WO2009055312A1 - Procédé de fabrication d'un gel de poloxamère - Google Patents

Procédé de fabrication d'un gel de poloxamère Download PDF

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Publication number
WO2009055312A1
WO2009055312A1 PCT/US2008/080310 US2008080310W WO2009055312A1 WO 2009055312 A1 WO2009055312 A1 WO 2009055312A1 US 2008080310 W US2008080310 W US 2008080310W WO 2009055312 A1 WO2009055312 A1 WO 2009055312A1
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WO
WIPO (PCT)
Prior art keywords
poloxamer
water
gels
gel
added
Prior art date
Application number
PCT/US2008/080310
Other languages
English (en)
Inventor
David N. Jaeger
Original Assignee
Dfb Pharmaceuticals, Inc.
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 Dfb Pharmaceuticals, Inc. filed Critical Dfb Pharmaceuticals, Inc.
Publication of WO2009055312A1 publication Critical patent/WO2009055312A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L71/00—Compositions of polyethers obtained by reactions forming an ether link in the main chain; Compositions of derivatives of such polymers
    • C08L71/02—Polyalkylene oxides
    • 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
    • A61L15/60—Liquid-swellable gel-forming materials, e.g. super-absorbents
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G2650/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
    • C08G2650/28—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule characterised by the polymer type
    • C08G2650/58—Ethylene oxide or propylene oxide copolymers, e.g. pluronics
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L2203/00—Applications
    • C08L2203/02—Applications for biomedical use

