WO2021229538A1 - Procédé d'obtention d'un agent hémostatique bioactif à base de chitosane, et agent hémostatique bioactif à base de chitosane - Google Patents

Procédé d'obtention d'un agent hémostatique bioactif à base de chitosane, et agent hémostatique bioactif à base de chitosane Download PDF

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WO2021229538A1
WO2021229538A1 PCT/IB2021/054169 IB2021054169W WO2021229538A1 WO 2021229538 A1 WO2021229538 A1 WO 2021229538A1 IB 2021054169 W IB2021054169 W IB 2021054169W WO 2021229538 A1 WO2021229538 A1 WO 2021229538A1
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Prior art keywords
chitosan
aqueous
solution
cross
aspartic acid
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PCT/IB2021/054169
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English (en)
Inventor
Marek PIĄTKOWSKI
Julia RADWAN-PRAGŁOWSKA
Łukasz JANUS
Aleksandra SIERAKOWSKA
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Politechnika Krakowska im. T. Kościuszki
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Publication of WO2021229538A1 publication Critical patent/WO2021229538A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
    • A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
    • A61L15/42—Use of materials characterised by their function or physical properties
    • A61L15/46—Deodorants or malodour counteractants, e.g. to inhibit the formation of ammonia or bacteria
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
    • A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
    • A61L15/22—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons containing macromolecular materials
    • A61L15/28—Polysaccharides or their derivatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
    • A61L26/0009—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form containing macromolecular materials
    • A61L26/0023—Polysaccharides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
    • A61L26/0061—Use of materials characterised by their function or physical properties
    • A61L26/0066—Medicaments; Biocides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
    • A61L26/0061—Use of materials characterised by their function or physical properties
    • A61L26/008—Hydrogels or hydrocolloids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
    • A61L2300/252—Polypeptides, proteins, e.g. glycoproteins, lipoproteins, cytokines
    • A61L2300/254—Enzymes, proenzymes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/404—Biocides, antimicrobial agents, antiseptic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2400/00—Materials characterised by their function or physical properties
    • A61L2400/04—Materials for stopping bleeding

