WO2016049791A1 - Gel utilisé in situ en tant que matériau de substitution du corps vitré, et son procédé de préparation et utilisation - Google Patents

Gel utilisé in situ en tant que matériau de substitution du corps vitré, et son procédé de préparation et utilisation Download PDF

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Publication number
WO2016049791A1
WO2016049791A1 PCT/CN2014/000885 CN2014000885W WO2016049791A1 WO 2016049791 A1 WO2016049791 A1 WO 2016049791A1 CN 2014000885 W CN2014000885 W CN 2014000885W WO 2016049791 A1 WO2016049791 A1 WO 2016049791A1
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WIPO (PCT)
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formula
zwitterionic
polymer represented
situ
situ gel
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PCT/CN2014/000885
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English (en)
Chinese (zh)
Inventor
常菁
陶勇
王斌
郭宝华
姜燕荣
黄延宾
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清华大学
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Priority to PCT/CN2014/000885 priority Critical patent/WO2016049791A1/fr
Publication of WO2016049791A1 publication Critical patent/WO2016049791A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/18—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
    • 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
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/52—Hydrogels or hydrocolloids
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J3/00—Processes of treating or compounding macromolecular substances
    • C08J3/02—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques
    • C08J3/03—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques in aqueous media
    • C08J3/075—Macromolecular gels
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J3/00—Processes of treating or compounding macromolecular substances
    • C08J3/24—Crosslinking, e.g. vulcanising, of macromolecules

