WO2020029432A1 - 医用水凝胶 - Google Patents

医用水凝胶 Download PDF

Info

Publication number
WO2020029432A1
WO2020029432A1 PCT/CN2018/111398 CN2018111398W WO2020029432A1 WO 2020029432 A1 WO2020029432 A1 WO 2020029432A1 CN 2018111398 W CN2018111398 W CN 2018111398W WO 2020029432 A1 WO2020029432 A1 WO 2020029432A1
Authority
WO
WIPO (PCT)
Prior art keywords
polyethylene glycol
aldehyde
terminated
solution
medical
Prior art date
Application number
PCT/CN2018/111398
Other languages
English (en)
French (fr)
Inventor
潘震
陈亮
侯森
Original Assignee
上海瑞凝生物科技有限公司
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 上海瑞凝生物科技有限公司 filed Critical 上海瑞凝生物科技有限公司
Priority to US17/267,788 priority Critical patent/US20210162092A1/en
Publication of WO2020029432A1 publication Critical patent/WO2020029432A1/zh

Links

Images

Classifications

    • 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
    • C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
    • C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
    • C08G65/32—Polymers modified by chemical after-treatment
    • C08G65/329—Polymers modified by chemical after-treatment with organic compounds
    • C08G65/331—Polymers modified by chemical after-treatment with organic compounds containing oxygen
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • 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
    • 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
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/001—Use of materials characterised by their function or physical properties
    • A61L24/0031—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
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
    • A61L24/043—Mixtures of macromolecular materials
    • 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
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/04—Macromolecular materials
    • A61L31/041—Mixtures of macromolecular compounds
    • 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
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/145—Hydrogels or hydrocolloids
    • 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
    • C08G12/00—Condensation polymers of aldehydes or ketones with only compounds containing hydrogen attached to nitrogen
    • C08G12/46—Block or graft polymers prepared by polycondensation of aldehydes or ketones on to macromolecular compounds
    • 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
    • A61L2430/00—Materials or treatment for tissue regeneration
    • A61L2430/40—Preparation and treatment of biological tissue for implantation, e.g. decellularisation, cross-linking
    • 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
    • C08G2650/30—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule characterised by the polymer type branched
    • 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
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L77/00—Compositions of polyamides obtained by reactions forming a carboxylic amide link in the main chain; Compositions of derivatives of such polymers
    • C08L77/04—Polyamides derived from alpha-amino carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L79/00—Compositions of macromolecular compounds obtained by reactions forming in the main chain of the macromolecule a linkage containing nitrogen with or without oxygen or carbon only, not provided for in groups C08L61/00 - C08L77/00
    • C08L79/02—Polyamines