Definitions

  • the subject-matter of the invention is a method for obtaining a chitosan-based bioactive hemostatic agent suitable for use as a biomaterial that inhibits bleeding of various origins and intensities, as well as an element of hemostatic dressings and systems for controlled delivery and release of bioactive substances, including hydrophobic ones.
  • a chitosan-based bioactive hemostatic agent suitable for use as a hemostatic biomaterial, an element of hemostatic dressings and systems for controlled delivery and release of bioactive substances, including hydrophobic ones.
  • Chitosan is a biopolymer obtained by a chemical or enzymatic deacetylation reaction of chitin, which results in obtaining a polymer with a degree of deacetylation of at least 60%. Its chain is formed by two types of monomer units: N-acetylaminoglucose and glucosamine They are linked by beta-glycosidic bonds. Chitosan in its chemical structure contains many hydroxyl and amino groups, due to which it can undergo a number of modifications. This biopolymer, as a result of physical or chemical cross-linking reactions, forms a hydrogel which has the capability to absorb large amounts of water.
  • native chitosan has hemostatic properties resulting from the presence of free amino groups that interact with erythrocytes and platelets.
  • chitosan finds application as an element of hemostatic agents, which are biomaterials used to stop the hemorrhages by sorbing aqueous fraction of blood and consequently concentrating components responsible for the induction of the blood coagulation cascade.
  • the best known methods for obtaining chitosan-based hemostatic agents include:
  • Chitosan and its derivatives due to their antibacterial properties and biocompatibility, are often used in medicine and pharmacy. It is known that the chitosan derivatives for medical and pharmaceutical use must be of high purity.
  • Chinese patent CN 101053669 B presents a method for obtaining a hemostatic agent, wherein water- soluble chitosan derivatives, e.g., carboxymethyl chitosan, are dissolved in water, and then subjected to lyophilization for 24-60 hours.
  • water- soluble chitosan derivatives e.g., carboxymethyl chitosan
  • US patent No. 8715719 B2 describes a method for obtaining a hemostatic agent, wherein a solution of chitosan having an average molar mass of less than 600,000 g/mol is prepared in a solvent other than water, a cross-linking agent in the form of an organic acid, e.g. lactic acid, is added, and then the lyophilization is performed.
  • a cross-linking agent in the form of an organic acid e.g. lactic acid
  • the aim of the invention is to develop a method for producing a chitosan-based bioactive hemostatic agent by a physical cross-linking reaction of chitosan using biocompatible modifiers, and then lysozyme incorporation, and lyophilization of the resulting agent, and to obtain a bioactive hemostatic agent which is a product of the physical cross-linking reaction of chitosan and the lysozyme incorporation into the structure of the cross-linked chitosan.
  • This aim is achieved by the method of the invention.
  • the gist of the embodiment according to the invention is that, in the method for obtaining a chitosan- based bioactive hemostatic agent, the chitosan is subjected to the physical cross-linking reaction using poly(aspartic acid) as a cross-linking agent, in an aqueous medium, and then lysozyme is added to the reaction product and the resulting composite is subjected to lyophilization.
  • the method for obtaining the chitosan-based bioactive hemostatic agent comprising converting a polysuccinimide by alkaline hydrolysis to poly(aspartic acid), which is purified before further use in the process, and dissolving the chitosan in an aqueous acid solution, precipitating the chitosan with an alkali, purifying it and subjecting it to the physical cross-linking reaction in an aqueous medium with poly(aspartic acid), and then cooling the reaction suspension to a temperature not higher than 5°C and adding an aqueous lysozyme solution, freezing, and subjecting to lyophilization, is based upon that the polysuccinimide (PSI) is hydrolyzed by introducing an aqueous alkali solution addition to the aqueous suspension of the polysuccinimide, with constant stirring and adding the alkali solution portionwise until the pH of the mixture reaches 11.
  • PSI polysuccinimide
  • chitosan having an average molar mass of 2,000 to 800,000 g/mol and a degree of deacetylation of 60- 100% is dissolved in an aqueous acid solution at a concentration of 1 to 5 wt%, after which the chitosan is precipitated with an aqueous alkali solution added until a neutral pH of the mixture is obtained.
  • the resulting salt of the acid used is removed from the mixture by membrane dialysis using MWCO dialysis membranes.
  • the precipitated, purified chitosan in the form of an aqueous suspension is placed in a reaction vessel, an aqueous solution of the obtained poly(aspartic acid) is introduced as a cross-linking agent, while maintaining continuous stirring, in the amount of 0.1 to 6 g of poly(aspartic acid) per 1 g of chitosan, and after the chitosan has been cross-linked, the temperature of the mixture is lowered to no more than 5°C and an aqueous lysozyme solution is added while stirring, then the mixture containing the cross- linked chitosan with the lysozyme incorporated into its structure is subjected to freezing and lyophilization at a temperature of -40°C to -60°C under a pressure of less than 1 mbar.
  • the polysuccinimide obtained by either aspartic acid or maleic anhydride and urea polycondensation is used as a source of poly(aspartic acid).
  • an aqueous solution of sodium or potassium hydroxide at a concentration of at least 1 wt%, and most preferably 5 wt%, is used as an agent hydrolyzing the polysuccinimide.
