EP3996748A2 - Hydrogels intelligents sensibles à la température à propriété antifongique réalisant une libération contrôlée de médicament - Google Patents

Hydrogels intelligents sensibles à la température à propriété antifongique réalisant une libération contrôlée de médicament

Info

Publication number
EP3996748A2
EP3996748A2 EP20836170.9A EP20836170A EP3996748A2 EP 3996748 A2 EP3996748 A2 EP 3996748A2 EP 20836170 A EP20836170 A EP 20836170A EP 3996748 A2 EP3996748 A2 EP 3996748A2
Authority
EP
European Patent Office
Prior art keywords
range
solution
acid
antifungal
process step
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP20836170.9A
Other languages
German (de)
English (en)
Other versions
EP3996748A4 (fr
Inventor
Bahar KANCI BOZOGLAN
Sibel TUNC
Osman Duman
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Akdeniz Univ
Akdeniz Universitesi
Original Assignee
Akdeniz Univ
Akdeniz Universitesi
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 Akdeniz Univ, Akdeniz Universitesi filed Critical Akdeniz Univ
Publication of EP3996748A2 publication Critical patent/EP3996748A2/fr
Publication of EP3996748A4 publication Critical patent/EP3996748A4/fr
Pending legal-status Critical Current

Links

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
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4174—Arylalkylimidazoles, e.g. oxymetazolin, naphazoline, miconazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • A61K47/02—Inorganic 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • 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
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders

