WO2012118461A1 - Composé cristallin comprenant du bromure de tiotropium - Google Patents

Composé cristallin comprenant du bromure de tiotropium Download PDF

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Publication number
WO2012118461A1
WO2012118461A1 PCT/TR2012/000049 TR2012000049W WO2012118461A1 WO 2012118461 A1 WO2012118461 A1 WO 2012118461A1 TR 2012000049 W TR2012000049 W TR 2012000049W WO 2012118461 A1 WO2012118461 A1 WO 2012118461A1
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Prior art keywords
crystalline compound
tiotropium bromide
composition
formula
particle size
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Mahmut Bilgic
Fritz Blatter
Eva RÖDEL
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Priority to EP12716717.9A priority Critical patent/EP2681212A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
    • C07D451/06—Oxygen atoms
    • C07D451/10—Oxygen atoms acylated by aliphatic or araliphatic carboxylic acids, e.g. atropine, scopolamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics

Definitions

  • the present invention refers to a crystalline compound comprising Tiotropium bromide and water and to a process for manufacturing the same.
  • Tiotropium bromide disclosed in EP 0 418 716 Al has the following chemical structure:
  • Tiotropium bromide is a highly effective anticholinegic with a long lasting effect. It can be used for treating respiratory complaints and particularly COPD (chronic obstructive pulmonary disease) and asthma.
  • Tiotropium bromide is preferably administered by the inhalation route.
  • use of inhalable powders containing active substance is of particular importance.
  • Tiotropium bromide is preferably administered by the inhalation route.
  • Suitable inhalable powders packed into appropriate capsules (inhalettes) blisters may be used.
  • it may be administered by the use of suitable inhalable aerosols.
  • suitable inhalable aerosols include powdered inhalable aerosols which contain, for example, HFA134a, HFA227 or mixtures thereof as propellant gas.
  • the pharmaceutically active substance suffices per single dose to achieve the desired therapeutic effect.
  • the pharmaceutically active substance has to be diluted in a suitable excipient in order to prepare an inhalable powder.
  • the amount of inhalable composition must be accurately metered in every single dose.
  • the properties of the inhalable powder are significantly influenced by the choice of the excipient.
  • the particle size of the pharmaceutically active substance and of the excipient is very important for the emptying characteristics of capsules or blisters when used in an inhaler.
  • the active substance particles that shall be administered by the inhalation route should optimally meet essential requirements such as appropriate aerodynamic particle size, appropriate particle shape, uniformity of particle size distribution, low aerodynamic dispersion forces, low density, high physical and chemical stability.
  • compositions which are suitable for use for the administration of a pharmaceutically active substance by the inhalation route is based on various parameters which are connected with the nature of the active substance itself.
  • pharmaceutical compositions which are used like tiotropium bromide in the form of inhalable powders or inhalable aerosols the crystalline active substance is used in ground (micronised) form for preparing the formulation. Since the pharmaceutical quality of a pharmaceutical formulation requires that the pharmaceutically active substance should always have the same crystalline modification, the stability and properties of the crystalline active substance are subject to stringent requirements from this point of view as well.
  • WO 03/000265 Al teaches the manufacture of anhydrous Tiotropium bromide as well as Tiotropium bromide monohydrate.
  • the molar ratio of Tiotropium bromide to water is at least 1 : 22. Since the crystallization is performed in pure water, the water activity a w is approximately 1.
  • Tiotropium bromide monohydrate can be converted to anhydrous Tiotropium bromide when it is heated to more than 50 °C, preferably in high-vacuum.
  • anhydrous Tiotropium bromide must be stored at a relative humidity of less than 75%. In the case that anhydrous Tiotropium bromide is micronized, it might be necessary storing it at an even lower relative humidity than 75%.
  • Tiotropium bromide monohydrate is obtained and subsequently the water comprised in said compound is removed to convert it to the pharmaceutically active substance anhydrous Tiotropium bromide.