  • the process for obtaining poly(aspartic acid) employs an aqueous suspension which contains 10 wt% of the polysuccinimide.
  • the alkaline hydrolysis process of the polysuccinimide is carried out with continuous stirring using a magnetic or mechanical stirrer at a speed of 300 rpm.
  • the alkali solution is added portionwise to the polysuccinimide suspension while stirring until the pH of the mixture reaches 11.
  • the cations derived from the alkali used are removed from the poly(aspartic acid) salt solution using a strong sulfonic acid ion-exchange resin.
  • an aqueous chitosan solution at a concentration of 1 to 10 wt% is used.
  • the chitosan is dissolved in a 2-5 wt% solution of hydrochloric acid.
  • a chitosan having an average molar mass of 100,000 to 400,000 g/mol is used.
  • a chitosan having a degree of deacetylation of more than 75% is used.
  • a chitosan of fungal origin is used.
  • the chitosan is precipitated with a 2 wt% aqueous sodium or potassium hydroxide solution.
  • the chitosan suspension is purified from the salts formed using dialysis membranes with MWCO (Molecular Weight Cut-Off) of 10,000-12,000 Da.
  • MWCO Molecular Weight Cut-Off
  • the poly(aspartic acid) is added portionwise to the chitosan using continuous stirring at speed of 300-400 rpm.
  • the physical cross-linking of the chitosan is carried out by maintaining a ratio of 0,5-2,25 g of poly(aspartic acid) to 1 g of chitosan.
  • the suspension containing the cross-linked chitosan is cooled to 3°C.
  • the lysozyme is added to the suspension with the cross-linked chitosan at 3°C with constant stirring.
  • lysozyme per 1 g of chitosan is used.
  • chicken egg white lysozyme is used.
  • freezing of the composite of cross-linked chitosan with incorporated lysozyme is carried out at a temperature below 0°C, preferably at -20°C.
  • the chitosan-based bioactive hemostatic agent containing lysozyme is characterized in that it is a product of the implementation of the method of the invention, which comprises converting the polysuccinimide, obtained either from aspartic acid or maleic anhydride and urea, by alkaline hydrolysis, to poly(aspartic acid), dissolving the chitosan in an aqueous acid solution, precipitating the chitosan with an alkali, purifying the chitosan and subjecting it to physical cross-linking reaction in an aqueous medium with the obtained poly(aspartic acid), and then cooling the reaction suspension and adding an aqueous lysozyme solution, freezing and subjecting to lyophilization the suspension containing cross-linked chitosan with lysozyme incorporated into its structure, wherein the polysuccinimide is hydrolyzed by introducing an aqueous alkali solution addition to the aqueous polysuccinimide
  • the bioactive hemostatic agent based on physically cross-linked chitosan with lysozyme incorporated, is characterized by a high sorption capacity of aqueous solutions, exhibits antibacterial activity and is easily biodegradable and non-cytotoxic as well.
  • polysuccinimide obtained by polycondensation of aspartic acid
  • 50 mL of water was added, the solution was stirred with a mechanical stirrer, and then, while stirring, portions of 5 wt% NaOH solution were added dropwise, until the pH of the solution reached 11.
  • the hydrolysis reaction was carried out for 1 hour.
  • the entire reaction mixture was transferred to an ion-exchange column to remove the sodium ions from the reaction mixture and convert the sodium salt of poly(aspartic acid) to poly(aspartic acid).
  • the resulting solution was diluted so that the total amount of aqueous poly(aspartic acid) solution was 50 ml.
  • chitosan in the amorphous form 10 g of chitosan with an average molar mass of 300,000 g/mol, obtained from shrimp, was added to 2000 mL of distilled water (conductivity 10 mS/cm) and while stirring, small portions of 5 wt% HCI solution were added dropwise, until pH 5 was reached. The mixture was heated to 50°C until the chitosan dissolved completely. Next, 5 wt% NaOH solution was added to the solution while stirring until pH 7 was reached. Chitosan was obtained in the amorphous form, which was then purified with dialysis membrane with MWCO in the range of 10,000-12,000 Da. The final concentration of chitosan suspension in water was 10 g/L.
  • the hemostatic agent was prepared using a mechanical stirrer (400 rpm). 4 mL of aqueous poly(aspartic acid) solution was added dropwise over 10 minutes, while stirring, to 40 mL of chitosan suspension at a concentration of 10 g/L. The product formed was left to stand for 20 minutes and then decanted. The aqueous suspension of such cross-linked chitosan was cooled to 3°C and then 5 mg of lysozyme in the form of an aqueous solution at a concentration of 1 mg/ml was added while stirring. Composite material formed was frozen and then subjected to lyophilization at a temperature -40°C to -60°C under a pressure of less than 1 mbar to obtain the finished hemostatic product.
  • the FT-IR (Fourier-Transform Infrared Spectroscopy) spectrum of the obtained hemostatic agent is shown in the accompanying drawing in Fig. 1 (Example 1).
  • the spectrum shows the characteristic bands for chitosan originating from free hydroxyl (3351 cm 1 ) and amine (1585 cm 1 ; 1149 cm 1 ) groups, bands typical of aliphatic moieties (2917 cm 1 ; 2879 cm 1 ) of glycosidic bonds between chitosan mer units (1063 cm 1 ) and glucopyranose rings (895 cm 1 ). Additionally, bands originating from carboxyl groups derived from poly(aspartic acid) (1706 cm 1 ) are present.
  • polysuccinimide obtained by polycondensation of urea and maleic anhydride in a microwave radiation field
  • 50 mL of water was added.
  • the solution was stirred with a mechanical stirrer, and then, while stirring, portions of 2 wt% KOH solution were added dropwise, until the pH of the solution reached 11.
  • the hydrolysis reaction was carried out for 1 hour and 30 minutes.
