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WO2024099063A1 - Gel d'injection pour cavité articulaire et son procédé de préparation - Google Patents

Gel d'injection pour cavité articulaire et son procédé de préparation Download PDF

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Publication number
WO2024099063A1
WO2024099063A1 PCT/CN2023/126089 CN2023126089W WO2024099063A1 WO 2024099063 A1 WO2024099063 A1 WO 2024099063A1 CN 2023126089 W CN2023126089 W CN 2023126089W WO 2024099063 A1 WO2024099063 A1 WO 2024099063A1
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WIPO (PCT)
Prior art keywords
gel
cross
carboxymethyl chitosan
polyethylene glycol
preparation
Prior art date
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Ceased
Application number
PCT/CN2023/126089
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English (en)
Chinese (zh)
Inventor
李晓盟
翟晖
江艳
牛睿
代金明
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Beijing Datsing Bio Tech Co Ltd
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Beijing Datsing Bio Tech Co Ltd
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Publication of WO2024099063A1 publication Critical patent/WO2024099063A1/fr
Anticipated expiration legal-status Critical
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Classifications

    • 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
    • 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
    • A61L31/06—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
    • 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
    • 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
    • A61L31/16—Biologically active materials, e.g. therapeutic substances
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the invention belongs to the field of biotribology, and in particular relates to a joint cavity injection gel and a preparation method thereof.
  • Osteoarthritis is a non-inflammatory degenerative joint disease, often manifested as joint pain and stiffness, especially after long-term activities.
  • the disease is more common in people over 50 years old and can start at the age of 20, but most are asymptomatic and generally difficult to detect.
  • the prevalence of osteoarthritis increases with age and is more common in women than in men.
  • the main pathology of osteoarthritis is cartilage degeneration and disappearance, as well as reactive hyperplasia of the ligament attachments at the joint margins and subchondral bone to form osteophytes, which cause joint pain, stiffness, deformity and dysfunction.
  • Joints include cartilage, synovium and joint capsule.
  • the basic components of joint cartilage are chondrocytes and extracellular matrix, of which chondrocytes account for only 1% and extracellular matrix accounts for 99%. About 3% of the extracellular matrix is glycosaminoglycan.
  • Synovial fluid is secreted by the synovial membrane of the joint bursa and tendon sheath. It contains a transparent viscous lubricant similar to mucin. It has a lubricating effect and is a secretion of human organs and tissues. It plays a role in lubricating, moisturizing organs and expelling toxins.
  • synovial fluid decreases or becomes viscous, metabolic products will remain in the body, causing various diseases: for example, the synovial fluid decreases with age, the joints lack lubricants, and the joints will develop degenerative arthritis, bone spurs, osteoporosis, etc. due to wear and tear. Long-term lack of synovial fluid in the joint cartilage will also cause osteoarthritis.
  • viscoelastic supplements include hyaluronic acid and carboxymethyl chitosan (also known as carboxymethyl glucosaminoglycan, chitosan).
  • carboxymethyl chitosan also known as carboxymethyl glucosaminoglycan, chitosan.
  • hyaluronic acid has been used for many years with good results, but carboxymethyl chitosan, as a new type of viscoelastic supplement, has a better therapeutic effect than hyaluronic acid as a viscoelastic supplement.
  • Patent application CN105709274A discloses a hyaluronic acid-like joint capsule thermosensitive gel for artificial joints and a preparation method thereof.
  • a hyaluronic acid-like joint capsule thermosensitive gel for artificial joints can be obtained.
  • the gel can be a sol, i.e., a liquid state, at a temperature below body temperature. After being injected into the human body, it is evenly distributed around the artificial joint to gel, forming a septum similar to the joint capsule.
  • the porous network after gelation forms a sustained-release environment for transporting artificial synovial fluid to the friction surface of the artificial joint.
  • Cida patent CN107349476B discloses a bionic Synovial fluid and its preparation method, specifically, carboxymethyl chitosan is used as the main raw material, and carboxymethyl chitosan with different cross-linking degrees and non-cross-linked carboxymethyl chitosan are respectively used to mix by physical method to prepare bionic synovial fluid, which can form bionic synovial fluid with viscoelasticity and fluidity index reaching normal synovial fluid, and can be used as a viscoelastic supplement when synovial fluid is missing or viscoelasticity decreases due to degenerative or traumatic arthritis, effectively slowing down the progression of degenerative or traumatic arthritis and relieving pain.