Definitions

  • the present invention relates generally to methods of producing poloxamer gels.
  • the invention is directed to a process of producing pharmaceutically acceptable aqueous-based poloxamer gels in a cost efficient manner.
  • gels are particularly useful for topical delivery of pharmaceutical active ingredients.
  • Aqueous poloxamer gels comprise at a minimum water and poloxamer. Many other ingredients are commonly added to the gels including pharmaceutical active ingredients, cosmetic ingredients, surfactants, humectants, moisturizers, emollients, preservatives, antioxidants, buffers, rheology modifiers, colorants, and fragrances.
  • the poloxamers used to make these gels are typically in solid form as a flake or granule (i.e. prilled).
  • Aqueous poloxamer gels are generally temperature sensitive, i.e. the gel can be in a liquid flowable state or a semi-solid state (gel) depending on the temperature.
  • Temperature sensitive gels can be thermoreversible or thermo-irreversible.
  • Temperature sensitive gels can be formulated to remain in a liquid state during processing at cold temperatures, e.g. 0 0 C - 15 0 C and change into a semi-solid when the formulation warms to room temperature, e.g. 20 0 C - 25 0 C, or above.
  • Some gels can be formulated to change to a semi-solid when the formulation reaches body temperature, e.g. 37 0 C.
  • aqueous poloxamer gels Two manufacturing processes for aqueous poloxamer gels are known in the art and are commonly used to produce these gels ("Technical Data on PLURONIC® Polyols", BASF Wyandotte Corporation, herein incorporated by reference).
  • One method is known as the “hot” process in which water and solid (flaked or granular) poloxamer are mixed and then heated to about 80 0 C allowing the poloxamer to melt into the hot water. The formulation is subsequently cooled to room temperature allowing a gel to form.
  • a disadvantage of the "hot” process is that the entire batch must be heated, thus a large amount of energy is required for heating and subsequent cooling.
  • the other method is known as the "cold" process in which water and solid (flaked or granular) poloxamer are mixed in cold water, e.g. from 5 0 C - 10 0 C. Mixing continues at that temperature until the poloxamer is completely dissolved. In this process, the poloxamer and water mixture remains liquid below the gel point until the temperature raises to room temperature or above, at which time the solution changes to a gel.
  • the disadvantage of this process is that the dissolution of the solid poloxamer in water at cold temperatures is extremely difficult resulting in long processing times. In some cases, processing times can be several hours or even days making this a very inefficient process requiring large amounts of energy to maintain the cold temperatures and long mixing times.
  • the present invention is directed to a process of efficiently producing an aqueous poloxamer gel with minimal energy.
  • the process comprises pre -melting the poloxamer in a separate vessel and then mixing the molten poloxamer with cold water and maintaining the resulting mixture at the cold temperature until the poloxamer is dissolved.
  • the molten poloxamer may be added to the water or the water may be added to the molten poloxamer.
  • the resulting solution is subsequently warmed to its gel point such as room temperature.
  • the molten poloxamer dissolves more rapidly in the water than the flaked or granular poloxamers as in the "cold” process, so process times are reduced resulting in a more efficient process.
  • This process is surprisingly efficient when used to make gels with high concentrations of poloxamer, i.e. greater than about 45% w/w. Additionally, it is not required to heat the entire batch of the poloxamer and water mixture as in the "hot” process, but only the poloxamer itself, therefore less mass is subjected to heating which results in less energy being expended for heating.
  • a "cold temperature” in various embodiments is a temperature from about 0
  • the term "about” is used to indicate that a value includes the inherent variation of error for the device obtaining the value, the method being employed to determine the value, or the variation that exists among the objects being evaluated.
  • the words “comprising” (and any form of comprising, such as “comprise” and “comprises”), “having” (and any form of having, such as “have” and “has”), "including” (and any form of including, such as “includes” and “include”) or “containing” (and any form of containing, such as “contains” and “contain”) are inclusive or open-ended and do not exclude additional, unrecited elements or method steps.
  • One aspect of the present invention provides for a manufacturing process for producing an aqueous poloxamer gel.
  • the process comprises pre-melting the poloxamer in a separate vessel and then mixing the molten poloxamer with cold water and maintaining the resulting mixture at the cold temperature until the poloxamer is dissolved.
  • the molten poloxamer is added to the water.
  • the water is added to the molten poloxamer. The resulting solution of poloxamer and water is subsequently warmed to the gel point or above.
  • the process of the present invention can be used to produce several types of aqueous poloxamer gels including temperature sensitive (i.e. thermoreversible or thermo-irreversible) and non-temperature sensitive gels.
  • the process produces gels with depressed congealing points whereby ingredients suspended in the gels do not settle out during storage even at very low temperatures.
  • the gels comprise poloxamer and water.
  • the gels can also include additional ingredients.
  • additional ingredients are pharmaceutical active ingredients, cosmetic ingredients, humectants, moisturizers, emollients, preservatives, antioxidants, buffers, colorants, and fragrances. Additional ingredients may be added at various times in the process.
  • an additional ingredient could be added to the cold water or to the molten poloxamer prior to mixing, or to the resulting poloxamer/water solution, or even to the resulting gel after the poloxamer/water solution has risen to its gel point (e.g. room temperature).
  • gel point e.g. room temperature
  • Different additional ingredients of a given formulation may be added at different times throughout the process.
  • the poloxamer can be melted in a jacketed vessel, such as a kettle or tank, by passing steam or hot water (above the melting point of the poloxamer) through the vessel jacket.
  • a jacketed vessel such as a kettle or tank
  • Mixers known in the art e.g., COWLES dissolvers, LIGHTNIN mixers, or SILVERSON homogenizers, can be used to mix the molten poloxamer with the cold water in a jacketed vessel.
  • a LEE TRI-MIX Turbo-Shear Mixer which includes a high shear homogenizer and a low shear side-scraping mixer integrated in one jacketed vessel, can also be used.
  • the cold temperature can be attained and maintained by passing water or a cooling fluid such as DOWTHERM through a refrigeration system and then through the vessel jacket.
  • the poloxamer and water solution can be warmed to its congealing point using room temperature water or allowing the batch to stand at room temperature.
  • the gels can be made in vacuum conditions, at atmospheric pressure, or at pressures greater than atmospheric.
  • Various batch sizes can be employed typically ranging from 3 Liters to 3400 Liters depending on the vessel/mixer size.
  • Laboratory size batches e.g. 100 grams to 2000 grams
  • Steam baths or hot water baths can be used for heating and ice baths can be used for cooling.
