WO2016082808A1 - Préparation orale - Google Patents

Préparation orale Download PDF

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Publication number
WO2016082808A1
WO2016082808A1 PCT/CZ2015/050011 CZ2015050011W WO2016082808A1 WO 2016082808 A1 WO2016082808 A1 WO 2016082808A1 CZ 2015050011 W CZ2015050011 W CZ 2015050011W WO 2016082808 A1 WO2016082808 A1 WO 2016082808A1
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WO
WIPO (PCT)
Prior art keywords
polymer
units
methacrylates
polyoxyethylene
methacrylamides
Prior art date
Application number
PCT/CZ2015/050011
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English (en)
Inventor
Zdenka Sedlakova
Lenka POLAKOVA
Original Assignee
Ustav Makromolekularni Chemie Av Cr, V.V.I.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Ustav Makromolekularni Chemie Av Cr, V.V.I. filed Critical Ustav Makromolekularni Chemie Av Cr, V.V.I.
Priority to CA2963582A priority Critical patent/CA2963582C/fr
Publication of WO2016082808A1 publication Critical patent/WO2016082808A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0065—Forms with gastric retention, e.g. floating on gastric juice, adhering to gastric mucosa, expanding to prevent passage through the pylorus
    • 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
    • A61K31/74—Synthetic polymeric materials
    • A61K31/785—Polymers containing nitrogen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the present invention relates to a polymeric preparation, which adjusts the internal environment of gastrointestinal tract (GIT) by removal of harmful substances, introduced into the GIT together with food or originated from processes taking place in GIT, mainly from inflammatory processes.
  • GIT gastrointestinal tract
  • the preparation has a beneficial influence on functioning of the mucose of the gastrointestinal tract and/or on inflammatory disease cure.
  • GIT mucose Inner surfaces of GIT mucose are exposed to a very aggresive environment of gastrointestinal juices, characterized by extremely low pH values, enzymatic activity of gastrointestinal juices and actions of substances introduced into the GIT together with food.
  • the inner surface of stomach wall and of other parts of GIT are covered by a layer of mucus, which has, among others, a protective function for the mucous membrane.
  • a layer of mucus which has, among others, a protective function for the mucous membrane.
  • stomach ulcers, Crohn disease and ulcerative colitis belong among the most frequent inflammatory diseases of GIT.
  • ROS reactive oxygen free radicals
  • Oxygen free radicals are for example hydroxyl, peroxyl and superoxide anionradicals. If the ROS concentration exceeds antioxidation capacity of the surrounding cells, the so-called oxidative stress occurs. The oxidative stress caused by ROS might cause further damage of the tissue, therefore worsen the overall progression of the inflammation, and importantly prolongate the course of treatment.
  • CZ 293419 B6 relates to hydrophilic polymers in the form of a gel or a cover foil, which enhances the treatment process upon its application on a skin inflammation wound.
  • the starting polymers contain a covalently bound sterically hindered amine or its oxidated derivative (nitroxide or hydroxylamine), which serve as very efficient free radical scavengers.
  • Materials and preparations according to the above mentioned patent can be used on external injuries, wherein the localised effect is reached by applying the preparation directly on the injury.
  • JP 2012-111700 A relates to polymeric antioxidants for use in GIT.
  • the polymeric antioxidant is in the form of particles or micelles and contains derivatives of cyclic nitroxides in its structure.
  • the described block copolymers contain chemically bound blocks of polyethylene glycol and polystyrene, whereas the polystyrene blocks contain styrene units functionalized in position 4 by functional groups capable of undergoing chemical modifications enabling introduction of cyclic nitroxides.
  • a disadvantage of such solution is the binding of functional nitroxides on the polystyrene block of the copolymer, which forms the hydrophobic core of a micelle or a particle, respectively, therefore it is separated from its surroundings by a layer of polyethylene glycol which forms the hydrophilic coating of the micelle or the particle, respectively. It results in a limited accessibility of hydrophilic ROS to the antioxidant placed in the core of the micelle.
  • Another factor influencing the progression of an inflammatory disease in GIT is the extremely low pH value, e.g. in stomach juices.
  • Compounds chemically binding hydrochloric acid contained in stomach juices, can serve as a supporting agent to prevent the inflammation of the stomach mucous membrane and as a protection of the mucous membrane during the inflammatory stage (gastritis, irritated stomach, heartburn, reflux, gastroesophageal reflux disease, stomach ulcer and duodenum ulcer). It particularly concerns inorganic compounds based on bicarbonates, hydroxides, metal oxides (alluminium, magnesium), and optionally their combinations with omeprazole, which acts as a proton pump inhibitor. Low molecular weight compounds are usually dispersed in a polymeric carrier which swells in stomach juices and therefore ensures their controlled release into the surrounding medium.
  • Object of the invention is a preparation for oral administration destined for prevention and treatment of inflammatory affections of the gastrointestinal tract.
  • the preparation contains a biocompatible, hydrophilic polymer with affinity towards the glycoproteins present on the GIT mucous membrane surface, said polymer containing functional groups in its structure, which are able to bind harmful substances from the GIT juice.
  • Individual functional components are covalently bound within polymeric chains, therefore they are effectively prevented from being released and absorbed into the bloodstream, which would lead to adverse systemic effects.
  • Said polymer contains three types of structural units which have different functions in the polymeric structure and in the functioning of the preparation. Those structural units are: Structural units A, characterized by an ability to change their hydrophilic properties depending on the surrounding pH. These structural units ensure good solubility of the linear polymer, and, eventually, good swellability of branched and cross-linked polymeric structures in gastrointestinal tract juices in a wide range of pH (from 1.0 to 7.0). They are also able to adjust the pH of gastric fluid.