Definitions

  • the invention belongs to the technical field of biomedicine, and particularly relates to a medical hydrogel, which can be used in the fields of postoperative tissue sealing and anti-leakage, anti-tissue adhesion, tissue filler, tissue repair, skin dressing, drug release and the like.
  • Hydrogel is a soft material containing a large amount of water obtained by cross-linking hydrophilic polymers. Hydrogels have excellent physical and chemical properties and biological characteristics, such as high water content, high elasticity, softness, and biocompatibility. They have important application value in biomedical research fields such as drug transport and tissue engineering.
  • Injectable hydrogel refers to a type of hydrogel that has certain fluidity and can be applied by injection. It shows a phase transition between sol and gel to external stimuli (temperature, temperature / pH, etc.). Before injection into the human body, it was liquid or semi-solid with shear thinning properties. After injection into the human body, it can be gelled in situ, so no invasive surgery is needed. This effectively avoids the risk of infection and reduces Patient suffering.
  • Various injectable PEG hydrogels that have been developed include amphiphilic polyester / polypeptide hydrogels with PEG as the hydrophilic segment, PEG hydrogels prepared by supramolecular action, and PEG waters prepared by mild chemical reactions gel.
  • Polyethylene glycol is a type of non-ionic polymer. Due to its good biocompatibility and safety, it is applicable to the US Food and Drug Administration (FDA). A class of synthetic polymers in human clinics. PEG can be used as a pharmaceutical excipient, or the drug can be modified (PEGylated) with PEG containing a terminally active functional group. PEGylation technology has many advantages, especially in the modification of protein and peptide drugs: it has the characteristics of extending its circulation time in vivo, enhancing biological activity, avoiding proteolysis and reducing immune response.
  • Polyethylene glycol conjugates can be prepared by linking active terminal functional groups such as amino, thiol, azide, alkynyl, and aldehyde groups to improve the performance of polyethylene glycol.
  • CN105963792A discloses a medical hydrogel composition including a first component and a second component, the first component includes polylysine and polyethyleneimine, and the second component includes four arms- One of polyethylene glycol-succinimide glutarate, four-arm-polyethylene glycol-succinimide succinate, four-arm-polyethylene glycol-succinimide carbonate, or Several.
  • the succinimide organic acid ester-terminated polyethylene glycol material has a short half-life in water and is very easy to hydrolyze. Special techniques are required to store it in the form of powder at room temperature for a long time, and after a short time after dissolution (generally For 1 hour) use, the convenience is low.
  • CN107693838 discloses a medical injectable gel and a method for preparing the same.
  • the polyamino compound solution is sprayed after being mixed through a two-component syringe, and the aldehyde group and the amino group are reacted to form a siffurine base to generate cross-linking to form a medical injectable gel.
  • the aldehyde group in the aldehyde-terminated hyperbranched polymer HP-PEG-CHO is connected to the polymer by an ester bond, and the long-term stability in aqueous solution is low.
  • the molecular weight distribution of the hyperbranched polymer is broad and may contain higher molecular weight. Polymer is not conducive to human discharge.
  • the invention aims at the shortcomings of the prior art, and provides a medical hydrogel based on dobby star polyethylene glycol, which can be stably stored for a long time in an aqueous solution.
  • a medical hydrogel is formed by in-situ cross-linking of a star-shaped multi-arm polyethylene glycol and a polyamino compound terminated with an aldehyde group.
  • the ether bond and amide are formed between the aldehyde group and the star-shaped multi-arm polyethylene glycol. Bonds, urethane bonds, imine bonds, or urea bonds are not easily hydrolyzed.
  • the polyamino compound is selected from one or more of polyethyleneimine and polylysine.
  • the aldehyde-terminated multi-arm polyethylene glycol is a multi-arm polyethylene glycol having a number of arms of not less than 2 and a molecular weight of not less than 2000.
  • the number of arms of the aldehyde-terminated multi-arm polyethylene glycol is 2-8, preferably 8.
  • the aldehyde group is selected from one or more of an aromatic aldehyde and an alkyl aldehyde, and is preferably a benzaldehyde group.
