WO2022119322A1 - Composition antioxydante comprenant un nouveau composé - Google Patents

Composition antioxydante comprenant un nouveau composé Download PDF

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WO2022119322A1
WO2022119322A1 PCT/KR2021/018035 KR2021018035W WO2022119322A1 WO 2022119322 A1 WO2022119322 A1 WO 2022119322A1 KR 2021018035 W KR2021018035 W KR 2021018035W WO 2022119322 A1 WO2022119322 A1 WO 2022119322A1
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iodine
hemostatic composition
hemostatic
tmc
povidone iodine
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PCT/KR2021/018035
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English (en)
Korean (ko)
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우승훈
아부에바셀린
배준상
류현석
정필상
엄주범
박소영
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단국대학교 천안캠퍼스 산학협력단
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Publication of WO2022119322A1 publication Critical patent/WO2022119322A1/fr

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    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/716—Glucans
    • A61K31/722—Chitin, chitosan
    • 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
    • A61K31/787—Polymers containing nitrogen containing heterocyclic rings having nitrogen as a ring hetero atom
    • A61K31/79—Polymers of vinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/18—Iodine; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/541—Organic ions forming an ion pair complex with the pharmacologically or therapeutically active agent
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/55—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/55—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
    • A61K47/552—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds one of the codrug's components being an antibiotic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/02—Local antiseptics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • the present invention relates to a hemostatic composition comprising a novel compound.
  • hemostatic agents in the operating room, general emergency situations, and battlefields is essential because it minimizes blood loss through effective early hemostasis and shortens the operating time by securing a quick surgical field of view, thereby greatly increasing the patient's chances of survival.
  • an ideal sterilization product should have antibacterial properties against a wide range of microorganisms including pathogens, have high penetration only in the wound area, and minimize the effect on systemic absorption.
  • an ideal product should not be able to acquire resistance to microorganisms, promote wound healing, and be low-cost and easy to apply.
  • povidone iodine has a broad spectrum of antibacterial properties, is not resistant to microorganisms, does not interfere with wound healing, and has greater benefits than harmful products.
  • povidone-iodine is an ion-bonded form of povidone (polyvinylpyrrolidone) and iodine. Iodine oxidizes DNA, fat, and amino acids of microorganisms to inactivate DNA/RNA and proteins , and povidone regulates the release of iodine.
  • Chitosan has advantages of biodegradability, non-toxicity, and antibacterial properties, and there have been many reports that it helps sterilize and heal wounds, and many chitosan-based products such as wound healing agents are being released.
  • chitosan has a disadvantage that it is difficult to use in the human body because it is dissolved in weakly acidic conditions.
  • N,N,N-trimethylchitosan methylated three times from chitosan is dissolved in a neutral state and has the advantage of being easy to apply to the human body.
  • the present inventors have developed a hemostatic composition comprising N,N,N-trimethylchitosan and povidone iodine, paying attention to the technical characteristics as described above.
  • An object of the present invention is to provide a hemostatic composition comprising N,N,N-trimethyl chitosan and povidone iodine.
  • Another object of the present invention is to provide a hemostasis method comprising; treating a subject in need thereof with N,N,N-trimethyl chitosan and povidone iodine.
  • hemostatic composition comprising N,N,N-trimethyl chitosan and povidone iodine.
  • the N,N,N-trimethyl chitosan of the present invention is a positively charged chitosan prepared through three rounds of N-methylation on chitosan, a natural polymer, and conventionally, chitosan itself is widely known as a positively charged polymer, but three times of N- It is possible to form an ionic complex with povidone iodine by further strengthening the electrostatic attraction through quaternary amine positive charge through methylation.
  • N,N,N-trimethyl chitosan is easy to apply to the human body, unlike chitosan that dissolves in weak acid in that it is soluble in neutrality.
  • N,N,N-trimethyl chitosan which is permanently positively charged, attracts the negative charge of red blood cells and activated platelets through the charge, thereby assisting aggregation and blood coagulation.
  • Povidone iodine of the present invention is a compound in which polyvinylpyrrolidone and iodine are combined in an ionic bond state, and is widely known as an antiseptic for trauma.