  • aqueous poloxamer gels made by the process of the present invention comprise poloxamer and water.
  • Poloxamers are water-soluble block copolymers of propylene oxide and ethylene oxide. Poloxamers are represented by the following chemical formula:
  • a and b represent whole integers. Generally a is from 2 to 150 and b is from 15 to 70 depending on the particular poloxamer. Poloxamers are generally known as being non-toxic and non-irritating.
  • the poloxamers used to make aqueous poloxamer gels are in solid form at room temperature, typically as a flake or granule (i.e. prilled). Depending on the particular poloxamer, the melting point is from about 48 0 C to about 57 0 C, and the molecular weight is from about 5000 to 14,000.
  • a is generally from 46 to 128 and b is generally from 16 to 67 in the chemical formula above.
  • polyxamer will refer to poloxamers that are in solid form at room temperature unless otherwise specified.
  • the poloxamers can be pharmaceutical grade (i.e. NF grade) or non- pharmaceutical grade.
  • Examples of pharmaceutical grade poloxamers that can be used to make aqueous poloxamer gels are poloxamer 407, poloxamer 338, and poloxamer 188, available commercially from the BASF Corporation under the tradenames PLURONIC F 127, PLURONIC F 108, and PLURONIC F 68 respectively. These tradenames are synonymous with the tradenames PLURACARE F 127, PLURACARE F 108, and PLURACARE F 68; and also LUTROL F 127, LUTROL F 108 and LUTROL F 68 all from the BASF Corporation.
  • Non- pharmaceutical grade poloxamers would generally be cosmetic or technical grades such as poloxamer 108, poloxamer 217, poloxamer 237, poloxamer 238, and poloxamer 288, also available commercially from the BASF Corporation under the tradenames PLURONIC F 38, PLURONIC F 77, PLURONIC F 87, PLURONIC F 88, and PLURONIC F 98 respectively. Poloxamers are also commercially available from the Uniqema Corporation under the trademark S YNPERONIC.
  • the concentration of poloxamer in a gel formulation ranges from about 5% w/w to about 60% w/w. In other embodiments, the concentration of poloxamer in a gel formulation ranges from about 45% w/w to about 55% w/w.
  • the aqueous poloxamer gels can contain additional formulation ingredients.
  • additional ingredients that can be included in the aqueous poloxamer gels are pharmaceutical active ingredients, cosmetic ingredients, surfactants, humectants, moisturizers, emollients, preservatives, antioxidants, buffers, rheology modifiers, colorants, and fragrances.
  • Non-limiting examples of pharmaceutical active ingredients include anti-acne agents (including those for the treatment of rosacea), analgesics, anesthetics, anorectals, antihistamines, anti-inflammatory agents including non-steroidal antiinflammatory drugs, antibiotics, antifungals, antimitotics, antivirals, antimicrobials, anti-cancer actives, scabicides, pediculicides, antineoplastics, antiperspirants, antipruritics, antipsoriatic agents (including anthralin), antiseborrheic agents, biologically active proteins and peptides, burn treatment agents (including silver sulfadiazine), cancer treatment agents, cauterizing agents, depigmenting agents, diaper rash treatment agents, enzymes, hair growth stimulants, hemostatics, kerotolytics, canker sore treatment agents, cold sore treatment agents, dental and periodontal treatment agents, photosensitizing actives, skin protectant/barrier agents, steroids including hormones and corticosteroids
  • fragrances e.g. Blue 1, Blue 1 Lake, Red 40, and titanium dioxide
  • antioxidants e.g. BHT and tocopherol
  • chelating agents e.g. disodium EDTA and tetrasodium EDTA
  • preservatives e.g. methylparaben, propylparaben, and phenoxyethanol
  • pH adjusters e.g. sodium hydroxide, triethanolamine, phosphoric acid, and citric acid
  • buffers e.g.
  • absorbents e.g. aluminum starch octenylsuccinate, kaolin, corn starch, oat starch, cyclodextrin, talc, and zeolite
  • skin bleaching and lightening agents e.g., hydroquinone and niacinamide lactate
  • humectants e.g. glycerin, propylene glycol, butylene glycol, pentylene glycol, sorbitol, urea, and manitol
  • emollients e.g. mineral oil, petrolatum, isopropyl myristate, cyclomethicone, and vegetable oil
  • exfoliants e.g.
  • alpha-hydroxyacids, and beta-hydroxyacids such as lactic acid, glycolic acid, and salicylic acid; and salts thereof) waterproofing agents (e.g. magnesium/aluminum hydroxide stearate), skin conditioning/moisturizing agents (e.g. aloe extracts, allantoin, bisabolol, ceramides, dimethicone, hyaluronic acid, and dipotassium glycyrrhizate), surfactants (e.g. ethoxylated alcohol, ethoxylated fatty esters and oils, quaternary surfactants, and sulfates of alcohols), and rheology modifiers (e.g. sodium polyacrylates, carbomers, natural gums, natural gum derivatives, clays, modified clays, cellulose, microcrystalline cellulose, cellulose derivatives, magnesium aluminum silicates, gellan gums, xanthan gums, starches and modified starches).
  • waterproofing agents e.g.
  • Additional ingredients may be incorporated into the aqueous poloxamer gel pursuant to various methods, including methods known in the art, depending on the characteristics of the additional ingredient to be added.
  • additional agents may be combined with poloxamer prior to or following heating the poloxamer to a molten state, and prior to mixing the poloxamer with a cold aqueous solution.
  • the agent may be incorporated with an aqueous solution prior to its combination with molten poloxamer.
  • the agent could also be incorporated with the aqueous poloxamer gel after the aqueous poloxamer gel has been formulated.
  • aqueous poloxamer gels are particularly suitable as wound and burn dressings.
  • Aqueous poloxamer gels containing silver sulfadiazine as a pharmaceutical active ingredient are particularly suited as wound or burn treatments. Such a treatment is exemplified below.
  • Example 1 Purified Water 55.0 grams The composition of Example 1 was prepared by heating the Poloxamer 188 to approximately 70 0 C in beaker using a hot water bath. The molten poloxamer was slowly added to cold Purified Water while mixing with a laboratory mixer with a COWLES-type dissolver blade and was mixed for about an hour while in an ice bath until dissolved. The resulting solution was allowed to reach room temperature. A gel was formed.
  • Example 2 The composition of Example 2 was prepared by heating the Poloxamer 188 in beaker using a hot water bath until molten. Phenoxyethanol was added to the Citrate/Phosphate Buffer Solution in a beaker and mixed with a laboratory mixer with a COWLES-type dissolver blade at 390 RPM until dissolved. The Silver Sulfadiazine was added to the Buffer Solution and mixed at 390 RPM until dissolved. The resulting Buffer Solution was cooled to 0 - 5 0 C using an ice bath.
  • the molten Poloxamer 188 was slowly added to the cold Buffer Solution while mixing with a laboratory mixer with a COWLES-type dissolver blade for approximately 1 hour at 780 RPM until dissolved while maintaining a temperature of 0 - 5 0 C using an ice bath. The batch was removed from the ice bath and allowed to reach room temperature while continuing to mix at 600 RPM. A gel was formed.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Medicinal Chemistry (AREA)
  • Polymers & Plastics (AREA)
  • Organic Chemistry (AREA)
  • Dispersion Chemistry (AREA)
  • Hematology (AREA)
  • Engineering & Computer Science (AREA)
  • Materials Engineering (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Preparation (AREA)
  • Cosmetics (AREA)