  • Another object of the present invention is to provide application of the medical hydrogel in postoperative tissue sealing and anti-leakage, anti-tissue adhesion, tissue filler, tissue repair, skin dressing, and pharmaceutical preparation.
  • Another object of the present invention is to provide a method for preparing the medical hydrogel.
  • the aldehyde-terminated star-shaped multi-arm polyethylene glycol is dissolved in a pH 4-10 buffer solution, and the aldehyde-terminated star-shaped multi-arm polyethylene is disposed.
  • a diol solution; the polyamino compound is dissolved in a pH 4-10 buffer solution, and the polyamino compound solution is configured; the two are mixed to obtain a medical hydrogel.
  • the aldehyde-terminated star-shaped multi-arm polyethylene glycol used in the present invention can be purchased commercially.
  • the pH 4-10 buffer is preferably a phosphate or borate buffer at pH 4-10.
  • the final concentration of the aldehyde-terminated star-shaped multi-arm polyethylene glycol solution is 2-30% (w / v), preferably 10-20% (w / v); the concentration of the polyamino compound solution is 0.5 -20%, preferably 1-5% (w / v)
  • the ratio of the amount of the aldehyde group in the aldehyde-terminated star-shaped multi-arm polyethylene glycol to the amino substance in the polyamino compound is 0.01-5: 1.
  • a two-component hydrogel is first prepared, which is a first component containing a nucleophilic functional group and a second component containing an electrophilic functional group, and the first component is an aldehyde group-terminated hydrophilic Compounds, in which the number of arms is not less than two, and the hydrophilic compounds are aldehyde-terminated star-shaped multi-arm polyethylene glycols, preferably eight-arm polyethylene glycols (molecular weight 5000-20,000), and the aldehyde groups are One or more of an aromatic aldehyde and an alkyl aldehyde, preferably a benzaldehyde group.
  • the aldehyde group and the polymer may be connected by chemical bonds that are not easily hydrolyzed, such as ether bonds and amide bonds.
  • the second component may be a compound containing a polyamino group, including a mixture of one or more of polylysine (including ⁇ -polylysine and polylysine) and polyethyleneimine. .
  • both of the above components can be provided in the form of aqueous solutions or powders.
  • the two components When used, the two components are separately dissolved in a buffer solution, and then the components are mixed to obtain a hydrogel.
  • the two components of the hydrogel can be separately stored in a double-tube syringe, and the two components are sprayed out through a mixing head or injected into a designated site to form a gel when in use.
  • the invention uses the aldehyde group at the end of the multi-arm polyethylene glycol and the amino group of the polyamino compound to react to form a schiff base, thereby generating cross-linking and forming a medical injectable gel.
  • the prepared gel has a short gelation time, has ideal gel bursting strength, and has good stability in an aqueous solution, and has better application value than existing medical gels.
  • Figure 1 shows the results of the gel-stability investigation of aldehyde-terminated polyethylene glycols with ether, amide, and ester linkages.
  • ether-bonded aldehyde group-terminated 8-arm polyethylene glycol 8-PEG-O-BA 600 mg was dissolved in 2 mL of phosphate buffer solution (pH 7.4) as A solution; Ethyleneimine 1.67% (w / v) phosphate buffer solution as B solution; mixing A, B solutions and other volumes to obtain a viscous hydrogel, gelling time is 22 seconds, gel bursting strength It is 11kPa.
  • amide bond-linked aldehyde group-terminated 4-arm polyethylene glycol 4-PEG-amide-BA was dissolved in 2 mL of phosphate buffer solution (pH 7.4) as a solution A; polyethylene polyethylene was configured Amine 2.2% (w / v) phosphate buffer solution, as B solution; mixing A, B solutions and other volumes to obtain a viscous hydrogel, gelling time is 20 seconds, gel burst strength is 11kPa .
  • ether-bonded aldehyde group-terminated 8-arm polyethylene glycol 8-PEG-O-BA 600 mg was dissolved in 2 mL of phosphate buffer solution (pH 7.4) as A solution; Lysine 2.75% (w / v) phosphate buffer solution as B solution; mixing A, B solutions and other volumes to obtain viscous hydrogel, gelation time is less than 5 minutes, gel bursting strength It is 2kPa.
  • ester-bonded aldehyde group-terminated 8-arm polyethylene glycol 8-PEG-amide-BA 400 mg was dissolved in 2 mL of phosphate buffer solution (pH 7.4) as A solution; polyethylene polyethylene was configured Amine (MW1.8K) 1.48% (w / v) phosphate buffer solution, as B solution; mixing A, B solutions and other volumes to obtain a viscous hydrogel, gel time is 5 seconds, gel The bursting strength is 13 kPa.