  • its friction coefficient is large, the gel granularity is heavy, and the lubrication performance is poor.
  • the present invention provides a joint cavity injection gel and a preparation method thereof.
  • the joint cavity injection gel obtained by the preparation method has a small friction coefficient, better lubrication performance, stronger safety performance and thermal stability.
  • the viscoelasticity and fluidity indicators of the formed gel meet the standards of normal joint cavity synovial fluid, effectively increase bone growth factor and have the effects of relieving pain and inflammation.
  • the invention provides a method for preparing a gel for joint cavity injection, wherein the active ester of polyethylene glycol is mixed with cross-linking carboxymethyl chitosan to produce a cross-linking reaction to obtain a gel, the gel is crushed and then mixed with a non-cross-linked carboxymethyl chitosan solution, sterilized, and cooled to obtain the gel for joint cavity injection;
  • the mass ratio of the polyethylene glycol active ester to the cross-linking carboxymethyl chitosan is 1:20-20:1.
  • the molecular weight of polyethylene glycol in the polyethylene glycol active ester is 2000Da-10000Da, 2-8 arms, and its chemical structure is as follows:
  • polyethylene glycol active ester PEG-NHS
  • PEG-NHS polyethylene glycol active ester
  • a cross-linking agent has a fast reaction speed and a short reaction time, which can reduce the growth of bacteria and endotoxins in the preparation process.
  • PEG-NHS polyethylene glycol active ester
  • it has lower toxicity and a long and controllable molecular chain. If the molecular weight is too small, the molecular chain is not long enough; if the molecular weight is too large, the molar ratio of the active group used for cross-linking is too low.
  • the molecular weight of polyethylene glycol in the polyethylene glycol active ester is 2000Da-5000Da, 2-4 arms;
  • the molecular weight of the polyethylene glycol in the polyethylene glycol active ester is 3500 Da, with 4 arms.
  • the carboxymethyl chitosan used for cross-linking has a deacetylation degree of 30-80%, a molecular weight of 500-1500 kDa, a substitution degree of 80%-200%, and a viscosity of 300-1000 mPa.s (at a mass fraction of 1%).
  • the carboxymethyl chitosan used for cross-linking has a deacetylation degree of 40-60%, a molecular weight of 600-800 kDa, a substitution degree of 100%-180%, and a viscosity of 300-500 mPa.s (at a mass fraction of 1%).
  • the carboxymethyl chitosan used for cross-linking has a deacetylation degree of 50%, a molecular weight of 700 KDa, a substitution degree of 120%, and a viscosity of 360 mPa.s (at a mass fraction of 1%).
  • the non-cross-linked carboxymethyl chitosan solution has a deacetylation degree of less than 30%, a molecular weight of 500-1500 kDa, a substitution degree of 80%-200%, and a viscosity of 300-1000 mPa.s (at a mass fraction of 1%).
  • the non-cross-linked carboxymethyl chitosan solution has a deacetylation degree of 10-28%, a molecular weight of 600-800 kDa, a substitution degree of 100%-180%, and a viscosity of 300-500 mPa.s (at a mass fraction of 1%).
  • the non-cross-linked carboxymethyl chitosan solution has a degree of deacetylation of 25%, a molecular weight of 700 kDa, a degree of substitution of 120%, and a viscosity of 360 mPa.s (at a mass fraction of 1%).
  • the pH of the cross-linking reaction is 7-8.5.
  • the preparation method specifically comprises the following steps:
  • the concentration of the phosphate buffer solution in step S1 is 0.2 mol/L and the pH is 7.2.
  • the mass fraction of the carboxymethyl chitosan used for cross-linking in step S1 is 1%-20%.
  • the conditions for the cross-linking reaction in step S2 are: temperature of 20-25° C., stirring speed of 60-90 rpm, and reaction time of 10-30 min.
  • the conditions for the cross-linking reaction in step S2 are: temperature of 25° C., stirring speed of 80 rpm, and reaction time of 15 min.
  • the standing time in step S2 is 2-4 hours.
  • the standing time in step S2 is 2 hours.
  • the polyethylene glycol active ester described in step S2 needs to be dissolved in PBS first.
  • the concentration of PBS is 0.2 mol/L and the pH is 7.2.
  • the gel in step S3 needs to be diluted by adding PBS first.
  • the mixed solution 2 described in step S3 also includes bone growth factor (SGF), anti-inflammatory and analgesic drugs such as lidocaine, moxifloxacin hydrochloride, vitamins, and polypeptide nutrients.