Definitions

  • the present invention relates to temperature-sensitive smart hydrogels that have antifungal property and perform controlled drug release.
  • Smart hydrogels were developed to be used in the treatment of nail fungus.
  • the inventive hydrogel formula comprises at least one natural polymer (polysaccharide and/or protein) additive, at least one inorganic or organic additive, and an active pharmaceutical ingredient with antifungal property.
  • the antifungal drug in hydrogel formulation is released in a controlled manner, and this not only shortens the treatment period but also reduces the amount of the drug administered since the necessity for regularly administering drugs to the fungal infection area is eliminated.
  • Nail fungus is a type of nail infection caused by dermatophytes, yeast, and molds. Treatment of nail fungus involves removing the infected nail through chemical or surgical interventions, systemic or topical drug use, or a combination of these [1]. Oral and topical treatment methods are usually preferred for the treatment of the disease. Available topical treatment methods include lacquer, spray and cream administrations, and commercially available topical products mainly comprise of various chemical agents such as; methyl vinyl ether, maleic acid monobutyl ester copolymer, ethyl acetate, and 2-propanol.
  • Another method that is frequently implemented for the treatment of the disease is systemic drug administration through the oral route.
  • recurrence of the disease and being unable to administer a full treatment are among the frequently encountered cases in treatment methods implemented via the oral route.
  • oral treatment is not suitable for many patients due to potential adverse effects [2].
  • griseofulvin fungicide was administered to patients at a dose of 990 mg for a duration of 78 weeks. Only 6% of patients were reported to make a full recovery at the end of the treatment period, and a number of patients with nail fungus failed to complete the treatment due to adverse effects of the drug. It was further reported that the disease recurred in a number of patients after the treatment period was completed [3].
  • nail lacquers prepared with ciclopirox and amorolfine active ingredients were also reported to be successful in practice in the treatment of nail fungus.
  • These nail lacquers are usually prepared with 2-n-nonyl-1 ,3-dioxolan or similar water- insoluble agents with film-forming capabilities, plasticizers, and a volatile solvent.
  • patients who were administered ciclopirox lacquer were observed to suffer from adverse effects including redness, and a rash around nail folds, nail malformation, irritation, ingrown toenails, and discoloration [4, 5].
  • the duration of treatment administered with topical nail lacquers containing amorolfine active ingredient is approximately 6 months for hand nails, while for toenails this period may last for approximately 9-12 months. Prolonged treatment periods and complaints such as pruritus, pain, and stinging around the nail bed are among the disadvantages of nail lacquer products containing amorolfine [5].
  • WO 2010/109418 A1 which is another patent application in the state of the art, relates to a chitosan-based biopolymer that cures fungal skin infections.
  • the aforementioned application discloses a cream comprising; chitosan, active pharmacological compound, emulsifying compounds, beeswax, acid, preservative agents, buffering agents, antioxidants, chelating agents, and moisturizers.
  • Treatments administered via oral route in the state of the art take prolonged periods of time and force patients to suffer various adverse effects including headaches, gastrointestinal disorders (diarrhea and/or dyspepsia), rash, high liver enzyme values, and drug interactions.
  • Topical cream administration does not provide any practicality of use for patients.
  • the present invention relates to a smart hydrogel formulation with antifungal property, as well as the preparation method thereof, that is developed to be used in the treatment of nail fungus, and that eliminates the disadvantages present in the state of the art.
  • the present invention discloses a smart hydrogel formulation with antifungal property, wherein the formulation comprises of at least one natural polymer (polysaccharide and/or protein), at least one inorganic and organic additive, and an active pharmaceutical ingredient with antifungal property.
  • the formulation comprises of at least one natural polymer (polysaccharide and/or protein), at least one inorganic and organic additive, and an active pharmaceutical ingredient with antifungal property.
  • An object of the present invention is to develop a biocompatible and biodegradable hydrogel formula for the treatment of nail fungus.
  • Another object of the present invention is to provide a hydrogel with antifungal property that does not show any toxic effects, thereby preventing the patient from suffering any adverse effects throughout the treatment period of nail fungus.
  • Another object of the present invention is to develop a hydrogel formula with antifungal property, that maintains its liquid form under room conditions, but transforms into gel form once it reaches to skin temperature value (32 °C) when it is administered to nail surface.
  • This particular characteristic of the inventive hydrogel formula provides ease of use for patients.
  • the inventive hydrogel formula also performs controlled drug release. This feature eliminates the necessity for regularly administering the drug to the fungal infection area, thereby shortening the treatment period and reducing the amount of drug administered.
  • Figure 1 illustrates the elastic modulus (G') and viscous modulus (G") graphs as a function of temperature for hydrogel sample without additive.