Abstract

本发明公开了一种医用水凝胶，由醛基封端的星形多臂聚乙二醇和多氨基化合物原位交联而成，所述醛基与星形多臂聚乙二醇之间以醚键、酰胺键、氨酯键、亚胺键或脲键化学键连接。本发明利用多臂聚乙二醇端部的醛基和多氨基化合物的氨基反应生成schiff碱从而产生交联，形成医用可注射凝胶。所制得的凝胶成胶时间短，具有理想的凝胶胀破强度，并且在水溶液中稳定性好，相较于现有医用凝胶具有更好的应用价值。

Description

医用水凝胶 技术领域
本发明属于生物医药技术领域，具体涉及一种医用水凝胶，可用于术后组织密封与防渗漏、防组织黏连、组织填充剂、组织修复、皮肤敷料和药物释放等领域。
背景技术
水凝胶是一种由亲水性聚合物交联得到的含有大量水分的软材料。水凝胶具有优良的理化性能和生物学特性，如高含水量、高弹性、柔软、具有生物相容性等特点，在药物转运、组织工程等生物医学研究领域有着重要的应用价值。可注射水凝胶是指具有一定流动性的、能够通过注射的方法应用的一类水凝胶，对于外界刺激(温度，温度/pH等变化)呈现出溶胶与凝胶间的相转变，在注射入人体之前呈液态或是具有剪切变稀性质的半固态，在注射入人体内之后能原位成胶，因而不需要侵入性手术，这有效地避免了感染的风险，并减捏了病人的痛苦。目前已发展的各种可注射的PEG水凝胶包括PEG为亲水段的两亲性聚酯/聚肽水凝胶、超分子作用制备的PEG水凝胶以及通过温和化学反应制备的PEG水凝胶。
聚乙二醇(polyethylene glycol，PEG)是一类非离子型聚合物，由于其本身有较好的生物相容性和安全性，是获美国食品和药品管理局(FDA)许可的可应用在人类临床的一类合成聚合物。PEG既可以作为药用辅料，又可以使用含有末端活泼官能团的PEG对药物进行修饰(聚乙二醇化)。聚乙二醇化技术具有较多的优点，尤其是在修饰蛋白和多肽类药物方面:具有延长其体内循环时间、增强生物活性、避免蛋白水解和降低免疫反应的特点。可通过连接活性末端官能团，如氨基、硫醇基、叠氮、炔基和醛基等制备聚乙二醇偶联物来提高聚乙二醇的性能。
CN105963792A公开了一种医用水凝胶组合物，包括第一组分和第二组分，所述第一组分包括聚赖氨酸和聚乙烯亚胺；所述第二组分包括四臂-聚乙二醇-琥珀酰亚胺戊二酸酯、四臂-聚乙二醇-琥珀酰亚胺丁二酸酯、四臂-聚乙二醇-琥珀酰亚胺碳酸酯中的一种或几种。使用时将第一组分的亲核试剂(聚赖氨酸和聚乙烯亚胺)与第二组分的亲电试剂(四臂-聚乙二醇-琥珀酰亚胺戊二酸酯、四臂-聚乙二醇-琥珀酰亚胺丁二酸酯、四臂-聚乙二醇-琥珀酰亚胺碳酸酯中的一种或几种)发生迈克尔加成反应，可以快速成胶具有低溶胀的优良性质。然而，琥珀酰亚胺有机酸酯封端的聚乙二醇材料在水中半衰期很短，极易水解，需要特别的技术才能以粉末的形式在室温长期保存，且在溶解之后很短时间内(一般为1个小时)使用，便利性较低。
CN107693838 A公开了一种医用可注射凝胶及其制备方法，将浓度为2-20％(w/v)醛基封端超支化聚合物HP-PEG-CHO溶液与浓度为2-20％(w/v)多氨基化合物溶液通过双组份注射器混合后喷涂，利用醛基和氨基反应生成西弗碱从而产生交联，形成医用可注射凝胶。醛基封端超支化聚合物HP-PEG-CHO中的醛基以酯键与聚合物连接，在水溶液中的长期稳定性较低，另外超支化聚合物分子量分布较宽，可能含有较高分子量的聚合物，不利于人体排出。
发明内容
本发明针对现有技术不足，提供了一种水溶液可长期稳定保存、基于多臂星形聚乙二醇的医用水凝胶。
本发明具体技术方案如下：
一种医用水凝胶，由醛基封端的星形多臂聚乙二醇和多氨基化合物原位交联而成，所述醛基与星形多臂聚乙二醇之间以醚键、酰胺键、氨酯键、亚胺键或脲键等不易水解键连接。
所述多氨基化合物选自聚乙烯亚胺和聚赖氨酸中的一种或多种。
所述醛基封端的多臂聚乙二醇为臂数不小于2，分子量不小于2000的多臂聚乙二醇。
