to a batch size of 150 g were first mixed without magnesium stearate and sieved, mixed with magnesium stearate and pressed into round tablets of 180 mg mass and a diameter of 8 mm and a breaking strength of about 80 N.
  • Each 10 tablets were packaged in a HDPE bottle with desiccant from molecular sieve and stored for 3 months at 40 ° C and 75% relative humidity.
  • Example 12 With the use of crospovidone (Polyplasdone ® XL), the tablets described in Example 12 were obtained. The water content of the tablets determined by the Karl Fischer method was 0.73%. The proportion of the degradation product neladenosone (III) only increased by 0.13 percentage points in the test period. The disintegration time of the tablets was 0.58 minutes and the release rate was 99.8% in 15 minutes.
  • crospovidone Polyplasdone ® XL
  • Carboxymethyl starch sodium (Primojel ®) 10.62
  • Croscarmellose sodium (Ac-Di- Sol® )
  • Crospovidone (Polyplasdone ® XL)
  • Crospovidone (Kollidon CL ®)
  • a partial batch of 656.8 g of the tablets was coated with a coating of 3 mg of dry lacquer substance per tablet, which consisted of 1.518 g of hypromellose 5 cP, 0.3036 mg of talc, 1.1748 mg of titanium dioxide and 0.0048 mg of red iron oxide ,
  • the paint components were sprayed as a 15% dispersion in water in a paint spray on the tablet cores.
  • 10 film-coated tablets each were packed in a HDPE bottle with molecular sieve desiccant and stored for 3 months at 40 ° C. and 75% relative humidity.
  • the proportion of the degradation product neladenosone (III) only increased by 0.31 percentage points.
  • the drug release from the tablets was 93.0% in 15 minutes.
  • a partial batch of 3640 g of the tablets was coated with 5 mg of lacquer dry matter per tablet, which consisted of 2.528 mg hypromellose 5 cP, 0.506 mg talc, 1.958 mg titanium dioxide and 0.008 mg red iron oxide.
  • the paint components were sprayed as a 15% dispersion in water in a paint spray on the tablet cores.
  • Each 10 film-coated tablets were packed in a HDPE bottle with molecular sieve desiccant and stored for 3 months at 40 ° C and 75% relative humidity.
  • the proportion of the degradation product neladenosone (III) only increased by 0.22 percentage points.
  • the drug release from the tablets was 100% in 15 minutes.
  • the tablets were coated with 5 mg of lacquer solids per tablet, which consisted of 2.528 mg hypromellose 5 cP, 0.506 mg talc, 1.958 mg titanium dioxide and 0.008 mg red iron oxide.
  • the paint components were sprayed as a 15% dispersion in water in a paint spray on the tablet cores.
  • Each 10 film tablets were packed in a HDPE bottle with desiccant from molecular sieve and stored for 3 months at 40 ° C and 75% relative humidity.
  • the proportion of the degradation product neladenosone (III) only increased by 0.23 percentage points.
  • the drug release from the tablets was 100% in 15 minutes.
  • the tablets were coated with 5 mg of lacquer solids per tablet, which consisted of 2.528 mg hypromellose 5 cP, 0.506 mg talc, 1.958 mg titanium dioxide and 0.008 mg red iron oxide.
  • the paint components were sprayed as a 15% dispersion in water in a paint spray on the tablet cores.
  • the film-coated tablets were packed in aluminum / aluminum blisters and stored for 3 months at 40 ° C. and 75% relative humidity. In the course of this stability test, the proportion of the degradation product neladenosone (III) increases by 0.74 percentage points.
  • a partial feed of 1500 g of the tablets was coated with 5 mg of lacquer solids per tablet, which consisted of 2.528 mg of hypromellose 5 cP, 0.506 mg of talc, 1.958 mg of titanium dioxide and 0.008 mg of red iron oxide.
  • the paint components were sprayed as a 15% dispersion in water in a paint spray on the tablet cores.
  • 10 film-coated tablets each were packed in a HDPE bottle with molecular sieve desiccant and stored for 3 months at 40 ° C. and 75% relative humidity.
  • the proportion of the degradation product neladenosone (III) only increases by 0.19 percentage points. Over a storage period of 9 months at 25 ° C and 60% relative humidity, the proportion of the degradation product neladenosone (III) increased from 0.36% to 0.45%, corresponding to 0.09 percentage points.
  • the drug release from the tablets was 100% in 15 minutes.
  • the proportion of degradation product neladenosone (III) increased by 0.80 percentage points.
  • the drug release from the tablets was 100% in 15 minutes.