  • Figure 2 illustrates the elastic modulus (G') and viscous modulus (G") graphs as a function of temperature for hydrogel sample containing additive of 5%.
  • Figure 3 illustrates the SEM images of hydrogel systems containing additive of 0% and 5%.
  • Figure 4 illustrates the TGA graphs of hydrogel systems containing additive of 0% and 5%.
  • Figure 5 illustrates the DSC graphs of hydrogel systems containing additive of 0% and 5%.
  • Figure 6 illustrates the transmittance versus wavelength graphs of hydrogels containing additive of 0% and 5%.
  • Figure 7 illustrates the compression stress versus compression strain graphs of hydrogels containing additive of 0% and 5%.
  • Figure 8 illustrates the variation of released drug amount as a function of time from new prepared hydrogels including active drug and containing additive of 0% and
  • Figure 9 illustrates the variation of released drug amount as a function of time from hydrogels including antifungal drug and containing additive of 0% and 5% after hydrogels were stored at +4°C for 3 months.
  • Figure 10 illustrates the variation of released drug amount as a function of time from hydrogels including antifungal drug and containing additive of 0% and 5% after hydrogels were stored at +4°C for 6 months.
  • the present invention relates to temperature-sensitive smart hydrogels with antifungal property that perform controlled drug release and the preparation method thereof.
  • the inventive smart hydrogel comprises chitosan, and apart from that, it contains; at least one natural polymer, at least one inorganic or organic additive, and at least one active pharmaceutical ingredient with antifungal effect.
  • chitosan collagen, starch, gelatin, dextran, actine, agar, alginate, chitin, keratin, cellulose, guar gum, carrageenan, gellan gum, scleroglucan, cyclodextrin, xanthan gum, pectin, inulin, hyaluronic acid, glucomannan and/or hyaluronan and/or at least one derivative thereof or a combination thereof may be used in the present invention.
  • kaolinite, halloysite, vemniculite, saponite, nontronite, disodium hydrogen phosphate (Na 2 HPO 4 ), sodium bicarbonate (NaHCO 3 ), sodium dihydrogen phosphate (Na 2 HPO 4 ), illite, montmorillonite, chlorite, attapulgite, sepiolite, bentonite, zeolite, fumed silica, starch, modified starch or talc and/or carbonate, b- glycerophosphate, benzoate, acetate, phosphate, malate, lactate, succinate, acrylate and at least one of sodium (Na) and/or potassium (K) and/or calcium (Ca) salts of sulfate or a combination thereof may be used in the present invention.
  • any one of active pharmaceutical ingredient/ingredients and/or salts with antifungal property such as; fluconazole, itraconazole, griseofulvin, ketoconazole, clotrimazole, oxiconazole, miconazole, and econazole or a combination thereof may be used as an active pharmaceutical ingredient with antifungal property in the present invention.
  • Method for preparing the inventive hydrogels with antifungal property comprises the process steps of; i. preparing chitosan or chitosan salt solution in a range between 0.1 % - 8.0% by weight/volume (w/v) inside hydrochloric acid, acetic acid, succinic acid, sulfuric acid, oxalic acid or phosphoric acid or purified water within a range of 0.02 M - 2.0
  • preparing the inventive hydrogels with antifungal property comprises the process steps of; i. preparing chitosan or chitosan salt solution in a range between 0.5% - 4.0% by weight/volume (w/v) inside hydrochloric acid, acetic acid, succinic acid, sulfuric acid, oxalic acid or phosphoric acid or purified water within a range of 0.05 M - 1.0
  • iV adjusting the pH value of the mixture to a value in a range between 5 - 9 by adding acid, base or salt solution in a range between 0.01 M - 1.0 M,
  • the acid used in the present invention is selected from; hydrochloric acid, acetic acid, succinic acid, sulfuric acid, oxalic acid, or phosphoric acid.
  • the base used in the present invention is selected from; sodium hydroxide, ammonia, or sodium carbonate.
  • the present invention comprises; acetone, acetonitrile, benzene, diethyl ether, dimethylformamide, dimethyl sulfoxide, ethyl alcohol, ethyl acetate, heptane, hexane, chloroform, xylene, petroleum ether, methyl alcohol, carbon tetrachloride or toluene.
  • the inventive smart hydrogel is in liquid form under room conditions and transforms into gel form once its temperature reaches 32 °C which is the external skin temperature.
  • Smart hydrogels are obtained in liquid form by means of the inventive method, and these smart hydrogels convert into gel form through body temperature once they are applied to the surface of the skin.
  • the inventive hydrogel comprises; chitosan at a rate of at least 15% and at least one natural polymer, one inorganic or organic additive at a rate of at least 3% and active pharmaceutical ingredient with antifungal property at a rate of at least 0.1 %.
  • Elastic modulus (G') and viscous modulus (G") values of the inventive hydrogel samples were obtained via rheologic analyses. Measuring operations were performed by gradually increasing the temperature from 20.0 °C to 60.0 °C. Gelling temperatures of hydrogel systems were determined from the results of rheological analysis, and corresponding graphs for smart hydrogels containing additive of 0% and 5% are illustrated in Figure 1 and Figure 2, respectively. Gelling temperature values observed in said graphs were determined to be in a range between 32.0 °C - 25.3 °C for systems that contain additive and for systems that do not.
  • TGA Thermal gravimetric analysis
  • T g values of hydrogels containing additive of 0% and 5% were determined to be 63.7 °C and 76.8 °C, respectively. It should be noted that an increase in the amount of additive present in the hydrogel matrix also increases the T g values.