所述醛基封端的多臂聚乙二醇的臂数为2-8，优选为8。
所述醛基选自芳香醛、烷基醛中的一种或几种，优选为苯醛基。
本发明另一目的在于提供所述医用水凝胶在术后组织密封与防渗漏、防组织黏连、组织填充剂、组织修复、皮肤敷料和药物制剂中的应用。
本发明另一目的在于提供所述医用水凝胶的制备方法，将醛基封端的星形多臂聚乙二醇溶解在pH4-10缓冲液中，配置醛基封端的星形多臂聚乙二醇溶液；将多氨基化合物溶解在pH4-10缓冲液中，配置多氨基化合物溶液；将两者混合得到医用水凝胶。
本发明所用的醛基封端的星形多臂聚乙二醇可以通过商业途径购买。
上述pH4-10缓冲液优选pH4-10的磷酸盐或硼酸盐缓冲液。
所述醛基封端的星形多臂聚乙二醇溶液的终浓度为2-30％(w/v)，优选为10-20％(w/v)；所述多氨基化合物溶液浓度为0.5-20％，优选为1-5％(w/v)
所述醛基封端的星形多臂聚乙二醇中醛基与多氨基化合物中氨基物质的量比例为0.01-5:1。
本发明在具体应用时先制备成双组份水凝胶，为包含亲核官能团的第一组分和包含亲电官能团的第二组分，所述第一组分为醛基封端的亲水性化合物，其中臂的个数不低于两个，亲水性化合物为醛基封端的星形多臂聚乙二醇，优选为八臂聚乙二醇(分子量5000- 20000)，醛基为芳香醛、烷基醛中的一种或几种，优选为苯醛基。醛基与聚合物之间可以以醚键、酰胺键等不易水解的化学键连接。
所述第二组分可以选择包含多氨基的化合物，包括聚赖氨酸(包括ε-聚赖氨酸和多聚赖氨酸)和聚乙烯亚胺中的一种或几种的混合组分。
Figure PCTCN2018111398-appb-000001
酰胺键连接苯醛基封端八臂聚乙二醇、醚键连接苯醛基封端八臂聚乙二醇、醚键连接丙醛基封端八臂聚乙二醇的化学结构如下所示。
Figure PCTCN2018111398-appb-000002
酰胺键连接苯醛基封端八臂聚乙二醇
Figure PCTCN2018111398-appb-000003
醚键连接苯醛基封端八臂聚乙二醇
Figure PCTCN2018111398-appb-000004
醚键连接丙醛基封端八臂聚乙二醇
由于醛基和氨基在水溶液中的稳定性，以上两组分均可以以水溶液或粉末形式提供。使用时将两组分分别溶解于缓冲液中，然后混合组分即得到水凝胶。可将水凝胶两组分分别存储在双管注射器中，使用时两个组分经混合头喷出或者注射到指定部位形成凝胶。
本发明利用多臂聚乙二醇端部的醛基和多氨基化合物的氨基反应生成schiff碱从而产生交联，形成医用可注射凝胶。所制得的凝胶成胶时间短，具有理想的凝胶胀破强度，并且在水溶液中稳定性好，相较于现有医用凝胶具有更好的应用价值。
附图说明
图1为醚键连接、酰胺键连接和酯键连接的醛基封端聚乙二醇成胶稳定性考察结果。
具体实施方式
以下通过实施例说明本发明的具体步骤，但不受实施例限制。
在本发明中使用的术语，除非另有说明，一般具有本领域普通技术人员通常理解的含义。
下面结合具体实施例并参照数据进一步详细描述本发明，应理解，这些实施例只是为了举例说明本发明，而非以任何方式限制本发明的范围。
在以下实施例中，未详细描述的各种过程和方法是本领域中公知的常规方法。
下面结合具体实施例对本发明进行进一步描述，但本发明的保护范围并不仅限于此。
实施例1
将600mg的醚键连接苯醛基封端8臂聚乙二醇8-PEG-O-BA(M.W.10K)溶解在2mL 的磷酸盐缓冲液中(pH7.4)，作为A溶液；配置聚乙烯亚胺2.2％(w/v)的磷酸盐缓冲液溶液，作为B溶液；将A、B溶液等体积混合即获得具有粘性的水凝胶，成胶时间为21秒，凝胶胀破强度为16kPa。
实施例2
将600mg的醚键连接苯醛基封端8臂聚乙二醇8-PEG-O-BA(M.W.13.5K)溶解在2mL的磷酸盐缓冲液中(pH7.4)，作为A溶液；配置聚乙烯亚胺1.67％(w/v)的磷酸盐缓冲液溶液，作为B溶液；将A、B溶液等体积混合即获得具有粘性的水凝胶，成胶时间为22秒，凝胶胀破强度为11kPa。