  • Povidone has antibacterial properties through the function of inactivating DNA/RNA as well as protein of povidone iodine, and povidone plays a role in regulating the release of iodine.
  • the sterilization function of iodine is not resistant and strong, it can cause problems in the human body when exposed to large amounts for a short time, so the release rate is controlled by using povidone.
  • the N,N,N-trimethyl chitosan and povidone iodine composition for hemostasis may include N,N,N-trimethyl chitosan and povidone iodine in a volume ratio of 0.5:1 to 2:1.
  • the volume ratio of N,N,N-trimethyl chitosan and povidone iodine is less than 0.5:1, the platelet aggregation effect of N,N,N-trimethyl chitosan decreases, and the hemostatic effect may be remarkably reduced.
  • the volume ratio of N,N,N-trimethyl chitosan and povidone iodine exceeds 2:1, the amount of negative iodine charge of povidone iodine may be insufficient, so that the ion complex may not be formed smoothly.
  • the hemostatic composition may be provided in a form selected from the group consisting of hydrogels, nanofibers, emulsions and powders.
  • the hemostatic composition may exhibit sterilization performance due to the presence of povidone-iodine. That is, the hemostatic composition of the present invention exhibits hemostatic properties and sterilization performance at the same time, so that it can be easily used for surgery, emergency measures, etc. of local bleeding sites.
  • the present invention provides a hemostatic composition
  • a hemostatic composition comprising N,N,N-trimethyl chitosan and povidone iodine, an ionic complex through electrostatic attraction between povidone iodine iodine and N,N,N-trimethyl chitosan It may be present in the hemostatic composition through formation.
  • a schematic diagram for the formation of the ion complex is shown in FIG. 1 .
  • the present invention provides a hemostatic agent comprising the composition for hemostasis.
  • the present invention provides a hemostasis method comprising; treating a subject in need thereof with N,N,N-trimethyl chitosan and povidone iodine.
  • the term “subject” refers to a subject of hemostasis, and more specifically, it may refer to mammals such as humans or non-human primates, mice, dogs, cats, horses, and cattle, The present invention is not limited thereto.
  • the hemostatic composition of the present invention contains N,N,N-trimethyl chitosan and povidone iodine simultaneously, it exhibits hemostatic performance due to the positive charge of N,N,N-trimethyl chitosan and at the same time exhibits sterilization performance due to povidone iodine can indicate
  • N,N,N-trimethyl chitosan and povidone iodine form an ionic complex centered on the negative charge of iodine, it is possible to control the release rate of iodine in the hemostatic composition in a stable form.
  • 1 is a schematic diagram showing an ionic complex of N,N,N-trimethylchitosan and povidone iodine.
  • Figure 2 shows the NMR peak results of the synthesized N,N,N-trimethylchitosan.
  • TMC N,N,N-trimethylchitosan
  • CTRL saline, TMC-0.5; 0.5% by weight, TMC-1: 1% by weight, TMC-2: 2% by weight, TMC-5: 5% by weight
  • B N,N,N-trimethylchitosan dissolved in povidone iodine [CTRL: povidonei] Odin 1% by weight solution, TMC-0.5; 5% by weight, TMC-1: 1% by weight, TMC-2: 2% by weight, TMC-5: 5% by weight]
  • C N,N,N-trimethylchitosan (TMC-5: 5% by weight) dissolved in saline %) and control (TMC-0, saline) cytotoxicity test results are shown.
  • TMC-0 PVPI
  • TMC-5 5 wt. %
  • TMC-10 10% by weight
  • Figure 5 shows the results of the fungal growth inhibition test of N,N,N-trimethylchitosan dissolved in povidone iodine and the control [TMC-0 (PVPI): 1 wt% solution of povidoneiodine, TMC-5: 5 wt. %, TMC-10: 10% by weight].
  • FIG. 7 shows an image confirming the platelet aggregation degree of N,N,N-trimethylchitosan dissolved in saline and the control [CTRL: saline] by scanning electron microscope.