  • Anhydrous Tiotropium bromide must be stored at a relative humidity of less than 75 % or at even lower relative humidity when micronized; otherwise it will be detrimentally affected.
  • Tiotropium bromide in form of salt having good chemical and/or physical stability and/or good processability both during its preparation as a pharmaceutically active substance as well as in the preparation of
  • compositions containing Tiotropium bromide It is a further objective to provide crystalline salts of Tiotropium bromide that are accessible in a reproducible manner and constant quality in inexpensive and well controlled production processes.
  • Tiotropium bromide has therapeutic efficacy as a pharmaceutically active substance even at very low doses indicates the need in the technical field to find a further effective substance for administration in inhalable composition form.
  • a further technical problem that the present invention relates to is to prepare useful dosage forms of Tiotropium bromide in inhalable composition form.
  • crystalline compound comprising Tiotropium bromide (formula I) and water
  • crystalline compound comprising Tiotropium bromide (formula I) and water
  • the crystalline compound I of the present invention can be admixed with suitable excipients in order to obtain an inhalable composition.
  • the crystalline compound can be ground in order to adjust the particle size very accurately.
  • an inhalable composition comprising the crystalline compound of the present invention can be stored without losing effectiveness.
  • the crystalline compound I has an XRPD pattern with at least one characteristic peak (expressed in 2 ⁇ ⁇ ⁇ , 2 ⁇ (CuKa radiation)) at 14.9°, 17.0°, 21.7°, 23.8° and 29.9°.
  • a further crystalline compound II is very useful, namely a crystalline compound comprising Tiotropium bromide (formula I) and CH 2 C1 2 , or a hydrate thereof characterized in that it has an FT-Raman spectrum comprising peaks at wavenumbers (expressed in ⁇ 2 cm “1 ) of 3109, 3074, 3057, 3023, 2979, 2970, 2955, 2935, 1747, 1479, 1433, 1348, 1324, 1244, 1161, 1071, 1039, 1000, 962, 886, 859, 797, 753, 665, 651, 626, 538, 432, 289, 253, 209 and 173 cm "1 or a hydrate thereof.
  • the crystalline compound II has an XRPD pattern with at least one characteristic peak (expressed in 2 ⁇ ⁇ 0,1° 2 ⁇ (CuKa radiation)) at 18.0°, 19.9°, 21.0°, 21.5°, 23.8°, 25.0°, 26.0°, 26.9°, 27.1°, 30.0°, 30.2°, 30.3°, 30.6°, 31.0° and 31.8°
  • the molar ratio of the compound of formula I and CH 2 C1 2 is in the range of from 1 : 0,3 to 1 : 0,7, more preferably of from 1 :0,4 to 1 :0,6 and most preferably 1:0,5.
  • crystalline compound comprising Tiotropium bromide (formula I) and CH 2 C1 2 or a hydrate thereof signifies that these two substances are in the same crystalline matrix or different crystalline/amorphous matrices.
  • the crystalline compound II of the present invention can be admixed with suitable excipients in order to obtain an inhalable composition.
  • the crystalline compound can be ground in order to adjust the particle size very accurately.
  • an inhalable composition comprising the crystalline compound of the present invention can be stored without losing effectiveness.
  • Compound II is also very useful as intermediate for obtaining the crystalline compound I.
  • Compound II can be obtained by a process comprising the steps of: a) providing Tiotropium bromide (formula I)
  • step b) adding CH 2 C1 2 to the composition of step a) c) optionally concentrating the composition of step b)
  • step d) optionally equilibrating the obtained suspension of step d)
  • step d) and/or e) seed crystals are added.
  • crystalline compound II can be used as starting material for obtaining the crystalline compound I of the present invention.