Definitions

  • the invention belongs to the technical field of gel preparation, and particularly relates to an in situ gel for a vitreous substitute material and a preparation method and application thereof.
  • the zwitterionic polymer has a large number of super-hydrophilic zwitterionic groups, it can form a super-ionic ionized layer, so it has unique biocompatibility and anti-biofouling properties, and can inhibit the adsorption of non-specific proteins. Bacterial adhesion and biofilm formation. These excellent properties make these materials increasingly used in antifouling coatings, antibacterial coatings, anticoagulant materials, biomedical diagnostics, drug delivery, gene delivery vehicles, separation membranes, and hull coatings.
  • PC phosphorylcholine
  • SB sulfobetaine
  • CB carboxylic acid betaine
  • Jiang Shaoyi's research group and others have carried out a large number of anti-non-specific protein adsorption properties, mechanism and application of poly(sulfobetaine amphoteric polymethacrylic acid) and poly(carboxylic acid betaine methyl acrylate) materials. the study.
  • the adsorption of fibrin on the surface of poly(sulfobetaine amphoteric polymethacrylic acid) and poly(carboxylic acid betaine methyl acrylate) modified materials is less than 0.3 nanograms per square centimeter; and zwitterionics
  • the polymer-modified vascular catheter material can effectively adsorb the protein to the surface of the material in 100% plasma and serum, inhibiting the occurrence of blood coagulation.
  • Jiang Shaoyi's research group also prepared a zwitterionic hydrogel.
  • the kit for forming an ophthalmic zwitterionic in situ gel comprises a zwitterionic polymer having a polyfluorenyl functional group represented by formula (I), a polymer represented by formula (II) ( ⁇ -PEG-MA), and Solvent composition;
  • the zwitterionic polymer having a polyfluorenyl functional group represented by the formula (I), the polymer represented by the formula (II) ( ⁇ -PEG-MA), and the solvent are separately packaged;
  • the molar ratio of the fluorenyl group in the zwitterionic polymer having a polyfluorenyl functional group represented by the formula (I) to the carbon-carbon double bond functional group in the polymer represented by the formula (II) is 1:1. -5:1, preferably in a molar ratio of 1:1 to 3:1, most preferably in a molar ratio of 2:1;
  • the solvent may be a buffer having a pH of 7.0 to 8.0, such as a phosphate buffer having a pH of 7.0 to 8.0. liquid. Specifically, it may be a phosphate buffer having a pH of 7.4 and a concentration of 0.02 to 0.2 mol/L.
  • a and b in the formula (I) are integers greater than 1, preferably a is an integer of 100-600, b is an integer of 8-50; m and n are each greater than or equal to 1 and less than 5, and X is O. Or an NH group, Y is SO 3 - or COO - , and the zwitterionic polymer represented by the formula (I) has a weight average molecular weight of from 1,000 Da to 1000 KDa, preferably a weight average molecular weight of from 10 kDa to 500 kDa.
  • z in the formula (II) may be an integer greater than 1, and preferably z is an integer greater than 20 and less than 200, further preferably 45 to 90, and the specific z value may be 45.
  • the concentration of the zwitterionic polymer having a polyfluorenyl functional group represented by the formula (I) in the kit may be 0.1-500 mg/mL (preferably 10-100 mg/mL), and the polymer represented by the formula (II) ( ⁇ -PEG)
  • the concentration of -MA) may be from 0.01 to 50 mg/mL (preferably from 0.5 to 5 mg/mL).
  • the components in the kit for forming the ophthalmic zwitterionic in situ gel are mixed at room temperature for 5-40 minutes (preferably 10-20 minutes), and then the mixed solution is injected into the vitreous cavity (eg, It can be injected in situ by gas-liquid exchange method to form a zwitterionic in situ gel in situ.
  • the zwitterionic in situ gel provided by the present invention is obtained by in situ crosslinking of a zwitterionic polymer having a polyfluorenyl functional group represented by the above formula (I) and a polymer represented by the formula (II) ( ⁇ -PEG-MA). Prepared by the combined reaction.
  • the in-situ crosslinking reaction can be carried out in a solvent which may be a buffer having a pH of 7.0 to 8.0, such as a phosphate buffer having a pH of 7.0 to 8.0. Specifically, it may be a phosphate buffer having a pH of 7.4 and a concentration of 0.02 to 0.2 mol/L.
  • the in situ crosslinking reaction is carried out at room temperature.