Abstract

La présente invention porte sur un procédé permettant de fabriquer de façon rentable des gels de poloxamère aqueux pharmaceutiquement acceptables. Le procédé implique la préfusion du poloxamère avant mélange avec de l'eau froide.
PCT/US2008/080310 2007-10-22 2008-10-17 Procédé de fabrication d'un gel de poloxamère WO2009055312A1 (fr)

Applications Claiming Priority (2)

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US98167007P 2007-10-22 2007-10-22
US60/981,670 2007-10-22

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Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013012725A1 (fr) * 2011-07-15 2013-01-24 Innovations In Wound Care, Llc Compositions cicatrisant les plaies et méthodes associées
JP2013505231A (ja) * 2009-09-22 2013-02-14 ヴイライフ サイエンシズ テクノロジーズ プライベート リミテッド 糖尿病性足潰瘍用の局所用製剤
WO2016081714A1 (fr) * 2014-11-20 2016-05-26 Broda Tech, Llc Complexes supramoléculaires hydrosolubles
US20160324971A1 (en) * 2014-01-20 2016-11-10 Ahmet Kilic Formulation for topical wound treatment
US20170009015A1 (en) * 2014-03-25 2017-01-12 Genentech, Inc. Methods of preparing a poloxamer for use in cell culture medium
US20180021435A1 (en) * 2015-01-27 2018-01-25 The Johns Hopkins University Hypotonic hydrogel formulations for enhanced transport of active agents at mucosal surfaces
US9937254B2 (en) 2011-03-21 2018-04-10 Broda Technologies Co., Ltd. Water-soluble supramolecular complexes
EP3247364A4 (fr) * 2015-01-20 2018-10-24 Plurogen Therapeutics, LLC Compositions et méthodes de traitement des microbes
US10568975B2 (en) 2013-02-05 2020-02-25 The Johns Hopkins University Nanoparticles for magnetic resonance imaging tracking and methods of making and using thereof
CN115353726A (zh) * 2022-05-16 2022-11-18 浙江大学 支持浴材料及其制备方法和组合
US12005089B2 (en) 2014-12-15 2024-06-11 The Johns Hopkins University CVS transplantation for treatment of bacterial vaginosis

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US6203809B1 (en) * 1995-05-15 2001-03-20 Rosemarie Nichols Smear-resistant cosmetic
US6413537B1 (en) * 2000-03-10 2002-07-02 Wisconsin Alumni Research Foundation Nystatin formulation having reduced toxicity
WO2005002542A2 (fr) * 2003-03-03 2005-01-13 Elan Pharma International Ltd. Formulations de meloxicane nanoparticulaires
WO2007010076A1 (fr) * 2005-07-15 2007-01-25 Consejo Superior De Investigaciones Científicas Systeme capteur de carbure de silicium semi-isolant, procede de fabrication et ses applications