  • a further aspect of the present invention is a process for obtaining the crystalline compound I comprising the steps of: a) providing Tiotropium bromide (formula I) in a suitable solvent or mixture of solvents or providing the crystalline compound II in a suitable solvent or mixture of solvents, wherein the water activity of the composition is adjusted to have a value of from 0,1 to 0,6
  • step b) optionally concentrating the composition of step a)
  • step c) optionally equilibrating the obtained suspension of step c)
  • a carboxyclic acid like L-lactic acid may be added to the composition.
  • Water activity is a function of the composition but is also a function of the temperature. For typical ambient conditions (room temperature) it essentially corresponds to the relative humidity in % divided by 100.
  • the tiotropium bromide monohydrate requires a high water activity of 1
  • the tiotropium bromide anhydrate requires a water activity of zero (waterfree environment).
  • the crystalline compound I of the present invention is obtained wherein the water activity of the composition of step a) is adjusted to have a value of from 0,1 to 0,6.
  • step a) and/or step f) the crystalline compound I of the present invention is prepared at water activities of from 0,2 to 0,5 and more preferably from 0,3 to 0,5.
  • the water activity in a suspension of Tiotropium bromide in an organic solvent is adjusted by addition of the correct amount of water to the system.
  • the amount of water to be added depends on the solvent used for the suspension experiment. The necessary data can be obtained from the literature, for instance, D.R. Lide, CRC Handbook of Thermophysical and Thermochemical Data (1994).
  • a possible way to adjust the water activity for drying the crystalline compound I is the proportional mixing of two equal flows of air, nitrogen or any other inert-gas in a defined ratio.
  • One gas-flow is dry gas, thus having a water activity of 0; and the other gas flow is previously saturated with water, thus exhibiting a water activity of 1.0.
  • the preferred solvents are organic solvents that preferably do not form solvates or preferably form only very metastable solvated forms. These are acetone or other ketones such as methyl ethyl ketone or 2-pentanone; other acetates such as ethyl acetate, or isopropyl acetate and butyl acetate; TBME, acetonitrile, DMSO or mixtures thereof.
  • the compound of formula I (tiotropium bromide) or crystalline compound II in an organic solvent or solvent mixture and adjust the water activity by addition of required amount of water.
  • Suitable solvents are, for instance, ethyl acetate, acetone, or other ketones such as methyl ethyl ketone, or 2-pentanone or other acetates such as isopropyl acetate and butyl acetate, TBME, acetonitrile, DMSO or mixtures thereof.
  • the compound of formula I (tiotropium bromide) or the crystalline compound II can be dissolved in an organic solvent or solvent mixture in which the water activity is adjusted by addition of the required amount of water.
  • Suitable solvents are, for instance, ethyl acetate, acetone, or other ketones such as methyl ethyl ketone, or 2-pentanone or other acetates such as isopropyl acetate and butyl acetate, TBME, acetonitrile, DMSO or mixtures thereof.
  • the measurements were carried out with a Bruker D8 Advance powder X-ray diffractometer using Cu Ka radiation in the Bragg-Brentano reflection geometry. Generally, the 2 ⁇ values are accurate within an error of ⁇ 0.1-0.2°. The relative peak intensities can vary considerably for different samples of the same crystalline form because of different preferred orientations of the crystals.
  • the samples were prepared without any special treatment other than the application of slight pressure to get a flat surface. Silicon single crystal sample holders of either 1.0, 0.5 mm or 0.1 mm depth and 12 mm cavity diameter were used. The tube voltage and current were 40 kV and 40 niA, respectively.
  • the X-ray diffractometer is equipped with a LynxEye detector. A variable divergence slight was used with a 3 ° window. The step size was 0.02 °2 ⁇ with a step time of 37 seconds. The samples were rotated at 0.5 rps during the measurement.
  • TG-FTIR was performed on a Netzsch Thermo-Microbalance TG 209 which is coupled to a Bruker FT-IR Spectrometer Vector 22. The measurements were carried out with aluminum crucibles with a micro pinhole under a nitrogen atmosphere and at a heating rate of 10 °C/min over the range 25-250 °C.
