WO2022246922A1 - Microgel, procédé de préparation associé et application correspondante - Google Patents
Microgel, procédé de préparation associé et application correspondante Download PDFInfo
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- WO2022246922A1 WO2022246922A1 PCT/CN2021/099657 CN2021099657W WO2022246922A1 WO 2022246922 A1 WO2022246922 A1 WO 2022246922A1 CN 2021099657 W CN2021099657 W CN 2021099657W WO 2022246922 A1 WO2022246922 A1 WO 2022246922A1
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- WIPO (PCT)
- Prior art keywords
- microgel
- hyaluronic acid
- chitosan
- preparation
- salt
- Prior art date
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- 238000002360 preparation method Methods 0.000 title claims abstract description 24
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 claims abstract description 78
- 229920002674 hyaluronan Polymers 0.000 claims abstract description 70
- 229960003160 hyaluronic acid Drugs 0.000 claims abstract description 70
- 229920001661 Chitosan Polymers 0.000 claims abstract description 66
- 239000003431 cross linking reagent Substances 0.000 claims abstract description 12
- 229910052751 metal Inorganic materials 0.000 claims abstract description 11
- 239000002184 metal Substances 0.000 claims abstract description 11
- 239000007864 aqueous solution Substances 0.000 claims abstract description 10
- 150000003839 salts Chemical class 0.000 claims abstract description 10
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- 238000006243 chemical reaction Methods 0.000 claims abstract description 7
- 239000003937 drug carrier Substances 0.000 claims abstract description 5
- 238000012383 pulmonary drug delivery Methods 0.000 claims abstract description 5
- 239000000243 solution Substances 0.000 claims description 55
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 claims description 32
- 235000002639 sodium chloride Nutrition 0.000 claims description 16
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 11
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 10
- -1 aluminum ions Chemical class 0.000 claims description 6
- 229910021645 metal ion Inorganic materials 0.000 claims description 6
- 239000011592 zinc chloride Substances 0.000 claims description 6
- 235000005074 zinc chloride Nutrition 0.000 claims description 6
- ZOIORXHNWRGPMV-UHFFFAOYSA-N acetic acid;zinc Chemical compound [Zn].CC(O)=O.CC(O)=O ZOIORXHNWRGPMV-UHFFFAOYSA-N 0.000 claims description 5
- 239000011780 sodium chloride Substances 0.000 claims description 5
- 238000006467 substitution reaction Methods 0.000 claims description 5
- 239000004246 zinc acetate Substances 0.000 claims description 5
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical group [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 claims description 4
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 claims description 4
- 239000001110 calcium chloride Substances 0.000 claims description 4
- 229910001628 calcium chloride Inorganic materials 0.000 claims description 4
- XEEYBQQBJWHFJM-UHFFFAOYSA-N iron Substances [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 4
- 229910052742 iron Inorganic materials 0.000 claims description 4
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical class [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 claims description 3
- 159000000007 calcium salts Chemical class 0.000 claims description 3
- 150000001879 copper Chemical class 0.000 claims description 3
- 159000000000 sodium salts Chemical class 0.000 claims description 3
- 150000003751 zinc Chemical class 0.000 claims description 3
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 claims description 2
- JPVYNHNXODAKFH-UHFFFAOYSA-N Cu2+ Chemical compound [Cu+2] JPVYNHNXODAKFH-UHFFFAOYSA-N 0.000 claims description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 2
- PTFCDOFLOPIGGS-UHFFFAOYSA-N Zinc dication Chemical compound [Zn+2] PTFCDOFLOPIGGS-UHFFFAOYSA-N 0.000 claims description 2
- 229910052782 aluminium Inorganic materials 0.000 claims description 2
- DIZPMCHEQGEION-UHFFFAOYSA-H aluminium sulfate (anhydrous) Chemical compound [Al+3].[Al+3].[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O DIZPMCHEQGEION-UHFFFAOYSA-H 0.000 claims description 2
- WDIHJSXYQDMJHN-UHFFFAOYSA-L barium chloride Chemical compound [Cl-].[Cl-].[Ba+2] WDIHJSXYQDMJHN-UHFFFAOYSA-L 0.000 claims description 2
- 229910001626 barium chloride Inorganic materials 0.000 claims description 2
- 229910001422 barium ion Inorganic materials 0.000 claims description 2