实施例3
将400mg酰胺键连接苯醛基封端8臂聚乙二醇8-PEG-amide-BA(M.W.10K)溶解在2mL的磷酸盐缓冲液中(pH7.4)，作为A溶液；配置聚乙烯亚胺1.48％(w/v)的磷酸盐缓冲液溶液，作为B溶液；将A、B溶液等体积混合即获得具有粘性的水凝胶，成胶时间为2秒，凝胶胀破强度为13kPa。
实施例4
将600mg酰胺键连接苯醛基封端4臂聚乙二醇4-PEG-amide-BA(M.W.10K)溶解在2mL的磷酸盐缓冲液中(pH7.4)，作为A溶液；配置聚乙烯亚胺2.2％(w/v)的磷酸盐缓冲液溶液，作为B溶液；将A、B溶液等体积混合即获得具有粘性的水凝胶，成胶时间为20秒，凝胶胀破强度为11kPa。
实施例5
将400mg酰胺键连接苯醛基封端8臂聚乙二醇8-PEG-amide-BA(M.W.10K)溶解在2mL的磷酸盐缓冲液中(pH7.4)，作为A溶液；配置聚赖氨酸2.44％(w/v)的磷酸盐缓冲液溶液，作为B溶液；将A、B溶液等体积混合即获得具有粘性的水凝胶，成胶时间为5秒，凝胶胀破强度为21kPa。
实施例6
将400mg酰胺键连接苯醛基封端8臂聚乙二醇8-PEG-amide-BA(M.W.10K)溶解在2mL的磷酸盐缓冲液中(pH7.4)，作为A溶液；配置聚赖氨酸3.66％(w/v)的磷酸盐缓冲液溶液，作为B溶液；将A、B溶液等体积混合即获得具有粘性的水凝胶，成胶时间为5秒，凝胶胀破强度为25kPa。
实施例7
将600mg的醚键连接丙醛基封端8臂聚乙二醇8-PEG-O-PA(M.W.10K)溶解在2mL 的磷酸盐缓冲液中(pH7.4)，作为A溶液；配置聚乙烯亚胺1.48％(w/v)的磷酸盐缓冲液溶液，作为B溶液；将A、B溶液等体积混合即获得具有粘性的水凝胶，成胶时间为15秒，凝胶胀破强度8kPa。
实施例8
将600mg的醚键连接苯醛基封端8臂聚乙二醇8-PEG-O-BA(M.W.13.5K)溶解在2mL的磷酸盐缓冲液中(pH7.4)，作为A溶液；配置聚赖氨酸2.75％(w/v)的磷酸盐缓冲液溶液，作为B溶液；将A、B溶液等体积混合即获得具有粘性的水凝胶，成胶时间小于5分钟，凝胶胀破强度为2kPa。
实施例9
将600mg的醚键连接苯醛基封端8臂聚乙二醇8-PEG-O-BA(M.W.13.5K)溶解在2mL的磷酸盐缓冲液中(pH7.4)，作为A溶液；配置含聚赖氨酸2.75％(w/v)和聚乙烯亚胺(M.W.1.8K)1％(w/v)的磷酸盐缓冲液溶液，作为B溶液；将A、B溶液等体积混合即获得具有粘性的水凝胶，成胶时间35秒，凝胶胀破强度为22kPa。
实施例10
将400mg酯键连接苯醛基封端8臂聚乙二醇8-PEG-amide-BA(M.W.10K)溶解在2mL的磷酸盐缓冲液中(pH7.4)，作为A溶液；配置聚乙烯亚胺(M.W.1.8K)1.48％(w/v)的磷酸盐缓冲液溶液，作为B溶液；将A、B溶液等体积混合即获得具有粘性的水凝胶，成胶时间为5秒，凝胶胀破强度为13kPa。
实施例11
比较醚键连接、酰胺键连接和酯键连接的苯醛基封端聚乙二醇在水溶液中的长期稳定性，为了缩短试验时间，选择碱性硼酸盐缓冲液作为溶剂，比较不同时间点成胶时间的变化。分别将400mg的醚键连接、酰胺键连接和酯键连接苯醛基封端8臂聚乙二醇(M.W.10K)溶解在2mL的0.1M硼酸盐缓冲液(pH9.2)，作为A溶液；配置含聚乙烯亚胺(M.W.1.8K)1.48％(w/v)的磷酸盐缓冲液溶液，作为B溶液；将A、B溶液等体积混合即获得具有粘性的水凝胶，初始成胶时间分别为25秒、2秒和5秒。将三种A液置于37℃烘箱1、2、4、16、24和40小时，再分别测定与B液混合后的成胶时间与初始成胶时间的变化(如图1所示)。结果显示，酯键连接的聚乙二醇在40小时后失去成胶能力，而醚键连接和酰胺键连接苯醛基封端8臂聚乙二醇成胶时间基本保持不变。