  • a partial batch of 875.8 g of the tablet cores was coated with a coating of 5 mg of dry lacquer substance per tablet, which consisted of 2.2 mg of hydroxypropylcellulose, 1.22 mg of titanium dioxide, 0.72 mg of hypromellose 3cP, 0.42 mg of propylene glycol, 0, There was 04 mg of red iron oxide and 0.40 mg of yellow iron oxide.
  • the paint components were sprayed as a dispersion of 8% paint dry substance, 82.8% isopropanol and 9.2% water in a paint spray on the tablet cores.
  • 10 film-coated tablets each were packed in a HDPE bottle with molecular sieve desiccant and stored for 3 months at 40 ° C. and 75% relative humidity.
  • the proportion of the degradation product neladenosone (III) only increased by 0.13 percentage points. Drug release from the tablets was 97.0% in 15 minutes.
  • Film-coated tablets were prepared containing per tablet 10.51 mg micronised Neladenoson bialanat hydrochloride (II), 150.23 mg anhydrous ß- / a-lactose (Supertab ® 24AN), 18.00 mg crospovidone and 1, 26 mg magnesium stearate.
  • the ingredients corresponding to a batch size of 2550 g were first mixed and sieved without magnesium stearate and granulated dry on a roll granulator at a specific pressing force of 6 kN / cm and a mesh width of 1 mm.
  • the granules were mixed with 1, 26 mg magnesium stearate and pressed into round tablets of 180 mg mass, a diameter of 8 mm and a breaking strength of about 82 N. Drug release from the tablets was 98.0% in 15 minutes (mean of five tablets).
  • Film-coated tablets were produced containing per tablet 2.63 mg micronised Neladenoson bialanat hydrochloride (II), 73.275 mg anhydrous ß- / a-lactose (Supertab ® 24AN), 8.50 mg crospovidone and 0.595 mg magnesium stearate.
  • the ingredients corresponding to a batch size of 2125 g were first mixed without magnesium stearate and sieved, mixed with magnesium stearate and pressed into round tablets of 85 mg mass and a diameter of 6 mm and a breaking strength of about 42 N.
  • a partial charge of 656.8 g of the tablet cores was coated with 3 mg of lacquer solids per tablet consisting of 1.32 mg of hydroxypropylcellulose, 0.732 mg of titanium dioxide, 0.432 mg of hypromellose 3cP, 0.252 mg of propylene glycol, 0.024 mg of red iron oxide and 0.24 mg of yellow iron oxide.
  • the paint components were sprayed as a dispersion of 8% Lacktrockensub- dance, 82.8% isopropanol and 9.2% water in a Lackier réelle on the tablet cores.
  • 10 film-coated tablets each were packed in a HDPE bottle with molecular sieve desiccant and stored for 3 months at 40 ° C. and 75% relative humidity. in the As a result of this stability test, the proportion of the degradation product neladenosone (III) only increased by 0.16 percentage points. The drug release from the tablets was 97% in 15 minutes.
  • a partial batch of 1350 g of unpainted tablets was coated with 7 mg of lacquer solids per tablet consisting of 3.5 mg hypromellose 5 cP, 0.7 mg talc, 2.1 mg titanium dioxide and 0.7 mg red iron oxide.
  • the paint components were sprayed as a 15% dispersion in water in a paint spray on the tablet cores. Drug release from the tablets was 98% in 15 minutes.
  • a partial batch of 3960 g of unpainted tablets was coated with 8.5 mg of dry paint per tablet, which consisted of 4.25 mg of 5 mg hypromellose, 0.85 mg of talc, 2.55 mg of titanium dioxide and 0.85 mg of red iron oxide.
  • the paint components were sprayed as a 15% dispersion in water in a paint spray on the tablet cores.
  • the drug release from the tablets was 100% in 15 minutes.
  • Tablets were prepared, which per tablet 10.51 mg of micronized Neladenoson bialanat hydrochloride (II), 150.23 mg xylose (Xylitab ®), crospovidone 18 mg of type A (poly- Plasdone ® XL) and 1, containing 26 mg of magnesium stearate.
  • the tablets are thus not in accordance with the present invention.
  • the ingredients corresponding to a batch size of 300 g were first mixed without magnesium stearate and sieved, mixed with magnesium stearate and pressed on an eccentric press into round tablets of 180 mg mass and a diameter of 8 mm and an average breaking strength of about 104 N.