  • the molar ratio of the fluorenyl group in the zwitterionic polymer having a polyfluorenyl functional group represented by the formula (I) and the carbon-carbon double bond functional group in the polymer represented by the formula (II) initially added in the in-situ crosslinking reaction is 1 : 1-5:1, preferably a molar ratio of 1:1 to 3:1, and most preferably a molar ratio of 2:1.
  • the zwitterionic polymer having a polyfluorenyl functional group represented by the formula (I) is added in the form of a solution having a polyfluorenyl zwitterionic polymer having a mass concentration of 0.1 to 500 mg/mL, preferably 10 to 100 mg/mL. .
  • the polymer ( ⁇ -PEG-MA) represented by the formula (II) is also added in the form of a solution in which the mass concentration of ⁇ -PEG-MA is from 0.01 to 50 mg/mL, preferably from 1 to 5 mg/mL.
  • the volume ratio of the solution of the polyfluorenyl zwitterionic polymer represented by the formula (I) to the solution of the ⁇ -PEG-MA of the formula (II) is from 1:10 to 10:1.
  • the invention also provides the use of the above zwitterionic in situ gel in the preparation of artificial vitreous.
  • the zwitterionic in situ gel prepared by the invention is used for the vitreous substitute material to maintain long-term stability after being implanted into the eye, and has no obvious toxicity reaction and inflammatory reaction (mainly as a vitreous cavity) compared with the traditional artificial vitreous substitute material. Transparent, no turbidity appears, and the time of mixing in vitro is significantly shortened (only about 15min), which is more conducive to surgical operations.
  • Figure 1 is a schematic view showing the structure of a zwitterionic in situ gel prepared by the present invention.
  • FIG. 2 is a synthetic route diagram of a polyfluorenyl zwitterionic polymer prepared according to the present invention.
  • Figure 3 is a nuclear magnetic resonance spectrum of a polyfluorenyl zwitterionic polymer prepared according to the present invention.
  • Figure 4 is a nuclear magnetic resonance carbon spectrum of a polyfluorenyl zwitterionic polymer prepared according to the present invention.
  • Figure 5 is a graph showing the storage modulus characterization data of different formulations of zwitterionic in situ gels prepared according to the present invention.
  • Figure 6 is a graph showing swelling data of zwitterionic in situ gels prepared in different formulations at 37 °C.
  • Figure 7 is a graph showing light transmittance test data of a zwitterionic in situ gel (molar ratio of sulfhydryl groups to carbon-carbon double bonds of 1:1) prepared by the present invention.
  • Figure 8 is a graph showing the results of cytotoxicity test of the zwitterionic polymer, ⁇ -PEG-MA and zwitterionic in situ gel prepared by the present invention.
  • Fig. 9 is a graph showing the test results of the zwitterionic in situ gel prepared by the present invention after filling the vitreous cavity of the rabbit eye.
  • poly(MPDSA-SH) used in the following examples was prepared as follows: [3-(methacrylamido)propyl]dimethyl (3- Thiopropyl) ammonium hydroxide inner salt 0.8g, N, N'-bis (acrylic) cystamine 0.047g, dissolved in 4mL 75% ethanol solution, adding ammonium persulfate 15.7mg, N, N, 11 ⁇ L of N',N'-tetramethylethylenediamine, reacted at room temperature for 20 h, and then immersed in H 2 O for 3 days to remove small molecules. Then, the obtained product was added to 30 mL of DTT solution for 1 hour, and after dialysis for 3 days, The final product is obtained after lyophilization.
  • the structure of the obtained polymer can be confirmed from the nuclear magnetic hydrogen spectrum of FIG. 3 and the nuclear magnetic carbon spectrum of FIG.
  • a 100-600
  • b 8-50
  • m 3
  • n 3
  • X NH
  • Y SO 3- .
  • the polymer produced has a molecular weight of 10 KDa to 500 KDa.
  • ⁇ -PEG-MA used in the following examples was prepared as follows:
  • a compound of the formula (II) wherein z is 45 is prepared by using a hydroxyl terminated PEG (number average molecular weight of about 2,000, supplied by Alfa-Aesar, Cat. No. B22181) as a starting material.
  • the specific preparation method is as follows:
  • ethyl hydroxyethyl methacrylate (TCI, product number H0916) was dissolved in 75 mL of anhydrous diethyl ether, and 2.3 mL of phosphorus tribromide was added dropwise under ice bath, and the reaction was continued at room temperature for 3 hours. After 24 hours, ethyl bromomethacrylate was obtained.
  • Dissolve poly(MPDSA-SH) and ⁇ -PEG-MA (z is 45) in phosphate buffer solution with a concentration of 0.02mol/L at pH 7.4, respectively, and prepare a concentration of 100mg/mL, 1.6mg/mL.