  • Structural units B are selected from a group of compounds characterized by their affinity towards glycoproteins present on the gastrointestinal tract mucous membrane surface. The presence of such units in the polymeric structure enhances the adhesion of the polymer on the mucous membrane surface, and therefore keeps the active substance, incorporated in the polymeric chain, in contact with the afflicted site of the mucous membrane.
  • Monomers suitable for providing affinity towards gastrointestinal tract mucous membrane surface are selected from hydroxy terminated (polyoxyethylene) acrylates and methacrylates, alkyloxy terminated (polyoxyethylene) acrylates and methacrylates, hydroxy terminated (polyoxyethylene) acrylamides and methacrylamides, alkyloxy terminated (polyoxyethylene) acrylamides and methacrylamides, preferably of an average molecular mass n in the range of 200 to 1000.
  • the term “trustalkyl” means Ci-C 6 alkyls, if it is not stated otherwise.
  • Salts include, in particular, salts of alkali metals and ammonium.
  • Structural units C contain chemical groups capable of binding or inactivating substances which are toxic to the gastrointestinal tract or which negatively influence inflammatory processes.
  • Suitable hydrophilic monomers capable of binding and inactivating free radicals are selected from a group of sterically hindered amines and their oxidated derivatives of general formula: wherein R 1 is -H or -OH or oxygen radical, R 2 to R 5 is (d - C4) alkyl, X is -CH(Y)- or - CH(Y)CH 2 - and Y is a chemical group capable of undergoing radical polymerization:
  • R is -H or -C3 ⁇ 4 and Z is -O- or -NH-, whereas the content of structural units C in the polymer is at least 1 %, preferably from 3 to 30 mol.%.
  • Structural units C are preferably derived from N-(2,2,6,6-tetramethylazinan-4-yl) methacrylamide or N-(2,2,6,6-tetramethylazinan-4-yl) methacrylate.
  • the polymer contains up to 98 % of units A, from 1 to 99 % of units B and at least 1 % of units C (in molar %).
  • Hydrophilic polymer according to the invention is prepared by radical polymerization of a mixture of precursors of structural units A, B and C.
  • Initiators are used to initiate the radical copolymerization.
  • Suitable initiators of the radical polymerization, as well as suitable polymerization procedures and conditions, are generally known to a skilled person.
  • radical thermic initiators such as azoinitiators, diacylperoxides and other peroxocompounds, UV initiators generating free radicals by UV irradiation or redox initiators, generating free radicals by oxidation-reduction reaction, can be suitable. Initiation does not have to be limited by the types of initiators mentioned above.
  • Polymers can be branched or crosslinked.
  • Crosslinking reagents for the preparation of branched or crosslinked polymers can be, for example, ethylenedi(meth)acrylate, diglycol and oligoglycol acrylates and methacrylates, ethylendiamindi(meth)acrylate, l,l '-divinyl- 3,3'-(ethan-l,l '-diyl)bis(pyrrolidin-2-one), 2,3-dihydroxybutan-l,4-diyl diacrylate or dimethacrylate, N,N'-methylenebisacrylamide or other crosslinkers commonly used in the field.
  • the hydrophilic polymer is, therefore, usually in the form of a high-molecular weight linear polymer, branched polymer or in the form of particles composed of covalently crosslinked gel. It is not absorbed by the gastrointestinal tract mucous membrane, neither does it enter the bloodstream, nor is it decomposed into low-molecular weight compounds which could be absorbed by the gastrointestinal tract. Non-absorbance of the polymer eliminates systemic contraindication. Moreover, the polymer is chemically neutral and does not undergo chain degradation in GIT juices.
  • the hydrophilic polymer is soluble or it has a high swelling ability in GIT juices.
  • the polymer upon its contact with juices of gastrointestinal tract, gradually swells, which makes the active structural units C, incorporated in polymeric chains, accessible.
  • the polymer at the same time adheres to the gastrointestinal tract mucose because of the presence of structural units B, showing affinity towards mucose proteins.
  • the active substance gets therefore in contact with the afflicted site of the mucous membrane; therewithal, the time for which the polymer (together with its active substance) rests in the particular part of the gastrointestinal tract is prolongated due to the adhesion of the polymer to the mucose.
  • the preparation according to the present invention can preferably be in a form of a tablet (simple or multilayered, coated and non-coated, effervescent), capsule suitable for oral use, syrup, solution, emulsion or suspension.
  • a tablet simple or multilayered, coated and non-coated, effervescent
  • capsule suitable for oral use, syrup, solution, emulsion or suspension.
  • the preparation can further contain other pharmaceutically acceptable auxiliary substances, for example excipients for easier tablet making, commonly used in the field; acid and base components ensuring the effervescent way of administration; disintegration agents, e.g. microcrystalline cellulose, starches (corn, potato and modified starches).
  • disintegration agents e.g. microcrystalline cellulose, starches (corn, potato and modified starches).
  • the content of disintegration agents in the preparation can reach up to 20 wt. %, preferably from 2 to 10 wt. %.
  • Sweeteners can be used as auxiliary substances in order to mask the bitter taste of active compounds or to enhance the sweet taste of the dosage form.
  • Sweeteners which can be used in the present invention, are selected from saccharides, such as monosaccharides or disaccharides (Z)-glucose, Z)-fructose, Z)-xylose, maltose, sucrose or sorbitol), polyols (glycerol, dulcitol, mannitol, sorbitol or xylitol), artificial sweeteners (saccharin and its sodium, potassium or calcium salts, cyclamate and its sodium or calcium salt, aspartame, acesulfame or their potassium salts).
  • the content of sweeteners in the preparation can range from 2 to 60 wt. %, preferably from 5 to 10 wt. % (relative to the weight of the dosage form).