  • the mixture was transferred to an ion-exchange column to remove the potassium ions from the reaction mixture and convert the potassium salt of poly(aspartic acid) to poly(aspartic acid).
  • the resulting solution was diluted so that the total amount of aqueous poly(aspartic acid) solution was 50 mL.
  • chitosan in the amorphous form, 10 g of chitosan with an average molar mass of 200,000 g/mol, obtained from mushrooms ( Agaricus ), was added to 2000 mL of distilled water (conductivity 10 mS/cm) and while stirring, small portions of 5 wt% acetic acid solution were added dropwise, until pH 5 was reached. The mixture was heated to 60°C until the chitosan dissolved completely. Next, 2 wt% KOH solution was added to the solution while stirring until pH 7 was reached. Chitosan was obtained in the amorphous form, which was then purified with dialysis membrane with MWCO in the range of 10,000-12,000 Da. The final concentration of chitosan suspension in water was 10 g/L.
  • the hemostatic agent was prepared using a mechanical stirrer (300 rpm). 4 mL of aqueous poly(aspartic acid) solution was added dropwise over 10 minutes, while stirring, to 40 mL of chitosan suspension at a concentration of 10 g/L. The product formed was left to stand for 20 minutes and then decanted. The aqueous suspension of such cross-linked chitosan was cooled to 5°C and then 10 mg of lysozyme in the form of an aqueous solution at a concentration of 2 mg/ml was added while stirring. Composite material formed was frozen and then subjected to lyophilization at a temperature of -40°C to -60°C under a pressure of less than 1 mbar to obtain the finished hemostatic product.
  • the FT-IR spectrum of the obtained hemostatic agent is shown in the accompanying drawing in Fig. 2 (Example 2).
  • the spectrum shows the characteristic bands for chitosan originating from free hydroxyl (3350 cm 1 ) and amine (1525 cm 1 ; 1156 cm 1 ) groups, bands typical of aliphatic moieties (2957 cm 1 ; 2880 cm 1 ) of glycosidic bonds between chitosan mer units (1061 cm 1 ) and glucopyranose rings (901 cm 1 ). Additionally, bands originating from carboxyl groups derived from poly(aspartic acid) (1705 cm 1 ) are present.
  • the invention makes it possible to obtain a chitosan-based bioactive hemostatic agent containing lysozyme, characterized by more advantageous biological properties, increased biodegradability, sorptive and antibacterial capabilities in comparison with native chitosan-based hemostatic agents.
  • the physical cross-linking of chitosan is carried out with the use of a cross-linking agent which is non-toxic, but unfortunately unstable over time, i.e. poly(aspartic acid), which requires performing the entire process of the hemostatic agent production in such a way that it is possible to obtain chitosan in an amorphous form and poly(aspartic acid) practically simultaneously, in two process steps independent of each other.
  • a chitosan hydrogel which has a chemically unmodified structure, has free amino groups responsible for the beneficial biological properties of chitosan and does not negatively affect living eukaryotic cells.
  • Cross-linked chitosan produced by the method of the invention contains the lysozyme enzyme, which is stabilized in the three-dimensional structure of the cross-linked chitosan by hydrogen bonds. Modification of chitosan by lysozyme introduction allows increasing the biodegradation rate of chitosan material.
  • the method of the invention makes it possible to modify the degree of chitosan hydrogel cross-linking by changing the amount of cross-linking agent and the final product biodegradation rate by changing the amount of lysozyme.
  • an advantageous feature of the method of the invention is the lack of harmful by-products.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Materials Engineering (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Hematology (AREA)
  • Dispersion Chemistry (AREA)
  • Materials For Medical Uses (AREA)
  • Polysaccharides And Polysaccharide Derivatives (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne un procédé d'obtention d'un agent hémostatique bioactif, dans lequel le chitosane est soumis à une réaction de réticulation physique avec un acide poly-aspartique, puis le lysozyme est incorporé dans la structure du chitosane réticulé, la réaction de réticulation étant réalisée à température ambiante sous une pression normale. Le rapport en masse chitosane:agent de réticulation est de 1:0,1 à 1:6, et la quantité de lysozyme est de 12,5-25 mg pour 1 g de chitosane. La présente invention concerne également l'agent hémostatique bioactif à base de chitosane obtenu par ce procédé.
PCT/IB2021/054169 2020-05-14 2021-05-14 Procédé d'obtention d'un agent hémostatique bioactif à base de chitosane, et agent hémostatique bioactif à base de chitosane WO2021229538A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
PL433975A PL242855B1 (pl) 2020-05-14 2020-05-14 Sposób otrzymywania bioaktywnego środka hemostatycznego na bazie chitozanu
PLPL433975 2020-05-14

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN100412113C (zh) * 2006-08-18 2008-08-20 天津理工大学 制备聚天冬酰胺与壳聚糖共聚仿生膜材料的方法
CN104162182A (zh) * 2014-08-06 2014-11-26 暨南大学 一种具有抗菌促愈合活性的复合止血粉及其制备方法

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN100412113C (zh) * 2006-08-18 2008-08-20 天津理工大学 制备聚天冬酰胺与壳聚糖共聚仿生膜材料的方法
CN104162182A (zh) * 2014-08-06 2014-11-26 暨南大学 一种具有抗菌促愈合活性的复合止血粉及其制备方法

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
RADWAN-PRAGLOWSKA JULIA ET AL: "Chitosan-Based Bioactive Hemostatic Agents with Antibacterial Properties-Synthesis and Characterization", MOLECULES, vol. 24, no. 14, 19 July 2019 (2019-07-19), pages 2629, XP055842196, DOI: 10.3390/molecules24142629 *

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PL433975A1 (pl) 2021-11-15

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