- 159000000009 barium salts Chemical class 0.000 claims description 2
- 229910001424 calcium ion Inorganic materials 0.000 claims description 2
- 229910001431 copper ion Inorganic materials 0.000 claims description 2
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 claims description 2
- 239000001103 potassium chloride Substances 0.000 claims description 2
- 235000011164 potassium chloride Nutrition 0.000 claims description 2
- 229910001414 potassium ion Inorganic materials 0.000 claims description 2
- OTYBMLCTZGSZBG-UHFFFAOYSA-L potassium sulfate Chemical compound [K+].[K+].[O-]S([O-])(=O)=O OTYBMLCTZGSZBG-UHFFFAOYSA-L 0.000 claims description 2
- 229910052939 potassium sulfate Inorganic materials 0.000 claims description 2
- 235000011151 potassium sulphates Nutrition 0.000 claims description 2
- 229910001415 sodium ion Inorganic materials 0.000 claims description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 claims description 2
- 235000011152 sodium sulphate Nutrition 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims description 2
- LRXTYHSAJDENHV-UHFFFAOYSA-H zinc phosphate Chemical compound [Zn+2].[Zn+2].[Zn+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O LRXTYHSAJDENHV-UHFFFAOYSA-H 0.000 claims description 2
- 229910000165 zinc phosphate Inorganic materials 0.000 claims description 2
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- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
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- NPYPAHLBTDXSSS-UHFFFAOYSA-N Potassium ion Chemical compound [K+] NPYPAHLBTDXSSS-UHFFFAOYSA-N 0.000 description 1
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- MHMNJMPURVTYEJ-UHFFFAOYSA-N fluorescein-5-isothiocyanate Chemical compound O1C(=O)C2=CC(N=C=S)=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 MHMNJMPURVTYEJ-UHFFFAOYSA-N 0.000 description 1
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Images
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
- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
-
- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/007—Pulmonary tract; Aromatherapy
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- 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
- C08J3/12—Powdering or granulating
-
- 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
- C08J2305/00—Characterised by the use of polysaccharides or of their derivatives not provided for in groups C08J2301/00 or C08J2303/00
- C08J2305/08—Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof
-
- 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
- C08J2405/00—Characterised by the use of polysaccharides or of their derivatives not provided for in groups C08J2401/00 or C08J2403/00
- C08J2405/08—Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof
Definitions
- the invention relates to the technical field of preparation and application of gel materials, in particular to a microgel and its preparation method and application.
- Fig. 3 is the microgel infrared spectrogram obtained in the embodiment of the present invention 1, wherein (a) is the infrared spectrum of HA (hyaluronic acid) and A-HA (oxidized hyaluronic acid); (b) is CS (chitosan) sugar) and CMCS (carboxymethyl chitosan) infrared spectra.
- HA hyaluronic acid
- A-HA oxidized hyaluronic acid
- CS chitosan
- CMCS carboxymethyl chitosan
- Fig. 9 is the distribution of the microgel in the lung tissue of the mouse in the application example of the present invention; wherein, (a) the fluorescence imaging images of the mouse administered for 2h, 24h, and 100h; (b) the change of the fluorescence intensity of the gel in the mouse Situation diagram.
- A-HA carboxymethyl chitosan
- A-HA oxidized hyaluronic acid
- CMCS carboxymethyl chitosan
- A-HA oxidized hyaluronic acid
- CMCS carboxymethyl chitosan
- A-HA oxidized hyaluronic acid
- Example 14-15 The experimental steps, raw materials and proportions are the same as those in Example 5, except that the cross-linking agent added in Examples 14-15 is a CaCl 2 solution, and the mass concentrations are 1.5% and 0.05%, respectively.
- Fig. 4 (a) is the degradation curve of microgel. In sodium acetate buffer solution, microgel degradation percentage rises rapidly from 0 to 64% in 0 to 3 hours, and stabilizes at this value no longer changes; In the lysozyme-containing buffer of 7.4, the degradation curve of the microgel did not change significantly within 0-5h.
- Example 2 Dilute the microgels obtained in Example 1 and Example 5 with PBS buffer solution to 10 ⁇ g/mL, 20 ⁇ g/mL, 50 ⁇ g/mL, 80 ⁇ g/mL, 100 ⁇ g/mL, 250 ⁇ g/mL, 500 ⁇ g/mL mL.