  • the solution is mixed in a volume ratio of 1:1 (the molar ratio of sulfhydryl groups to carbon-carbon double bonds in the mixed system is 2:1), and the in-situ cross-linking reaction is carried out at room temperature for 24 hours to obtain zwitterionic in situ coagulation. gum.
  • the corresponding zwitterionic in situ gel product can be prepared by adjusting the molar ratio of sulfhydryl groups to carbon-carbon double bonds in the mixed system to 1:1 and 3:2, respectively, according to the above method.
  • Example 2 Characterization of in vitro performance of zwitterionic in situ gel of the present invention
  • the gel prepared in Example 1 was used for the swelling, strength, and light transmittance performance test.
  • Dissolve poly(MPDSA-SH) and ⁇ -PEG-MA (z is 45) in phosphate buffer solution with pH 7.4 concentration of 0.2mol/L, respectively, and prepare a concentration of 100mg/mL, 1.6mg/mL.
  • the solution is mixed in a ratio of 1:1 to 2:1 by volume (ie, the molar ratio of sulfhydryl to carbon-carbon double bonds is 1:1, 2:1, respectively), and the in-situ cross-linking reaction is carried out at room temperature.
  • a zwitterionic in situ gel was obtained for cell experiments.
  • Cell line human retinal pigment epithelial cells, RPE cells
  • the cells were collected by trypsin digestion, and apoptosis was measured by BD PE Annexin V Apoptosis Detection Kit I. The results are shown in Fig. 8.
  • Example 4 Animal intraocular filling safety test of zwitterionic in situ gel of the present invention
  • the animal experiment steps are as follows:
  • the perfusate formula is as follows: 500mL lactated Ringer's solution contains glucose 2g, dexamethasone 8mg, adrenaline hydrochloride 0.5mg, Botomycin 16,000 U.
  • the formulation of the gel solution is: 0.2 mol/L phosphate buffer (pH 7.4) containing 50 mg/mL of poly(MPDSA-SH), and 0.8 mg/mL of ⁇ -PEG-MA (thiol and double bond) The ratio of functional groups is 2:1). After mixing for 20 minutes at room temperature, the mixed solution is injected into the vitreous cavity by gas-liquid exchange method, and cross-linked in situ to form a zwitterionic in situ gel.
  • the zwitterionic in situ gel material prepared by the invention can form a complete transparent gel in the vitreous cavity of the rabbit eye, and maintains good stability, and remains intact when removed from the vitreous cavity after two months.
  • Sexuality and good transparency see Figure 9B.
  • Figure 9A, C Through fundus photo observation and fluoroscopy (see Figure 9A, C), after 3 months of gel filling, the vitreous cavity remained clear and transparent, and the retina and choroid were normal without any bleeding or exudation.
  • a B-ultrasound examination of the gel-filled vitreous cavity for 2 months showed no abnormal changes compared to the control eye, so the material did not cause significant damage to the retina and other tissues.
  • Example 5 Animal intraocular filling safety test of zwitterionic in situ gel of the present invention
  • the animal experiment steps are as follows:
  • the perfusate formula is as follows: 500mL lactated Ringer's solution contains glucose 2g, dexamethasone 8mg, adrenaline hydrochloride 0.5mg, Botomycin 16,000 U.
  • the formulation of the gel solution is: 0.2 mol/L phosphate buffer (pH 7.4) containing 50 mg/mL poly(MPDSA-SH), and 1.6 mg/mL ⁇ -PEG-MA (sulfhydryl and double bonds) The ratio of functional groups is 1:1). After mixing for 15 minutes at room temperature, the mixed solution is injected into the vitreous cavity by gas-liquid exchange method, and cross-linked in situ to form a zwitterionic in situ gel.
  • the experimental results were the same as those in Example 4.
  • the injected solution formed a complete transparent gel in the vitreous cavity of the rabbit eye, and no abnormal changes were observed in the retina and other tissues, and no inflammatory cell infiltration was observed.
  • the zwitterionic in situ gel material can form a complete gel in the vitreous cavity of the rabbit eye, and can be stable and transparent for a long time. After filling the vitreous cavity, the gel effectively inhibits inflammatory cell infiltration, and the vitreous cavity can remain transparent for a long time without any punctate turbidity. It has not caused any toxicity to the retina and other tissue structures and has been pathologically altered. Therefore, it has been proved by animal experiments that the filling of the gel in the vitreous cavity is non-toxic and safe.
  • the zwitterionic in situ gel prepared by the invention is used for the vitreous substitute material to maintain long-term stability after implantation in the eye, and has no obvious toxicity reaction and inflammatory reaction as compared with the traditional artificial vitreous substitute material.