Claims (10)

  1. 一种医用水凝胶，其特征在于由醛基封端的星形多臂聚乙二醇和多氨基化合物原位交联而成，所述醛基与星形多臂聚乙二醇之间以醚键、酰胺键、氨酯键、亚胺键或脲键化学键连接。
  2. 根据权利要求1所述医用水凝胶，其特征在于所述多氨基化合物选自聚乙烯亚胺和聚赖氨酸中的一种或多种。
  3. 根据权利要求1所述医用水凝胶，其特征在于所述醛基封端的星形多臂聚乙二醇为臂数不小于2，分子量不小于2000的多臂聚乙二醇。
  4. 根据权利要求1所述医用水凝胶，其特征在于所述醛基封端的星形多臂聚乙二醇的臂数为2-8。
  5. 根据权利要求1所述医用水凝胶，其特征在于所述醛基选自芳香醛、烷基醛中的一种或几种。
  6. 根据权利要求1-5任一项所述医用水凝胶在术后组织密封与防渗漏、防组织黏连、组织填充、组织修复、皮肤敷料和药物制剂中的应用。
  7. 根据权利要求1-5任一项所述医用水凝胶的制备方法，其特征在于将醛基封端的星形多臂聚乙二醇溶解在pH4-10缓冲液中，配置醛基封端的星形多臂聚乙二醇溶液；将多氨基化合物溶解在pH4-10缓冲液中，配置多氨基化合物溶液；将两者混合得到医用水凝胶。
  8. 根据权利要求7所述医用可注射凝胶制备方法，其特征在于所述醛基封端的星形多臂聚乙二醇溶液的终浓度为2-30％，所述多氨基化合物溶液浓度为0.5-20％。
  9. 根据权利要求7所述医用可注射凝胶制备方法，其特征在于所述醛基封端多臂的星形聚乙二醇溶液的终浓度为10～20％，所述多氨基化合物溶液浓度为1-5％。
  10. 根据权利要求7所述医用可注射凝胶制备方法，其特征在于所述醛基封端的星形多臂聚乙二醇中醛基与多氨基化合物中氨基物质的量比例为0.01-5:1。
PCT/CN2018/111398 2018-08-10 2018-10-23 医用水凝胶 WO2020029432A1 (zh)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US17/267,788 US20210162092A1 (en) 2018-08-10 2018-10-23 Medical hydrogel

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201810909023.2 2018-08-10
CN201810909023.2A CN109939065B (zh) 2018-08-10 2018-08-10 医用水凝胶

Publications (1)

Publication Number Publication Date
WO2020029432A1 true WO2020029432A1 (zh) 2020-02-13

Family

ID=67006324

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2018/111398 WO2020029432A1 (zh) 2018-08-10 2018-10-23 医用水凝胶

Country Status (3)

Country Link
US (1) US20210162092A1 (zh)
CN (1) CN109939065B (zh)
WO (1) WO2020029432A1 (zh)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113171463A (zh) * 2021-03-31 2021-07-27 北京诺康达医药科技股份有限公司 原位载药水凝胶及其制备方法与应用

Families Citing this family (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP4100072A1 (en) * 2020-02-04 2022-12-14 Boston Scientific Scimed Inc. Injectable in vivo crosslinking materials for use as soft tissue fillers
CN111440310B (zh) * 2020-05-26 2022-02-22 中国科学院长春应用化学研究所 一种聚乙二醇衍生物、其制备方法及可快速发生交联反应的聚乙二醇水凝胶
CN112225912B (zh) * 2020-10-19 2022-11-29 上海瑞凝生物科技有限公司 可降解医用水凝胶
CN113461973B (zh) * 2021-07-21 2023-04-07 上海瑞凝生物科技有限公司 可注射型医用水凝胶
CN114369354A (zh) * 2021-08-05 2022-04-19 上海瑞凝生物科技有限公司 用于血管栓塞的可注射水凝胶
CN115869456A (zh) * 2021-08-09 2023-03-31 上海其胜生物制剂有限公司 一种原位凝胶化抗溶胀增强型组织粘合剂材料的制备
CN114767625A (zh) * 2022-05-19 2022-07-22 四川大学 具有心脏损伤修复功能的智能水凝胶及其制备方法和应用
CN115025281A (zh) * 2022-07-15 2022-09-09 上海交通大学 糖基化聚赖氨酸-聚乙二醇水凝胶及其制备方法和应用
CN115120591A (zh) * 2022-08-03 2022-09-30 上海瑞凝生物科技有限公司 一种peg化喜树碱长效缓释凝胶
CN115068413B (zh) * 2022-08-04 2024-02-23 上海瑞凝生物科技有限公司 一种盐酸阿霉素/盐酸表阿霉素缓释凝胶
CN116983466A (zh) * 2023-08-16 2023-11-03 南方科技大学 一种医用凝胶敷料及其制备方法和应用