  • the auxiliary substances can include also aromatic compounds, which can be used in the present invention and which are not limited to the following examples: e.g., orange, lemon or grape flavour, peppermint flavour etc.
  • the aromatic compounds can be used in the range of 0.01 to 5 wt. % (relative to the weight of the dosage form).
  • the polymer structure is designed to enable preferential concentration of the preparation close to the gastrointestinal tract mucose, e.g. utilising the adhesion of the preparation towards the mucose surface.
  • the protective effect of the preparation towards the gastrointestinal tract mucose is enhanced by its adhesion to the mucose, the adjustment of the local pH in the mucose proximity or by protection of the mucose cells against harmful substances.
  • the preparation includes chemical structures which specifically bind harmful substances of gastrointestinal tract juices, e.g. structures which bind and inactivate free radicals, structures adjusting pH of the gastric fluid by binding hydrochloric acid etc. Functional structures specifically binding harmful substances are covalently incorporated into the material of the preparation.
  • the present invention is a polymeric preparation composed of copolymers, in which different types of hydrophilic units (A, B, C) are statistically incorporated into the whole length of the polymeric chain. It ensures an even swelling of the polymer, which highly enhances the accessibility of the bound ROS antioxidant and enables molecules of the antioxidant to act in a close proximity of the mucose surface.
  • Another advantage of the present invention is the method of incorporating the molecules of antioxidants into the polymer by radical copolymerization, in which the antioxidant acts as comonomer. It simplifies the production of the preparation on industrial scale, which increases the industrial applicability of the invention.
  • Fig. 1 Time dependence of relative fluorescence intensity of the reaction mixture containing peroxyl free radicals and the polymer according to Example 4.
  • the curve a corresponds to the reference sample without polymer
  • curves b, c, d, e correspond to samples containing 5 mg, 10 mg, 20 mg and 40 mg of the polymer.
  • Fig. 2 EPR spectrum of the polymer solution according to Example 5, after the reaction with in situ generated peroxyl free radicals.
  • Fig. 3 In vivo imaging of three mice 2 h, 5 h and 12 h after p.o. application of polymer solution labeled according to Example 8 (ca 50 MBq/mouse).
  • Fig. 4 Ex vivo biodistribution of the polymer according to Example 8 in DBA/2 mice; 2 h, 6 h and 24 h after the p.o. application, expressed as a percentage of the total dosage (% ID).
  • Fig. 5 A part of a large intestine of a BALB/c mouse before (left) and after the exposure to the ABC polymer suspension (right) under UV light.
  • Fig. 7 Time dependence of the relative fluorescence intensity of the reaction mixture containing hydroxyl free radicals and the polymeric network according to Example 14.
  • the continuous curve corresponds to a blank sample, other dependences belong to samples with polymer concentrations of 0.9 mg/mL ( ⁇ ), 4.5 mg/mL (A) and 9.0 mg/mL (o).
  • Fig. 9 Development of average weight of mice tested in individual groups in the course of the treatment described in Example 20.
  • Example 5 Antioxidation ability of a solution of the linear polymer obtained in Example 4 was determined against in situ generated peroxyl radicals. The experiment was as follows: Stock buffered solutions of the polymer at concentrations 8 mg/mL, 16 mg/mL, 32 mg/mL and 64 mg/mL were prepared. In each vial, 650 ⁇ ⁇ of the polymer stock solution was placed together with 1.3 mL of fluorescein solution (2.4 x 10 "5 M) and 1.95 mL of AAPH solution (0,16 M). Directly after addition of all components, a continuous decrease of fluorescence intensity was measured during 60 minutes at 37 °C. The measurement was repeated twice for each polymer concentration. Fig. 1 shows that the polymer at the above mentioned conditions acts as a very efficient peroxyl radical scavenger.
  • Example 6 shows that the polymer at the above mentioned conditions acts as a very efficient peroxyl radical scavenger.
  • EPR spectrum of the polymer solution from Example 5 was measured after a reaction with peroxyl radicals (Fig. 2). EPR spectrum confirmed the presence of the oxidated form of a sterically hindered amine.
  • radioisotope I according to the following procedure:
  • the radioactivity was measured in the organs using an automatic gamma counter. The results were expressed as percentages of the originally applied dose (% ID). The ex vivo biodistribution study confirmed a complete elimination of the polymer via the gastrointestinal tract (Fig. 4).
  • the precipitated polymer (ABC) was filtered off, extracted by dioxane and dried into a constant weight. Analogical procedure was used to prepare a polymeric sample (AC), which does not contain the structural unit based on poly(ethyleneglycol) methyl ether methacrylate.
  • Antioxidation capacity against in situ generated hydroxyl free radicals in solution of the polymer network prepared in Example 15 was determined, according to the following procedure. Eight Eppendorf tubes containing appropriate amounts of the polymer were placed into a thermoblock and tempered to 37 °C. Then 900 ⁇ ⁇ of a buffer, 200 ⁇ ⁇ of Na 2 W0 4 .2 H 2 0 solution in a buffer (7.3 mM), 10 iL of fluorescein solution (2.4 x 10 "5 M) were placed into each tube and the polymer was kept to swell in this mixture for 5 minutes. Hydroxyl radical generation was started by an addition of 10 ⁇ ⁇ of hydrogen peroxide solution. The tubes were shaken and tempered to 37 °C during the whole time of the reaction.
  • Example 20
  • Example 15 The therapeutic effect of the preparation prepared in Example 15 in the GIT was performed with the Balb/C induced chronic colitis experimental model.
  • mice 20 male Balb/C mice were divided into three groups:
  • DSS sodium dextran sulfate
  • Fig. 9 shows the comparison of average weight of mice in individual groups during the course of the treatment. There is a clearly visible difference between the N group and the L group which shows slowing down (or even reversing) of the pathological process in the L group.