  • Transmittance (%) values were measured at a wavelength range between 300 - 800 nm by using a UV-Vis spectrophotometry ( Figure 6) in order to calculate the opacity (O) values of hydrogels, and accordingly, the opacity values of hydrogels were calculated by using the equation provided below.
  • Cylindrical hydrogel samples with the same dimensions were prepared in order to perform the mechanical resistance tests of hydrogels with and without additives. Subsequently, the samples were subjected to a compression test with a velocity of 1 mm/min by using a load cell of 500 N. The compression test results did not reveal any physical deformation or breakage (fragmentation) on hydrogel samples. Hydrogel sample containing additive of 5% was observed to revert to its original shape by a rate of 61.5%, and this measurement for the hydrogel sample that does not contain any additives was determined to be 46.2% once the physical force was removed. This result shows that the hydrogel sample that contained additive managed to preserve its elasticity better against the force applied thereto when compared to the hydrogel sample that did not contain any additives.
  • Hydrogel samples containing active pharmaceutical ingredients were dried in a vacuum oven in order to examine the drug release activity of smart hydrogels.
  • Dried hydrogel samples were placed into buffer solution at physiological pH and at 32 °C which is the external skin temperature and subjected to release tests by being agitated at 32 °C and 60 rpm via a temperature-controlled water bath with agitation.
  • increasing the amount of additive in the hydrogel matrix significantly reduces the antifungal drug release.
  • percentage drug release amounts were determined as 70.33 ⁇ 1.74 for the system that did not contain additive and 52.89 ⁇ 0.21 for the system that contained additive of 5%. It was observed that putting additive into the hydrogel matrix allows for controlling the drug release amounts.
  • Hydrogel samples loaded with active pharmaceutical ingredients with antifungal property were kept at 4 °C for durations of 3 and 6 months in a light- and moisture-proof environment to be able to determine that whether hydrogels loaded with the active pharmaceutical ingredient with antifungal property can preserve the pharmaceutical ingredient contained therein or not.
  • Amounts of drug released from hydrogels were measured via UV-Vis spectrophotometry at the end of preservation periods ( Figure 9 and Figure 10). Percentage drug release amounts for systems containing additive of 0% and 5% were calculated as 66.90 ⁇ 0.90 and 51.5 ⁇ 0.66, respectively, at the end of the 3-month period. Whereas the percentage drug release amounts at the end of the 6-month period were determined as 64.76 ⁇ 0.21 and 51 55 ⁇ 1.02. Hydrogels preserved for 3 and 6 months showed no significant differences from one another in terms of the percentage of drug release amounts.
  • Lyophilized Trichophyton mentagrophytes strain was activated in order to test the antifungal property of hydrogels. Transmittance (%) value of inoculum solution was adjusted to be 70% at 520 nm by using a UV-Vis Spectrophotometry. The solution's spore count was measured with a hemocytometer and determined as 5.0x10 6 spore/mL. The disk diffusion method was employed in order to observe the effect the hydrogels will produce against the fungi to reproduce in the medium. Inoculum solution of Trichophyton mentagrophytes fungus was cultured in the Saboroud medium.
  • hydrogel containing additive of 0%, hydrogel containing additive of 0% and active pharmaceutical ingredient with antifungal property, hydrogel containing additive of 5%, hydrogel containing additive of 5% and active pharmaceutical ingredient with antifungal property and control group samples were prepared and placed inside mediums, and inhibition diameters formed around the gels were measured at the end of the incubation period. Hydrogels that did not contain any active pharmaceutical ingredients did not form any inhibition zones. Whereas the inhibition zones formed by hydrogels that did contain additive of 0% and 5% and active pharmaceutical ingredient with antifungal property were measured as 42 ⁇ 2.65 mm and 42.67 ⁇ 1.5 mm, respectively.
  • Antifungal activity test revealed the fact that hydrogels that contain additive of 0% and 5% and loaded with the active pharmaceutical ingredient with antifungal property are substantially effective against Trichophyton mentagrophytes species in the fungal genus.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Dermatology (AREA)
  • Inorganic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention concerne des hydrogels intelligents sensibles à la température qui présentent une propriété antifongique et réalisent une libération contrôlée de médicament. Des hydrogels intelligents ont été mis au point pour être utilisés dans le traitement de la mycose des ongles. La formule d'hydrogel de l'invention comprend au moins un additif polymère naturel (polysaccharide et/ou protéine), au moins un additif inorganique ou organique, et un principe pharmaceutique actif à propriété antifongique. Le médicament antifongique dans la formulation d'hydrogel est libéré de manière contrôlée, et ceci non seulement raccourcit la période de traitement mais réduit également la quantité du médicament administré puisque le besoin d'administration régulière des médicaments à la zone d'infection fongique est éliminé.
EP20836170.9A 2019-07-09 2020-07-07 Hydrogels intelligents sensibles à la température à propriété antifongique réalisant une libération contrôlée de médicament Pending EP3996748A4 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
TR2019/10214A TR201910214A2 (tr) 2019-07-09 2019-07-09 Kontrollü i̇laç salimi yapan, sicakliğa duyarli anti̇fungal özelli̇kli̇ akilli hi̇drojeller
PCT/TR2020/050592 WO2021006845A2 (fr) 2019-07-09 2020-07-07 Hydrogels intelligents sensibles à la température à propriété antifongique réalisant une libération contrôlée de médicament