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102108119A (zh) * 2009-12-25 2011-06-29 天津键凯科技有限公司 多臂聚乙二醇衍生物及其与药物的结合物和凝胶
CN102604011A (zh) * 2012-02-28 2012-07-25 中国科学院化学研究所 一种两亲性多臂星型聚合物及其制备方法
CN105561404A (zh) * 2015-01-07 2016-05-11 北京赛奇科科技有限公司 一种用于妇产科防粘连的医用材料及其制备方法
CN107693838A (zh) * 2017-11-09 2018-02-16 杭州亚慧生物科技有限公司 一种医用可注射凝胶及其制备方法

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR100452972B1 (ko) * 2000-05-16 2004-10-14 주식회사 삼양사 경피투여용 하이드로젤 조성물
CA2711455C (en) * 2008-02-13 2016-06-07 Hyperbranch Medical Technology, Inc. Crosslinked polyalkyleneimine hydrogels with tunable degradation rates
US8617519B2 (en) * 2011-07-07 2013-12-31 DePuy Synthes Products, LLC Injectable cross-linked hydrogels for biomaterial applications
WO2014046127A1 (ja) * 2012-09-18 2014-03-27 日産化学工業株式会社 ヒドロゲル形成性組成物及びそれより作られるヒドロゲル

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102108119A (zh) * 2009-12-25 2011-06-29 天津键凯科技有限公司 多臂聚乙二醇衍生物及其与药物的结合物和凝胶
CN102604011A (zh) * 2012-02-28 2012-07-25 中国科学院化学研究所 一种两亲性多臂星型聚合物及其制备方法
CN105561404A (zh) * 2015-01-07 2016-05-11 北京赛奇科科技有限公司 一种用于妇产科防粘连的医用材料及其制备方法
CN107693838A (zh) * 2017-11-09 2018-02-16 杭州亚慧生物科技有限公司 一种医用可注射凝胶及其制备方法

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113171463A (zh) * 2021-03-31 2021-07-27 北京诺康达医药科技股份有限公司 原位载药水凝胶及其制备方法与应用

Also Published As

Publication number Publication date
CN109939065A (zh) 2019-06-28
US20210162092A1 (en) 2021-06-03
CN109939065B (zh) 2021-08-03

Similar Documents

Publication Publication Date Title
WO2020029432A1 (zh) 医用水凝胶
CN109646723B (zh) 具有辐射防护作用的医用水凝胶
CN112225912B (zh) 可降解医用水凝胶
JP5053758B2 (ja) 急速ゲル化生体適合性ポリマー組成物
US8426492B2 (en) Oxidized cationic polysaccharide-based polymer tissue adhesive for medical use
JP6017646B2 (ja) 医療用ヒドロゲル組織接着剤
US8211418B2 (en) Protein-based polymer tissue adhesives for medical use
US9259473B2 (en) Polymer hydrogel adhesives formed with multiple crosslinking mechanisms at physiologic pH
EP3406270B1 (en) Surgical sealant
JP2012523289A (ja) 減少した分解時間を有するハイドロゲル組織接着剤
US20200277449A1 (en) Injectable hybrid alginate hydrogels and uses thereof
JP2011509713A (ja) 生体接着性ヒドロゲル
JP2011074075A (ja) 多機構外科用組成物
CN112006976A (zh) 一种消化道粘膜下注射短肽水凝胶及其应用
US8889889B2 (en) Crosslinked polymers with the crosslinker as therapeutic for sustained release
CN114369354A (zh) 用于血管栓塞的可注射水凝胶
JPH09103479A (ja) 医用材料及びその製造法
CN113461973B (zh) 可注射型医用水凝胶
CN115403760B (zh) 用于预防沾粘的氨基酸改质的聚合物及其应用
Keshari et al. In Situ Gelling Tissue Adhesive Hydrogels for Wound Closure and Tissue Regeneration

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 18929642

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 18929642

Country of ref document: EP

Kind code of ref document: A1