  • SGF bone growth factor
  • anti-inflammatory and analgesic drugs such as lidocaine, moxifloxacin hydrochloride, vitamins, and polypeptide nutrients.
  • the mass ratio of the gel in step S3 to the non-cross-linked carboxymethyl chitosan solution is 1:1-9:1.
  • the mass ratio of the gel in step S3 to the non-cross-linked carboxymethyl chitosan solution is 4:1.
  • the concentration of the non-cross-linked carboxymethyl chitosan in the mixed solution 2 in step S3 is 10-50 mg/ml.
  • the sterilization conditions in step S3 are: temperature 115°C-121°C, time 12-45 min; the cooling temperature is 18-25°C.
  • the sterilization conditions in step S3 are: temperature of 121° C., time of 15 min; and the cooling temperature of 25° C.
  • the present invention also provides a gel for joint cavity injection, which is prepared by the above-mentioned preparation method.
  • the high cross-linked gel of the invention has better flexibility and no granularity.
  • the increase of carbon chains leads to increased hydrophobicity, so that the swelling degree of the gel is lower, and the tissue compression caused by the increase of swelling volume is reduced.
  • the polyethylene glycol in the cross-linking agent forms reversible hydrogen bonds between carboxymethyl chitosan and polyol molecules, thereby enhancing the stability of the molecular structure of carboxymethyl chitin, reducing the damage of carboxymethyl chitin molecular chains by high temperature and high pressure, improving the sterilization stability of carboxymethyl chitin, and extending the degradation time.
  • the deacetylation degree of the non-cross-linked carboxymethyl chitosan solution is required to be less than 30 to avoid the immune response that may be caused by its amino group, which in turn affects the safety of the organism, and also to avoid the Maillard reaction with the carboxyl group on the molecular chain to cause self-cross-linking, destroy the product stability, and make the product yellow.
  • the deacetylation degree of the cross-linked carboxymethyl chitosan is required to be 30%-80%, because its amino group needs to undergo a cross-linking reaction with the active ester in the cross-linking agent to form a stable amide bond, and the amino group cannot be too much after cross-linking.
  • the carboxymethyl substitution degree of all carboxymethyl chitosans should be optimally 80%-200%, and have better water solubility within this substitution range.
  • the present invention has the following beneficial effects:
  • polyethylene glycol active ester as cross-linking agent, which has fast reaction speed, short reaction time and reduces pollution
  • the prepared high-crosslinked intra-articular injection gel has better flexibility and no granularity.
  • the increase in carbon chains leads to an increase in hydrophobicity, which makes the gel swelling lower and reduces tissue compression caused by the increase in swelling volume;
  • the intra-articular injection gel of the present invention has a small friction coefficient and better lubrication performance
  • Lysozyme is used to degrade the intra-articular injection gel of the present invention, and the degradation time is long;
  • the intra-articular injection gel prepared by the present invention has good thermal stability and is safer.
  • a carboxymethyl chitosan (deacetylation degree 25%, substitution degree 1.2, molecular weight 700kDa, viscosity 360mpa.s) solution was prepared with a concentration of 20mg/ml and a pH of 7.2.
  • the gel and solution were crushed and dispersed by compressed air through a 70-mesh sieve according to a mass ratio of 4:1, mixed 15 times, and the mixed gel was filled into a pre-filled syringe, sterilized with high-temperature steam at 121°C for 15min, and the sample was obtained after cooling.
  • carboxymethyl chitosan (deacetylation degree 30%, substitution degree 0.85, molecular weight 500kDa, viscosity 300mpa.s) solution with a concentration of 20mg/ml and pH 7.2. According to the ratio of 3:1, the gel and solution were crushed and dispersed by compressed air through a 70-mesh screen, mixed 15 times, and the mixed gel was filled into a pre-filled syringe, sterilized with high-temperature steam at 121°C for 15min, and the sample was obtained after cooling.
  • carboxymethyl chitosan (deacetylation degree 25%, substitution degree 0.85, molecular weight 600kDa, viscosity 330mpa.s) solution with a concentration of 20mg/ml and pH7.2. According to the ratio of 2:1, the gel and solution are crushed and dispersed by compressed air through a 70-mesh screen, mixed 15 times, and the mixed gel is filled into a pre-filled syringe, sterilized with high-temperature steam at 121°C for 15min, and the sample is obtained after cooling.
