WO2023197401A1 - 生物凝胶制剂、其制备方法及应用 - Google Patents

生物凝胶制剂、其制备方法及应用 Download PDF

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WO2023197401A1
WO2023197401A1 PCT/CN2022/093861 CN2022093861W WO2023197401A1 WO 2023197401 A1 WO2023197401 A1 WO 2023197401A1 CN 2022093861 W CN2022093861 W CN 2022093861W WO 2023197401 A1 WO2023197401 A1 WO 2023197401A1
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mass
dihydrogen phosphate
sodium dihydrogen
biogel
injection
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PCT/CN2022/093861
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English (en)
French (fr)
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王刚
于寅
黄健
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臻赫医药(杭州)有限公司
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Publication of WO2023197401A1 publication Critical patent/WO2023197401A1/zh

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    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • 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
    • A61K47/02—Inorganic compounds
    • 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
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis

Definitions

  • the present application relates to the field of biomedical technology, and in particular to a biogel preparation, its preparation method and application.
  • Osteoarthritis is the third most disabling disease in Europe and the United States and the fourth most common disabling disease in China. It can lead to reduced physical function and quality of life and increase the risk of all-cause death.
  • oral non-steroidal anti-inflammatory drugs NSAIDs
  • paracetamol acetaminophen
  • opioids are generally used for drug treatment.
  • osteoarthritis is a chronic disease, and long-term oral administration of the above drugs will cause stomach and kidney problems. Complications such as damage and addiction, as well as the fact that bone and joint tissues rely on tissue fluid nutrition, make it difficult for oral drugs to form effective drug concentrations in the bones and joints. Therefore, the preparation of pharmaceutical preparations for non-oral delivery routes has become an urgent technical problem to be solved in this field.
  • the purpose of this application is to provide a biogel preparation, its preparation method and application, so as to solve the technical problems in the prior art that oral administration is not conducive to increasing the effective drug concentration and systemic complications, and the biogel is difficult to sterilize.
  • the technical solution of this application is as follows: a biogel preparation is provided.
  • the raw materials of the biogel preparation include hyaluronic acid, sodium chloride, sodium dihydrogen phosphate dodecahydrate, sodium dihydrogen phosphate anhydrous and injectable drugs.
  • the biogel preparation is a freeze-dried powder.
  • the raw materials of the biogel preparation include 2 to 50 parts by mass of hyaluronic acid, 1 to 20 parts by mass of sodium chloride, 0.01 to 0.9 parts by mass of sodium dihydrogen phosphate dodecahydrate, 0.01 to 0.5 parts by mass of anhydrous sodium dihydrogen phosphate and 0.05 to 0.8 parts by mass of injection drugs.
  • the raw materials of the biogel preparation include 15 to 40 parts by mass of hyaluronic acid, 5 to 20 parts by mass of sodium chloride, 0.1 to 0.6 parts by mass of sodium phosphate dihydrogen phosphate dodecahydrate, 0.1 to 0.4 parts by mass of anhydrous sodium dihydrogen phosphate and 0.2 to 0.6 parts by mass of injection drugs.
  • the injection drug is amobarbital, pentobarbital, secobarbital, phenobarbital, metformin, metformin derivatives, nifedipine, Wnt pathway inhibitor SM04690, Wnt pathway inhibitor Agent SM04690 derivatives, osteoarthritis drug KA34, osteoarthritis drug KA34 derivatives, Galapagos GLPG1972, disulfiram, oxalopapaverine, TGF-beta encoding DNA, FGF18 encoding DNA, IL-1 encoding DNA, TGF-beta Encoding mRNA, FGF18 encoding mRNA, IL-1 encoding mRNA, FGF18 protein, BMP protein, TGF-beta protein, IL-1 protein, aminobenzoates, amides, aminoketones, aminoethers or carbamates one of them.
  • the molecular weight of the hyaluronic acid is 500,000 to 21.5 million.
  • a preparation method of a biogel preparation including:
  • the filtered and sterilized second solution is freeze-dried to obtain the biogel preparation.