Patent Citations (5)

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Publication number Priority date Publication date Assignee Title
US6203809B1 (en) * 1995-05-15 2001-03-20 Rosemarie Nichols Smear-resistant cosmetic
US5702717A (en) * 1995-10-25 1997-12-30 Macromed, Inc. Thermosensitive biodegradable polymers based on poly(ether-ester)block copolymers
US6413537B1 (en) * 2000-03-10 2002-07-02 Wisconsin Alumni Research Foundation Nystatin formulation having reduced toxicity
WO2005002542A2 (fr) * 2003-03-03 2005-01-13 Elan Pharma International Ltd. Formulations de meloxicane nanoparticulaires
WO2007010076A1 (fr) * 2005-07-15 2007-01-25 Consejo Superior De Investigaciones Científicas Systeme capteur de carbure de silicium semi-isolant, procede de fabrication et ses applications

Cited By (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2013505231A (ja) * 2009-09-22 2013-02-14 ヴイライフ サイエンシズ テクノロジーズ プライベート リミテッド 糖尿病性足潰瘍用の局所用製剤
US9937254B2 (en) 2011-03-21 2018-04-10 Broda Technologies Co., Ltd. Water-soluble supramolecular complexes
WO2013012725A1 (fr) * 2011-07-15 2013-01-24 Innovations In Wound Care, Llc Compositions cicatrisant les plaies et méthodes associées
US10568975B2 (en) 2013-02-05 2020-02-25 The Johns Hopkins University Nanoparticles for magnetic resonance imaging tracking and methods of making and using thereof
US20160324971A1 (en) * 2014-01-20 2016-11-10 Ahmet Kilic Formulation for topical wound treatment
RU2653488C2 (ru) * 2014-01-20 2018-05-08 Ахмет КИЛИДЖ Композиция для местного лечения ран
US10568966B2 (en) * 2014-01-20 2020-02-25 Ahmet Kilic Formulation for topical wound treatment
US11633350B2 (en) 2014-02-23 2023-04-25 The Johns Hopkins University Hypotonic microbicidal formulations and methods of use
US11912823B2 (en) 2014-03-25 2024-02-27 Genentech, Inc. Methods of preparing a poloxamer for use in cell culture medium
US20170009015A1 (en) * 2014-03-25 2017-01-12 Genentech, Inc. Methods of preparing a poloxamer for use in cell culture medium
US11034793B2 (en) * 2014-03-25 2021-06-15 Genentech, Inc. Methods of preparing a poloxamer for use in cell culture medium
CN107108905A (zh) * 2014-11-20 2017-08-29 博任达生化科技有限公司 水溶性超分子复合物
JP2021050337A (ja) * 2014-11-20 2021-04-01 ブローダ・テクノロジーズ・カンパニー・リミテッドＢｒｏｄａ Ｔｅｃｈｎｏｌｏｇｉｅｓ Ｃｏ．， Ｌｔｄ． 水溶性超分子複合体
JP7369683B2 (ja) 2014-11-20 2023-10-26 ブローダ・テクノロジーズ・カンパニー・リミテッド 水溶性超分子複合体
WO2016081714A1 (fr) * 2014-11-20 2016-05-26 Broda Tech, Llc Complexes supramoléculaires hydrosolubles
US12005089B2 (en) 2014-12-15 2024-06-11 The Johns Hopkins University CVS transplantation for treatment of bacterial vaginosis
US10456416B2 (en) 2015-01-20 2019-10-29 Plurogen Therapeutics, Llc Compositions and methods of treating microbes
EP3247364A4 (fr) * 2015-01-20 2018-10-24 Plurogen Therapeutics, LLC Compositions et méthodes de traitement des microbes
US10485757B2 (en) * 2015-01-27 2019-11-26 The Johns Hopkins University Hypotonic hydrogel formulations for enhanced transport of active agents at mucosal surfaces
US11426345B2 (en) 2015-01-27 2022-08-30 The Johns Hopkins University Hypotonic hydrogel formulations for enhanced transport of active agents at mucosal surfaces
US20180021435A1 (en) * 2015-01-27 2018-01-25 The Johns Hopkins University Hypotonic hydrogel formulations for enhanced transport of active agents at mucosal surfaces
CN115353726A (zh) * 2022-05-16 2022-11-18 浙江大学 支持浴材料及其制备方法和组合
CN115353726B (zh) * 2022-05-16 2023-08-08 浙江大学 支持浴材料及其制备方法和组合

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