  • carboxymethyl chitosan (deacetylation degree 50%, substitution degree 1.2, molecular weight 700kDa, viscosity 360mpa.s). 25%, degree of substitution 1.2, molecular weight 700kDa, viscosity 360mPa.s) solution, concentration 20mg/ml, pH 7.2.
  • Gel and solution were crushed and dispersed by compressed air through a 70-mesh sieve according to a mass ratio of 4:1, mixed 15 times, and the mixed gel was filled into a pre-filled syringe, sterilized with high-temperature steam at 121°C for 15 minutes, and the sample was obtained after cooling.
  • carboxymethyl chitosan (deacetylation degree 25%, substitution degree 1.2, molecular weight 700kDa, viscosity 360mpa.s) solution with a concentration of 20mg/ml and pH 7.2. According to the mass ratio of 4:1, the gel and solution are crushed and dispersed by compressed air through a 70-mesh screen, mixed 15 times, and the mixed gel is filled into a pre-filled syringe, sterilized with high-temperature steam at 121°C for 15min, and the sample is obtained after cooling.
  • carboxymethyl chitosan (deacetylation degree 25%, substitution degree 1.2, molecular weight 700kDa, viscosity 360mpa.s) solution with a concentration of 20mg/ml and pH 7.2. According to the mass ratio of 4:1, the gel and solution were crushed and dispersed by compressed air through a 70-mesh screen, mixed 15 times, and the mixed gel was filled into a pre-filled syringe, sterilized with high-temperature steam at 121°C for 15min, and the sample was obtained after cooling.
  • lysozyme was used to degrade the mixed gel, and the degradation product was determined by the third method of potassium ferrocyanide reducing sugar determination method in GB/T5009.7-2016 "Determination of reducing sugar in food in national food safety standard". The specific results are shown in the following table.
  • the articular injection gel of the present invention has a longer complete degradation time and a strong in vitro degradation ability.
  • the mixed gel was filled into a prefilled syringe and sterilized with high-temperature steam at 121°C for 15 minutes.
  • the appearance of the sterilized sample and the sample before sterilization were compared and the elastic modulus was tested. It was found that the intra-articular injection gel of the present invention had better stability. The specific results are shown in the following table.
  • Swelling rate (mass of the sample after swelling - sampling amount) ⁇ 100% / sampling amount.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Surgery (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Vascular Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un gel d'injection pour cavité articulaire et son procédé de préparation, se rapportant au domaine de la biotribologie. Plus particulièrement, un ester actif de polyéthylène glycol et du carboxyméthyl chitosane pour réticulation sont mélangés et soumis à une réaction de réticulation pour obtenir un gel, puis le gel est fragmenté et mélangé à une solution de carboxyméthyl chitosane non réticulé, et le mélange est stérilisé et refroidi pour obtenir le gel d'injection pour cavité articulaire, le rapport de masse entre l'ester actif de polyéthylène glycol et le carboxyméthyl chitosane pour réticulation étant compris entre 1:20 et 20:1. Le gel d'injection pour cavité articulaire préparé selon ce procédé se caractérise par une meilleure flexibilité, l'absence de sensation granuleuse, un faible coefficient de frottement, une meilleure performance de lubrification, une bonne stabilité thermique et une plus grande sécurité ; en outre, l'utilisation de l'ester actif de polyéthylène glycol comme agent de réticulation permet une vitesse de réaction rapide et un temps de réaction court.
PCT/CN2023/126089 2022-11-08 2023-10-24 Gel d'injection pour cavité articulaire et son procédé de préparation Ceased WO2024099063A1 (fr)

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CN202211389774.9A CN115671405B (zh) 2022-11-08 2022-11-08 一种关节腔注射凝胶及其制备方法
CN202211389774.9 2022-11-08

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CN115671405B (zh) * 2022-11-08 2023-11-10 北京大清生物技术股份有限公司 一种关节腔注射凝胶及其制备方法
CN119564949B (zh) * 2025-02-10 2025-04-08 烟台万利医用品有限公司 一种关节腔用羧甲基甲壳素复合材料及其制备方法

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US20140170224A1 (en) * 2012-12-14 2014-06-19 Agency For Science, Technology And Research Gelatin-based microgels
US20150084232A1 (en) * 2013-09-26 2015-03-26 Northwestern University Poly(ethylene glycol) cross-linking of soft materials to tailor viscoelastic properties for bioprinting
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