  • Tablets were prepared, which per tablet 10.51 mg of micronized Neladenoson bialanat hydrochloride (II), 48.54 mg xylose (Xylitab ®), 101, 69 mg of anhydrous .beta. / a-lactose (Supertab ® 24an), 18 mg Crospovidone of type A (Polyplasdone ® XL) and 1, 26 mg of magnesium stearate contained. The tablets are thus not in accordance with the present invention.
  • the ingredients corresponding to a batch size of 300 g were first mixed without magnesium stearate and sieved, mixed with magnesium stearate and pressed on an eccentric press into round tablets of 180 mg mass and a diameter of 8 mm and an average breaking strength of about 73 N.
  • Each 10 tablets were packed in a HDPE bottle with desiccant from molecular sieve and stored for 3 months at 40 ° C and 75% relative humidity.
  • the proportion of the degradation product neladenosone (III) increased significantly by 0.56 percentage points.
  • drug release from the tablets was slow at 83.8% after 15 minutes.
  • Tablets were prepared, which per tablet 10.51 mg of micronized Neladenoson bialanat hydrochloride (II), 150.23 mg pregelatinized starch (Lycatab ® CLM), 18 mg Crospovidone of type A (Polyplasdone ® XL) and 1, 26 mg of magnesium stearate contained ,
  • the tablets are thus not in accordance with the present invention.
  • the ingredients corresponding to a batch size of 300 g were first mixed without magnesium stearate and sieved, mixed with magnesium stearate and pressed on an eccentric press into round tablets of 180 mg mass and a diameter of 8 mm and an average breaking strength of about 29 N.
  • Tablets were prepared, which per tablet 10.51 mg of micronized Neladenoson bialanat hydrochloride (II), 150.23 mg of calcium sulfate dihydrate (Compactrol ®), crospovidone 18 mg of type A (Polyplasdone ® XL) and 1, 26 mg of magnesium stearate contained ,
  • the tablets are thus not in accordance with the present invention.
  • the ingredients corresponding to a batch size of 300 g were first mixed without magnesium stearate and sieved, mixed with magnesium stearate and pressed on an eccentric press into round tablets of 180 mg mass and a diameter of 8 mm and an average breaking strength of about 77 N.
  • neladenoson bialanate hydrochloride (II) tablets were prepared, which per tablet 10.51 mg micro Nes nadesoson bialanat hydrochloride (II), 52.55 mg xylitol, 97.14 mg co-processed mixture of 75% ⁇ -lactose monohydrate and 25% microcrystalline cellulose (MicroceLac ®), crospovidone 18 mg of type A (Polyplasdone ® XL) and 1, 8 mg of magnesium stearate contained.
  • the tablets are not in accordance with the present invention as they had only a low level of 43% lactose (w / w, based on the mass of all the excipients of the tablet).
  • the ingredients corresponding to a batch size of 300 g were first mixed without magnesium stearate and sieved, mixed with magnesium stearate and pressed on an eccentric press into round tablets of 180 mg mass and a diameter of 8 mm and an average breaking strength of about 73 N.
  • Each 10 tablets were packaged in a HDPE bottle with desiccant from molecular sieve and stored for 3 months at 40 ° C and 75% relative humidity.
  • the proportion of the degradation product neladenosone (III) increased significantly by 0.56 percentage points.
  • drug release from the tablets was slow at only 82.9% after 15 minutes.
  • tablets were prepared containing bialanat per tablet 21, 02 mg of micronized Neladenoson hydrochloride (II), 4.18 mg hydroxypropyl cellulose (L-HPC), 4.18 mg of silicon dioxide (Aerosil ®), 8.36 mg of croscarmellose sodium ( Ac-Di-Sol ®) 67.63 mg D-mannitol (Pearlitol SD 100 ®), 10.45 mg citric acid and 4.18 mg of magnesium stearate contained.
  • the tablets are thus not in accordance with the present invention.
  • the ingredients corresponding to a batch size of 300 g were first mixed without magnesium stearate and sieved, mixed with magnesium stearate and pressed on an eccentric press into round tablets of 120 mg mass and a diameter of 7 mm and an average breaking strength of about 80 N.
  • Each 10 tablets were packaged in a HDPE bottle with desiccant from molecular sieve and stored for 3 months at 40 ° C and 75% relative humidity.
  • the proportion of the degradation product neladenosone (III) increased significantly by 0.44 percentage points.