- the above microgel solution was used for MTT experiments in 3T3 cells and Beas-2B cells, and a blank control group was set at the same time. The specific steps are as follows:
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pulmonology (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Inorganic Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Polymers & Plastics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
L'invention concerne un microgel et un procédé de préparation associé. Une solution aqueuse d'acide hyaluronique et une solution aqueuse de chitosane sont mélangées de manière uniforme, un agent de réticulation est ajouté et une réaction de mélange est effectuée pour obtenir un microgel, l'agent de réticulation étant un sel métallique. Le microgel peut être utilisé dans la préparation d'un support de médicament, peut également être utilisé dans la préparation d'un système d'administration de médicament pulmonaire et présente une bonne biocompatibilité.
Applications Claiming Priority (2)
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| CN202110585929.5A CN113262198A (zh) | 2021-05-27 | 2021-05-27 | 一种微凝胶及其制备方法与应用 |
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| CN101676000A (zh) * | 2008-09-19 | 2010-03-24 | 上海建华精细生物制品有限公司 | 一种透明质酸-几丁糖生物膜的制备方法 |
| CN103897206A (zh) * | 2013-03-01 | 2014-07-02 | 四川大学 | N,o-羧甲基化壳聚糖-多醛基透明质酸凝胶及其用途 |
| US20180049980A1 (en) * | 2015-04-10 | 2018-02-22 | Tillotts Pharma Ag | Microgel particles |
| CN110974778A (zh) * | 2019-05-14 | 2020-04-10 | 暨南大学 | 一种高载药量的缓释微凝胶药膏及其制备方法与应用 |
| CN111518289A (zh) * | 2020-05-21 | 2020-08-11 | 山东大学 | 一种力学性能可调的可注射自愈合水凝胶及其制备方法与应用 |
| WO2020239591A1 (fr) * | 2019-05-24 | 2020-12-03 | Kiomed Pharma | Chitosane et ses applications |
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| GB0129489D0 (en) * | 2001-12-10 | 2002-01-30 | Quadrant Healthcare Uk Ltd | Sustained-release compositions |
| WO2014161085A1 (fr) * | 2013-04-02 | 2014-10-09 | University Of Manitoba | Compositions d'hydrogel comprenant un chitosane et un acide hyaluronique aldéhydique à base de schiff et leurs utilisations |
| US20170216341A1 (en) * | 2016-01-28 | 2017-08-03 | Oligo Médic Inc | Composition comprising polyglucosamine-glyoxylate solutions mixed with hyaluronan |
| JP6188660B2 (ja) * | 2014-09-29 | 2017-08-30 | 株式会社ダステック | キレート化合物及びその製造方法 |
| CN104479150A (zh) * | 2014-10-29 | 2015-04-01 | 上海大学 | 多重交联多糖可注射型水凝胶制备方法 |
| KR101865168B1 (ko) * | 2016-06-01 | 2018-07-04 | 한양대학교 산학협력단 | 히알루로네이트 기반 자가치유 하이드로젤 및 이의 용도 |
| CN107814981B (zh) * | 2017-11-09 | 2020-09-22 | 四川艾医生医疗科技有限公司 | 一种壳聚糖水凝胶敷料及其制备方法 |
| CN111154149A (zh) * | 2019-12-31 | 2020-05-15 | 广州医科大学附属第一医院（广州呼吸中心） | 一种水凝胶及其制备方法与敷料 |
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- 2021-05-27 CN CN202110585929.5A patent/CN113262198A/zh active Pending
- 2021-06-11 WO PCT/CN2021/099657 patent/WO2022246922A1/fr active Application Filing
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| CN101676000A (zh) * | 2008-09-19 | 2010-03-24 | 上海建华精细生物制品有限公司 | 一种透明质酸-几丁糖生物膜的制备方法 |
| CN103897206A (zh) * | 2013-03-01 | 2014-07-02 | 四川大学 | N,o-羧甲基化壳聚糖-多醛基透明质酸凝胶及其用途 |
| US20180049980A1 (en) * | 2015-04-10 | 2018-02-22 | Tillotts Pharma Ag | Microgel particles |
| CN110974778A (zh) * | 2019-05-14 | 2020-04-10 | 暨南大学 | 一种高载药量的缓释微凝胶药膏及其制备方法与应用 |
| WO2020239591A1 (fr) * | 2019-05-24 | 2020-12-03 | Kiomed Pharma | Chitosane et ses applications |
| CN111518289A (zh) * | 2020-05-21 | 2020-08-11 | 山东大学 | 一种力学性能可调的可注射自愈合水凝胶及其制备方法与应用 |
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| CN113262198A (zh) | 2021-08-17 |
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