  • Raman spectra were recorded using a Bruker RFSIOO Raman spectrometer equipped with a germanium detector and a Nd:YAG laser with an excitation wavelength of 1064 nm. A few milligrams of material were pressed into aluminum sample holders. Spectra in the range of 50- 3500 cm “1 and with a resolution of 2 cm “1 were measured with a laser power of 300 mW. 64 scans were accumulated.
  • HPLC was carried out on a TSP HPLC chromatograph (UV3000, AS3000, P4000, SCM1000 software version 4.1).
  • the column type used was a Waters XTerra MS CI 8, 100 x 4.6 mm, 5 ⁇ (CC01C).
  • Mobile phase A was H 2 0 / ACN 95:5 + 0.1 % TFA and mobile phase B was H 2 0 / ACN 5:95 + 0.1 % TFA.
  • the applied flow rate was 1.0 mL per minute, the injection volume was 10 microliter and the detection wavelength was 240 nm.
  • the gradient was at 0 min 100% mobile phase A, at 20 min 100% mobile phase B, from 20 to 30 minutes pure mobile phase A.
  • Example 1 Preparation of seed crystals of the crystalline compound I with the known orthorhombic anhydrate as starting material.
  • the mixture is sonicated for one minute and stirred for 7 days and room temperature.
  • the suspension is filtered and the obtained solid dried in air at room temperature at a water activity of 0.2 to 0.3 for a few minutes.
  • the product is investigated by FT-Raman spectroscopy, powder X-ray diffraction, TG-FTIR, and dynamic water vapour sorption.
  • a new and characteristic Raman spectrum as displayed in Figure 3 and Figure 4 is obtained for which a peak list is provided in Table 2.
  • the obtained crystalline form I exhibits a characteristic XRPD pattern as shown in Figure 1 which exhibits X-ray diffraction reflexions as listed in Table 1.
  • TG-FTIR reveals a mass loss of 2.3% which is attributable to loss of water.
  • Example 2 Preparation of the crystalline compound I in presence of L-lactic acid.
  • 106 mg of crystalline compound II prepared according to example 4 are suspended in 1.0 ml ethyl acetate.
  • the suspension is seeded with the new hydrate according to example 1, and 10 microliter of water is added to adjust the water activity a w in the composition to be 0,5.
  • This mixture is sonicated for about one minute and stirred at room temperature overnight.
  • a crystalline solid sample is recovered by filtration and after a few minutes of drying in air at room temperature in investigated by FT-Raman spectroscopy, which shows that crystalline compound I is obtained.
  • compositions comprising pharmaceutically acceptable, nontoxic and a therapeutically effective amount of the crystalline compound I or crystalline compound II of the present invention and also preparation methods thereof are the characteristic features of the present invention.
  • the pharmaceutical compositions comprising the crystalline compound I or crystalline compound II of the present invention are in dry powder form or pressurized metered dose inhalation composition form, preferably in dry powder inhalation composition form.
  • two methods are commonly implemented in order to transmit effective amount of the medicament to the target area. One of them is based on controlled agglomeration of undiluted medicament; the other one is based on adhesion of micronized medicament particles to the surface of an inert carrier having large particle size.
  • the pharmaceutical compositions of the present invention are preferably prepared by implementing the both methods, preferably by implementing the second method.
  • the pharmaceutical composition comprises at least one pharmaceutically acceptable inert carrier and optionally at least one pharmaceutically acceptable excipient different from the carrier(s) along with the active substance.
  • micronized medicament particles refers to propionic acid solvate of tiotropium bromide.
  • the solvate of tiotropium bromide of the present invention is characterized by having an average particle size in the range of 1-10 ⁇ , preferably in the range of 1-5 ⁇ .
  • the pharmaceutical compositions of the present invention are characterized by comprising propionic acid solvate of tiotropium bromide of the present invention in the range of 0.001- 50%, preferably in the range of 0.01-10%.