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  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
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  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
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  • Bioinformatics & Cheminformatics (AREA)
  • Epidemiology (AREA)
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  • Pain & Pain Management (AREA)
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Abstract

La présente invention concerne une préparation pour une utilisation par voie orale pour prévenir et traiter des affections inflammatoires du tractus gastro-intestinal, ladite préparation contenant un polymère hydrophile, biocompatible et muco-adhérent contenant : - au moins un type d'unités structurelles A choisies dans un groupe comportant des unités dérivées d'acides acrylique et méthacrylique et leurs sels, de méthacrylates et d'acrylates d'hydroxyalkyle, de méthacrylamides et d'acrylamides d'hydroxyalkyle, de méthacrylates et d'acrylates de N,N-dialkylaminoalkyle, de méthacrylamides et d'acrylamides de N,N-dialkylaminoalkyle, de N-vinyle-2-pyrrolidone et des mélanges de ceux-ci ; - au moins un type d'unités structurelles B choisies dans un groupe comprenant des unités dérivées de méthacrylates et d'acrylates (polyoxyéthylène) à terminaison hydroxy, de méthacrylates et d'acrylates (polyoxyéthylène) à terminaison alkyloxy, de méthacrylamides et d'acrylamides (polyoxyéthylène) à terminaison hydroxy, de méthacrylamides et d'acrylamides (polyoxyéthylène) à terminaison alkyloxy et des mélanges de ceux-ci ; - au moins un type d'unités structurelles C dérivées d'amines à encombrement stérique.
PCT/CZ2015/050011 2014-11-28 2015-11-20 Préparation orale WO2016082808A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CA2963582A CA2963582C (fr) 2014-11-28 2015-11-20 Preparation orale renfermant un polymere mucoadhesif, hydrophile, biocompatible destinee a la prevention et au traitement d'etats inflammatoires du tractus gastro-intestinal