Publications (2)

Publication Number Publication Date
EP3996748A2 true EP3996748A2 (fr) 2022-05-18
EP3996748A4 EP3996748A4 (fr) 2023-09-13

Family

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Family Applications (1)

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EP20836170.9A Pending EP3996748A4 (fr) 2019-07-09 2020-07-07 Hydrogels intelligents sensibles à la température à propriété antifongique réalisant une libération contrôlée de médicament

Country Status (3)

Country Link
EP (1) EP3996748A4 (fr)
TR (1) TR201910214A2 (fr)
WO (1) WO2021006845A2 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115160613A (zh) * 2022-08-17 2022-10-11 江苏省农业科学院 一种保鲜水凝膜的制备工艺

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Publication number Priority date Publication date Assignee Title
CN116535541A (zh) * 2023-04-25 2023-08-04 武汉大学 一种温敏性甲基化甲壳素的制备方法及其应用
CN117700777B (zh) * 2024-02-06 2024-04-09 上海瑛泰璞润医疗器械有限公司 一种超声测温凝胶及其制备方法

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Publication number Priority date Publication date Assignee Title
GB0024489D0 (en) 2000-10-06 2000-11-22 Reckitt Benckiser Uk Ltd Improvements in or relating to organic compositions
CN101260191B (zh) * 2008-04-01 2011-04-20 武汉大学 一种温度敏感型壳聚糖/明胶水凝胶及其制备方法和用途
WO2010109418A1 (fr) * 2009-03-25 2010-09-30 Sulur Subramaniam Vanangamudi Crème médicinale antifongique et son procédé de fabrication
ES2371898B2 (es) * 2011-09-29 2012-06-13 Universidade De Santiago De Compostela Nanogeles de ciclodextrina.
CN103524795A (zh) * 2012-07-06 2014-01-22 中国科学院大连化学物理研究所 一种温敏型可注射壳聚糖水凝胶产品及其应用

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115160613A (zh) * 2022-08-17 2022-10-11 江苏省农业科学院 一种保鲜水凝膜的制备工艺

Also Published As

Publication number Publication date
WO2021006845A2 (fr) 2021-01-14
WO2021006845A3 (fr) 2021-03-11
EP3996748A4 (fr) 2023-09-13
TR201910214A2 (tr) 2021-01-21

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Ipc: C08J 3/075 20060101ALI20230810BHEP

Ipc: A61K 47/36 20060101AFI20230810BHEP