  • drug release from the tablets was slow at only 86.7% after 15 minutes. Comparative Example 43
  • Tablets were produced as proposed in WO 2010/086101 A1 (page 187). Specifically, tablets were prepared containing per 100 mg of Micronized Neladenoson Bialanate Hydrochloride (II), 50 mg of Lactose Monohydrate, 50 mg of Corn Starch (native), 10 mg of Polyvinylpyrrolidone (PVP 25) and 2 mg of Magnesium Stearate. Thus, the tablets are not in accordance with the present invention as they had only a low level of 44.6% lactose (w / w, based on the mass of all the excipients of the tablet).
  • II Micronized Neladenoson Bialanate Hydrochloride
  • Lactose Monohydrate 50 mg of Corn Starch (native)
  • PVP 25 Polyvinylpyrrolidone
  • Magnesium Stearate Magnesium Stearate
  • the ingredients corresponding to a batch size of 1000 g were first mixed without magnesium stearate and sieved, mixed with magnesium stearate and pressed on a rotary press into round tablets of 180 mg mass and a diameter of 8 mm and an average breaking strength of about 73 N.
  • a partial charge of 750 g of the tablets was applied to a paint application of 5 mg of lacquer substance per tablet, which consisted of 2.528 mg of 5 mmoles of Hypromellose, 0.506 mg of talc, 1.958 mg of titanium dioxide and 0.008 mg of red iron oxide.
  • the paint components were sprayed as a 15% dispersion in water in a paint spray on the tablet cores.

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Abstract

La présente invention concerne une formulation de comprimés pharmaceutiques stables contenant 2-{4-[2-({[2-(4-chlorophényl)-1,3-thiazol-4-yl]methyl}sulfanyl)-3,5-dicyano-6-(pyrrolidin-1-yl)pyridin-4- yl]phénoxy}éthyl-L-alanyl-L-alaninate (neladenoson bialanate) sous la forme d'un de ses sels, caractérisée en ce qu'elle libère rapidement le principe actif, ainsi que son procédé de fabrication, son utilisation comme médicament, et son utilisation en termes de prophylaxie et/ou de traitement de maladies cardiovasculaires comme, par exemple, une insuffisance cardiaque chronique (worsening chronic heart failure), une insuffisance cardiaque avec fraction d'éjection ventriculaire gauche réduite ou préservée (heart failure with reduced or with preserved ejection fraction, HFrEF ou HFpEF), une angine de poitrine et une lésion ischémique lors d'un syndrome coronaire aigü.
PCT/EP2017/082379 2016-12-16 2017-12-12 Formulation de comprimés pharmaceutiques Ceased WO2018108884A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100130606A1 (en) 2006-06-09 2010-05-27 Schwarz Pharma Ag Pharmaceutical compositions comprising fesoterodine
WO2010086101A1 (fr) 2009-01-29 2010-08-05 Bayer Schering Pharma Aktiengesellschaft Dicyanopyridine à substitution alkylamino et ses promédicaments d'ester d'acide aminé
WO2016188711A1 (fr) 2015-05-06 2016-12-01 Bayer Pharma Aktiengesellschaft Procédé de préparation de monohydrochlorure de 2-{4-[2-({[2-(4-chlorophényl)-1,3-thiazol-4-yl]méthyl}sulfanyl)-3,5-dicyan-6-(pyrrolidin-1-yl)pyridin-4-yl]phénoxy}éthyl-l-alanyl-l-alaninate

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100130606A1 (en) 2006-06-09 2010-05-27 Schwarz Pharma Ag Pharmaceutical compositions comprising fesoterodine
WO2010086101A1 (fr) 2009-01-29 2010-08-05 Bayer Schering Pharma Aktiengesellschaft Dicyanopyridine à substitution alkylamino et ses promédicaments d'ester d'acide aminé
WO2016188711A1 (fr) 2015-05-06 2016-12-01 Bayer Pharma Aktiengesellschaft Procédé de préparation de monohydrochlorure de 2-{4-[2-({[2-(4-chlorophényl)-1,3-thiazol-4-yl]méthyl}sulfanyl)-3,5-dicyan-6-(pyrrolidin-1-yl)pyridin-4-yl]phénoxy}éthyl-l-alanyl-l-alaninate

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BAUER KH; FRÖMMING KH; FÜHRER C: "Lehrbuch der Pharmazeutischen Technologie", 1999, pages: 352
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SHERIF I.F. BADAWY ET AL: "Quality by design development of brivanib alaninate tablets: Degradant and moisture control strategy", INTERNATIONAL JOURNAL OF PHARMACEUTICS, vol. 469, no. 1, 26 April 2014 (2014-04-26), AMSTERDAM, NL, pages 111 - 120, XP055373457, ISSN: 0378-5173, DOI: 10.1016/j.ijpharm.2014.04.059 *

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