  • inert carrier refers to lactose, more preferably lactose monohydrate for dry powder inhalation compositions of the present invention.
  • the pharmaceutical compositions of the present invention can comprise at least one inert carrier having large particle size and at least one inert carrier having small particle size and optionally at least one excipient together.
  • the inert carrier having large particle size of the present invention is characterized by having an average particle size (d 50 ) in the range of 10-250 ⁇ , preferably in the range of 10-150 ⁇ , more preferably of 150 ⁇ ;
  • the inert carrier having small particle size of the present invention is characterized by having an average particle size (d 5 o) in the range of 1-10 ⁇ , preferably of 10 ⁇ .
  • the inert carriers having large particle size and small particle size can be the same or different substances.
  • At least one pharmaceutically acceptable excipient can be selected from carbohydrates such as lactose, glucose, fructose, galactose, sucrose, maltose, trehalose, maltodextrins, dextrans, cyclodextrins, starch and cellulose; polyalcohols such as sorbitol, mannitol and xylitol; amino acids such as glycine, arginine, lysine, aspartic acid and glutamic acid; peptides such as human serum albumin; gelatine; various salts and taste masking agents. Said at least one excipient is not limited to these substances.
  • the pharmaceutical composition preferred comprises propellant gases, surface active agents and at least one basic excipient selected from the group of co-solvents and optionally at least one other pharmaceutically acceptable excipient along with the active substance.
  • active substance refers to crystalline compound I or crystalline compound II.
  • the active substance comprised in the pharmaceutical composition is characterized by having an average particle size in the range of 1-10 ⁇ , preferably in the range of 1-5 ⁇ .
  • the pharmaceutical compositions of the present invention are characterized by comprising crystalline substance I or crystalline substance II in the range of 0.001-50%, preferably in the range of 0.01 -10%.
  • At least one pharmaceutically acceptable excipient can be selected from propellant gases (propellants) such as chlorofluorocarbons, hydrofluoroalkanes and hydrocarbons; surface active agents (surfactants) such as oleic acid, polysorbates, propylene glycol, polyethylene glycol, cetyl alcohol, stearyl alcohol, sorbitan fatty acid esters, sugar esters of fatty acids, glycerides of fatty acids, isopropyl myristate and lecithin; cosolvents such as ethanol, water and diethyl ether; antioxidants such as butylated hydroxyanisole (BHA), sodium ascorbate, butylated hydroxytoluene (BHT), sodium sulphide, gallates (such as propyl gallate), tocopherol, citric acid, malic acid, ascorbic acid, acetylcysteine, fumaric acid, lecithin, ascorbyl palmitate, ethylened
  • propellant gases
  • the pharmaceutical compositions comprising crystalline substance I or crystalline substance II of the present invention can additionally comprise at least one active substance selected from the medicaments such as other anticholinergic agents, adrenergic agonists, antiallergic agents, anti-inflammatory agents, antihistaminics, steroids, leukotriene receptor antagonists, antimuscarinic agents, PDE inhibitors and EGFR inhibitors.
  • the crystalline substance I and crystalline substance II of the present invention can be used separately, sequentially or simultaneously with at least one active substance selected from the specified group.