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
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  • Chemical Kinetics & Catalysis (AREA)
  • Oral & Maxillofacial Surgery (AREA)
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Abstract

L'invention concerne un ensemble permettant de générer un gel ophtalmique zwitterionique in situ, et son application. L'ensemble est constitué d'un polymère zwitterionique tel que représenté par la formule (I), un polymère tel que représenté par la formule (II) et un solvant, un rapport molaire d'un groupe sulfhydryle dans la formule (I) et d'un groupe fonctionnel à double liaison carbone-carbone dans la formule (II) étant de 1:1-5:1, et le solvant étant une solution tamponnée ayant un pH de 7,0-8.0. Lors de l'utilisation de l'ensemble, divers constituants dans l'ensemble de génération d'un gel ophtalmique zwitterionique in situ sont mélangés selon une proportion et sous une température ambiante pendant 5 à 40 minutes, et la solution mixte est injectée dans une cavité de corps vitré, générant ainsi le gel in situ zwitterionique dans un corps par l'intermédiaire d'une réticulation in situ. Le gel zwitterionique in situ préparé est utilisé en tant que matériau de substitution du corps vitré et comparé à un matériau de substitution artificiel classique de corps vitré, le gel zwitterionique in situ préparé demeure stable pendant une longue période de temps après avoir été implanté dans un oeil, et ne présente pas de réaction toxique évidente ni de réaction d'ordre inflammatoire.
PCT/CN2014/000885 2014-09-29 2014-09-29 Gel utilisé in situ en tant que matériau de substitution du corps vitré, et son procédé de préparation et utilisation WO2016049791A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018013819A1 (fr) * 2016-07-13 2018-01-18 Massachusetts Eye And Ear Infirmary Procédés et compositions de polymère pour le traitement du décollement de la rétine et d'autres troubles oculaires
WO2019140212A1 (fr) * 2018-01-12 2019-07-18 Pykus Therapeutics, Inc. Procédés et formulations contenant des polymères pour le traitement du décollement de la rétine et d'autres troubles oculaires
US11883378B2 (en) 2021-11-24 2024-01-30 Pykus Therapeutics, Inc. Hydrogel formulations and methods and devices for focal administration of the same

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US3671502A (en) * 1970-11-12 1972-06-20 Kendall & Co Betaine copolymers with hydroxyalkylacrylates and hydroxyalkylmethacrylates
CN102049067A (zh) * 2009-11-10 2011-05-11 清华大学 一种可原位交联的高分子水凝胶玻璃体替代材料
CN102952278A (zh) * 2011-08-23 2013-03-06 北京大学人民医院 一种用于眼内填充的原位交联水凝胶及其制备方法与应用

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3671502A (en) * 1970-11-12 1972-06-20 Kendall & Co Betaine copolymers with hydroxyalkylacrylates and hydroxyalkylmethacrylates
CN102049067A (zh) * 2009-11-10 2011-05-11 清华大学 一种可原位交联的高分子水凝胶玻璃体替代材料
CN102952278A (zh) * 2011-08-23 2013-03-06 北京大学人民医院 一种用于眼内填充的原位交联水凝胶及其制备方法与应用

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018013819A1 (fr) * 2016-07-13 2018-01-18 Massachusetts Eye And Ear Infirmary Procédés et compositions de polymère pour le traitement du décollement de la rétine et d'autres troubles oculaires
CN109641077A (zh) * 2016-07-13 2019-04-16 马萨诸塞眼科耳科诊所 用于治疗视网膜脱离和其他眼部疾病的方法和聚合物组合物
US10874767B2 (en) 2016-07-13 2020-12-29 Massachusetts Eye And Ear Infirmary Methods and polymer compositions for treating retinal detachment and other ocular disorders
US10973955B2 (en) 2016-07-13 2021-04-13 Massachusetts Eye And Ear Infirmary Methods and polymer compositions for treating retinal detachment and other ocular disorders
US10973954B2 (en) 2016-07-13 2021-04-13 Massachusetts Eye And Ear Infirmary Methods and polymer compositions for treating retinal detachment and other ocular disorders
US11077232B2 (en) 2016-07-13 2021-08-03 Massachusetts Eye And Ear Infirmary Methods and polymer compositions for treating retinal detachment and other ocular disorders
US11547779B2 (en) 2016-07-13 2023-01-10 Massachusetts Eye And Ear Infirmary Methods and polymer compositions for treating retinal detachment and other ocular disorders
WO2019140212A1 (fr) * 2018-01-12 2019-07-18 Pykus Therapeutics, Inc. Procédés et formulations contenant des polymères pour le traitement du décollement de la rétine et d'autres troubles oculaires
WO2019140184A1 (fr) * 2018-01-12 2019-07-18 Pykus Therapeutics, Inc. Méthodes, formulations contenant un polymère et compositions polymères pour traiter un décollement de rétine et d'autres troubles oculaires
US11883378B2 (en) 2021-11-24 2024-01-30 Pykus Therapeutics, Inc. Hydrogel formulations and methods and devices for focal administration of the same

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