  • Example 1 Preparation of a powder composition comprising N,N,N-trimethylchitosan
  • N-methylchitosan iodine was added to N-methylchitosan iodine and mixed at 60° C. for 60 minutes. During mixing, NaCl aqueous solution (10% v/v) was added to replace the iodine. Then, ethanol was added and centrifuged at 4°C at 10,000 x g for 30 minutes. The precipitated N,N-dimethylchitosan (DMC) was collected. Thereafter, the ethanol was removed in a dry oven. DMC was mixed with sodium iodide, NaOH aqueous solution (15% v/v), and methyl iodine at 60°C for 60 minutes.
  • DMC N,N-dimethylchitosan
  • Example 3 Preparation of a hemostatic composition comprising N,N,N-trimethylchitosan and povidone iodine
  • the chitosan derivative N,N,N-trimethyl chitosan (TMC) was dissolved in deionized water to obtain an aqueous solution of N,N,N-trimethyl chitosan in an amount of 0.05 to 20% by weight. Thereafter, a povidone-iodine (PVPI) complex is dissolved in deionized water to prepare a povidone-iodine solution in which 0.1 to 12% by weight of iodine is present.
  • the PVPI and TMC solution were mixed to form a uniform composition in a volume ratio of 2:1 and 1:1 of PVPI:TMC.
  • the mixture comprising N,N,N-trimethylchitosan and povidone iodine was 0.1 to 10% by weight of TMC and 1 to 10% by weight of povidone-iodine (PVPI) complex.
  • Example 4 Cytotoxicity evaluation of a hemostatic composition comprising N,N,N-trimethylchitosan and povidone iodine
  • the cytotoxicity results of the hemostatic composition prepared in Example 3 were tested and are shown in FIG. 3 .
  • human fibroblast cells BJ, ATCC CRL-2522TM were cultured using a medium composed of Eagle's minimal essential medium (EMEM), 10% fetal bovine serum albumin (FBS), and 1% penicillin streptomycin (PS). Cells were cultured on a culture plate, and the hemostatic composition of Example 3 was treated in the culture medium. The final concentration of PVPI in the treated hemostatic composition was 1% by weight, and the final concentration of TMC was 0.5, 1.0, 2.0 and 5.0% by weight. This was performed to determine the potential cytotoxicity of TMCs after 24 h survival by MTT assay.
  • EMEM Eagle's minimal essential medium
  • FBS fetal bovine serum albumin
  • PS penicillin streptomycin
  • Example 5 Bacterial growth inhibition experiment of hemostatic composition comprising N,N,N-trimethylchitosan and povidone iodine
  • inhibition zone assay was performed to measure bacterial growth inhibition and bactericidal effect.
  • the strains used were methicillin sensitive Staphylococcus aureus (MSSA, KCCM: 40881, ATCC 29213), multidrug-resistant Staphylococcus aureus (KCCM: 11256, ATCC 25923) in Gram-positive bacteria.
  • MSSA methicillin sensitive Staphylococcus aureus
  • KCCM multidrug-resistant Staphylococcus aureus
  • 0.5g agarose was added to 50ml LB broth and melted using a microwave oven. When the temperature was below 60°C, each bacteria was diluted so that the absorbance ( OD600 ) value was 0.01, 400ul was added, and 8ml each was put in a Petri dish and coagulated. After that, about 2 mm holes were drilled, and 4 ul of each solution was treated and then cultured at 37° C. for 24 h. After incubation, the MTT solution was treated for 30 minutes to
  • Example 6 Fungal growth inhibition experiment of hemostatic composition comprising N,N,N-trimethylchitosan and povidone iodine
  • the fungal growth inhibition experiment of the hemostatic composition prepared in Example 3 was performed and is shown in FIG. 5 .
  • an inhibition zone assay was performed to measure the fungal growth inhibition and bactericidal effect.
  • the strain used was Candida albicans (KCCM: 11282, ATCC: 10231). Put 0.5g agarose in 50ml LB broth and melt it using a microwave oven. When the temperature is below 60°C, dilute each bacteria so that the absorbance ( OD600 ) value is 0.01, add 400ul, put 8ml each in a Petri dish, and harden. After that, a hole of about 2 mm was drilled, and 4 ul of each solution was treated and incubated at 37° C. for 24 hours. After incubation, the MTT solution was treated for 30 minutes to check the clear zone, and the results were confirmed.