  • Another characteristic feature of the present invention is that the pharmaceutical compositions comprising the crystalline substance I and crystalline substance II of the present invention are used in treatment of respiratory tract diseases, particularly COPD (chronic obstructive pulmonary disease) and asthma.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Pulmonology (AREA)
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  • Life Sciences & Earth Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
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  • General Health & Medical Sciences (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Glass Compositions (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Abstract

La présente invention concerne un composé cristallin I comprenant du bromure de tiotropium (formule I) et de l'eau, et caractérisé en ce qu'il présente un spectre Raman-TF comprenant des crêtes à des nombres d'ondes (exprimés en ± 2 cm-1) de 3070, 3053, 2982, 2967, 1743, 1479, 1429, 1238, 1078, 699, 295 et 121 cm-1, et un composé cristallin II comprenant du bromure de tiotropium (formule I) et CH2C12, ou un hydrate de celui-ci, caractérisé en ce qu'il présente un spectre Raman-TF comprenant des crêtes à des nombres d'ondes (exprimés en ± 2 cm-1) de 3109, 3074, 3057, 3023, 2979, 2970, 2955, 2935, 1747, 1479, 1433, 1348, 1324, 1244, 1161, 1071, 1039, 1000, 962, 886, 859, 797, 753, 665, 651, 626, 538, 432, 289, 253, 209 et 173 cm-1. L'invention concerne également des procédés d'obtention de ces composés.
PCT/TR2012/000049 2011-03-03 2012-03-05 Composé cristallin comprenant du bromure de tiotropium Ceased WO2012118461A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP12716717.9A EP2681212A1 (fr) 2011-03-03 2012-03-05 Composé cristallin comprenant du bromure de tiotropium

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
TR2011/02068A TR201102068A2 (tr) 2011-03-03 2011-03-03 Tiotropyum bromür içeren kristal maddeler
TR2011/02068 2011-03-03

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WO2012118461A1 true WO2012118461A1 (fr) 2012-09-07

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014042605A1 (fr) * 2012-09-11 2014-03-20 Mahmut Bilgic Nouvelle forme cristalline du bromure de tiotropium
RU2567539C1 (ru) * 2015-02-04 2015-11-10 Индивидуальный предприниматель Михайлов Олег Ростиславович КРИСТАЛЛИЧЕСКАЯ γ-МОДИФИКАЦИЯ (1α,2β,4β,5α,7β-7)-[(ГИДРОКСИДИ-2-ТИЕНИЛАЦЕТИЛ)ОКСИ]-9,9-ДИМЕТИЛ-3-ОКСА-9-АЗОНИАТРИЦИКЛО[3.3.1.02,4]НОНАН БРОМИДА МОНОГИДРАТА, СПОСОБ ЕЁ ПОЛУЧЕНИЯ И ФАРМАЦЕВТИЧЕСКАЯ КОМПОЗИЦИЯ НА ЕЁ ОСНОВЕ
WO2018084817A3 (fr) * 2016-11-04 2018-06-07 Si̇ma Patent Ve Li̇sanslama Hi̇zmetleri̇ Ltd. Şti̇ Nouvelle forme d'agent actif

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014042605A1 (fr) * 2012-09-11 2014-03-20 Mahmut Bilgic Nouvelle forme cristalline du bromure de tiotropium
RU2567539C1 (ru) * 2015-02-04 2015-11-10 Индивидуальный предприниматель Михайлов Олег Ростиславович КРИСТАЛЛИЧЕСКАЯ γ-МОДИФИКАЦИЯ (1α,2β,4β,5α,7β-7)-[(ГИДРОКСИДИ-2-ТИЕНИЛАЦЕТИЛ)ОКСИ]-9,9-ДИМЕТИЛ-3-ОКСА-9-АЗОНИАТРИЦИКЛО[3.3.1.02,4]НОНАН БРОМИДА МОНОГИДРАТА, СПОСОБ ЕЁ ПОЛУЧЕНИЯ И ФАРМАЦЕВТИЧЕСКАЯ КОМПОЗИЦИЯ НА ЕЁ ОСНОВЕ
WO2018084817A3 (fr) * 2016-11-04 2018-06-07 Si̇ma Patent Ve Li̇sanslama Hi̇zmetleri̇ Ltd. Şti̇ Nouvelle forme d'agent actif
EP3430011A4 (fr) * 2016-11-04 2019-08-14 Sima Patent Ve Lisanslama Hizmetleri Ltd. STI Nouvelle forme d'agent actif

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