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CZPV2014-825 2014-11-28
CZ2014-825A CZ305391B6 (cs) 2014-11-28 2014-11-28 Přípravek pro orální použití

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WO2016082808A1 true WO2016082808A1 (fr) 2016-06-02

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Publication number Priority date Publication date Assignee Title
CZ2018359A3 (cs) * 2018-07-17 2019-11-20 Ústav makromolekulární chemie AV ČR, v. v. i. Tekutý krycí přípravek pro ošetření ran

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999028359A1 (fr) * 1997-12-03 1999-06-10 Ústav Makromolekulární Chemie Akademie Ved C^¿Eské Republiky Preparation de prevention et de guerison d'affections inflammatoires
JP2012111700A (ja) 2010-11-22 2012-06-14 Univ Of Tsukuba 高分子化環状ニトロキシドラジカル化合物の潰瘍性消化管の炎症の処置剤

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WO2009133647A1 (fr) * 2008-05-02 2009-11-05 国立大学法人筑波大学 Composé radicalaire de nitroxyde cyclique polymérisé, et utilisation associée
CZ2008490A3 (cs) * 2008-08-15 2010-02-24 Labský@Jirí Synergický vliv benzofenonu a stericky stínených aminu pri lécení povrchových poranení
JP2013173689A (ja) * 2012-02-24 2013-09-05 Univ Of Tsukuba 高分子化ニトロキシドラジカル化合物と非ステロイド性抗炎症薬の複合体

Patent Citations (3)

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WO1999028359A1 (fr) * 1997-12-03 1999-06-10 Ústav Makromolekulární Chemie Akademie Ved C^¿Eské Republiky Preparation de prevention et de guerison d'affections inflammatoires
CZ293419B6 (cs) 1997-12-03 2004-04-14 Ústav Makromolekulární Chemie Av Čr Přípravek k prevenci a hojení zánětlivých onemocnění
JP2012111700A (ja) 2010-11-22 2012-06-14 Univ Of Tsukuba 高分子化環状ニトロキシドラジカル化合物の潰瘍性消化管の炎症の処置剤

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DONG ZHANG ET AL: "Synthesis and Solubility of (Mono-) End-Functionalized Poly(2-hydroxyethyl methacrylate- g -ethylene glycol) Graft Copolymers with Varying Macromolecular Architectures", MACROMOLECULES, vol. 38, no. 6, 1 March 2005 (2005-03-01), US, pages 2530 - 2534, XP055252484, ISSN: 0024-9297, DOI: 10.1021/ma049330k *
L. POLÁKOVÁ ET AL: "Antioxidant Properties of 2-Hydroxyethyl Methacrylate-Based Copolymers with Incorporated Sterically Hindered Amine", BIOMACROMOLECULES, vol. 16, no. 9, 14 September 2015 (2015-09-14), US, pages 2726 - 2734, XP055252383, ISSN: 1525-7797, DOI: 10.1021/acs.biomac.5b00599 *
SERRA L ET AL: "Design of poly(ethylene glycol)-tethered copolymers as novel mucoadhesive drug delivery systems", EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS, ELSEVIER SCIENCE PUBLISHERS B.V., AMSTERDAM, NL, vol. 63, no. 1, 1 May 2006 (2006-05-01), pages 11 - 18, XP027998014, ISSN: 0939-6411, [retrieved on 20060501], DOI: 10.1016/J.EJPB.2005.10.011 *

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CZ2014825A3 (cs) 2015-08-26
CA2963582C (fr) 2017-12-05
CA2963582A1 (fr) 2016-06-02
CZ305391B6 (cs) 2015-08-26

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