  • Example 7 Hemostatic performance test of hemostatic composition comprising N,N,N-trimethylchitosan and povidone iodine
  • Example 3 a sample obtained by dissolving various concentrations of TMC (0.5, 1.0, 2.0, or 5%) in a 1 wt% PVPI solution) was added per well of the culture plate. PVPI only played a control role.
  • Blood citrate was mixed with 0.1M calcium chloride (CaCl 2 ) to initiate coagulation and distributed in a 1:1 volume ratio in the wells containing the TMC solution. Blood was allowed to come into contact with the solution and was observed every 30 seconds. The reaction was stopped by adding deionized water or saline into the wells without disturbing the thrombus. The time it took to form a clot was recorded and light micrographs were taken every minute.
  • Example 3 The hemostatic composition of Example 3 (PVPI-TMC solution) significantly shortened the in vitro blood clotting time compared to the control. However, no significant difference between concentrations was observed, suggesting that the minimum concentration of 0.5% TMC was sufficient to induce blood clotting in vitro.
  • the platelet activation test was performed by collecting blood at a ratio of 4:1 using a syringe containing 0.109M sodium citrate. To separate the high-concentration platelet solution, whole blood was centrifuged at 2500 rpm for 5 minutes, platelet rich plasma (PRP) was separated from red blood cells, and further centrifuged at 2500 rpm for 5 minutes to obtain rich plasma pellets. TMC solution or saline (controller) was dropped on the filter paper (50ul) placed in the well (24-well) of the culture plate. The pellet was diluted with PBS at a ratio of 1:4 and then added to each filter paper (50ul) loaded with TMC solution.
  • PRP platelet rich plasma
  • each dressing was removed and fixed with 2% glutaraldehyde or 4% paraformaldehyde in PBS. Activated platelets were observed under an electron microscope (SEM, JSM-6701F, JEOL, Japan).
  • TMC supports platelet adhesion and activates platelets only against control or saline. That is, in the control group, platelets were not activated, whereas in the TMC, platelets were activated and it was confirmed that the platelets were extended in a pseudo-legged branch shape.
  • Example 9 Hemostatic performance test of hemostatic composition comprising N,N,N-trimethylchitosan and povidone iodine
  • the hemostatic performance of the hemostatic composition prepared in Example 3 was tested and shown in FIG. 8 .
  • anesthetized Sprague Dolly rats were fixed to a Styrofoam board using a needle and tilted at about 45 degrees. After abdominal incision, the left lateral lobe of the liver was exposed. And to prevent absorption of blood other than that of the wound site, 5 ⁇ 5 cm 2 of parafilm was placed under the liver lobe. The wound was made in the middle of the lobe using a 4 mm biopsy punch. Free bleeding was allowed for 5 seconds. During heavy bleeding, a TMC solution was applied to the left liver lobe and a filter paper was placed under the liver. The filter paper was changed every 60 seconds and the wet filter paper was immediately weighed to determine the total amount of bleeding and clotting time. Acute hemostatic bleeding was defined as cessation of bleeding prior to 5 minutes.

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Abstract

La présente invention concerne une composition hémostatique comprenant du N,N,N-triméthyl-chitosane et de la povidone iodée. Étant donné que la composition hémostatique de la présente invention comprend en même temps du N,N,N-triméthyl-chitosane et de la povidone iodée, la composition hémostatique peut présenter des performances hémostatiques en raison de la charge positive du N,N,N-triméthyl-chitosane et présente en même temps des performances de stérilisation dues à la povidone iodée. De plus, dans la mesure où le N,N,N-triméthyl-chitosane et la povidone iodée forment un complexe ionique sur la base de la charge négative de l'iode, il est possible de réguler la vitesse de libération d'iode dans la composition hémostatique sous une forme stable.
PCT/KR2021/018035 2020-12-04 2021-12-01 Composition antioxydante comprenant un nouveau composé WO2022119322A1 (fr)

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