  • the mass concentration of the hyaluronic acid is 2-50 mg/L
  • the mass concentration of the sodium chloride is 1-20 mg/L parts by mass
  • the dodecahydrate The mass concentration of sodium dihydrogen phosphate is 0.01-0.9 mg/L
  • the mass concentration of the anhydrous sodium dihydrogen phosphate is 0.01-0.5 mg/L
  • the mass concentration of the injection drug is 0.05-0.8 mg/L.
  • the molecular weight of the hyaluronic acid is 500,000 to 21.5 million.
  • the injection drug is amobarbital, pentobarbital, secobarbital, phenobarbital, metformin, metformin derivatives, nifedipine, Wnt pathway inhibitor SM04690, Wnt pathway inhibitor Agent SM04690 derivatives, osteoarthritis drug KA34, osteoarthritis drug KA34 derivatives, Galapagos GLPG1972, disulfiram, oxalopapaverine, TGF-beta encoding DNA, FGF18 encoding DNA, IL-1 encoding DNA, TGF-beta Encoding mRNA, FGF18 encoding mRNA, IL-1 encoding mRNA, FGF18 protein, BMP protein, TGF-beta protein, IL-1 protein, aminobenzoates, amides, aminoketones, aminoethers or carbamates one of them.
  • Another technical solution of the present application is as follows: providing an application of the above-mentioned biogel preparation in the treatment of osteoarthritis.
  • the biogel preparation of the present application, its preparation method and application, the raw materials include hyaluronic acid, sodium chloride, sodium dihydrogen phosphate dodecahydrate, anhydrous sodium dihydrogen phosphate and injectable drugs, and the biogel preparation is Lyophilized powder; through the above method, hyaluronic acid is prepared into a biogel preparation loaded with corresponding injectable drugs, and the biogel preparation is adjusted by sodium chloride, sodium phosphate dihydrogen dodecahydrate and sodium dihydrogen phosphate anhydrous
  • the pH value and osmotic pressure of the injection prepared by dissolving in water can be directly obtained by dissolving the biogel preparation in water to obtain a corresponding sterile injection that meets the injection requirements for clinical applications for local bone and joint injection, which can form local bone joints.
  • the effective drug concentration avoids gastric and renal damage caused by oral administration, and realizes the sterilization of biogel.
  • Figure 1 is a diagram of the experimental effects of each group in the application example of this application.
  • Embodiments of the present application provide a biogel preparation.
  • the raw materials of the biogel preparation include hyaluronic acid, sodium chloride, sodium phosphate dihydrogen dodecahydrate, sodium phosphate dihydrogen anhydrous, and injectable drugs.
  • the biogel preparation The preparation is lyophilized powder.
  • the biogel preparation in this embodiment is made into a freeze-dried powder, and hyaluronic acid is prepared into a medicated biogel to serve as a delivery carrier for injectable drugs, where the injectable drugs are small molecule drugs or macromolecule drugs, which can be used when needed. , dissolve the freeze-dried powder in water to obtain an injection.
  • the injection does not require further adjustment of pH value and osmotic pressure.
  • the injection can be directly injected into local bone and joints and is easy to use.
  • hyaluronic acid can control the release rate of injected drugs in local bones and joints, further increasing the efficacy of injected drugs.
  • the raw materials of the biogel preparation include 2 to 50 parts by mass of hyaluronic acid, 1 to 20 parts by mass of sodium chloride, and 0.01 to 0.9 parts by mass of dihydrogen phosphate dodecahydrate.
  • the raw materials of the biogel preparation include 15-40 parts by mass of hyaluronic acid, 5-20 parts by mass of sodium chloride, 0.1-0.6 parts by mass of sodium phosphate dihydrogen phosphate dodecahydrate, 0.1-0.4 parts by mass parts of anhydrous sodium dihydrogen phosphate and 0.2 to 0.6 parts by mass of injection drugs.
  • the injection drugs are amobarbital, pentobarbital, secobarbital, phenobarbital, metformin, metformin derivatives, nifedipine, Wnt pathway inhibitor SM04690, Wnt Pathway inhibitor SM04690 derivatives, osteoarthritis drug KA34, osteoarthritis drug KA34 derivatives, Galapagos GLPG1972, disulfiram, oxalopapaverine, TGF-beta encoding DNA, FGF18 encoding DNA, IL-1 encoding DNA, TGF -beta encoding mRNA, FGF18 encoding mRNA, IL-1 encoding mRNA, FGF18 protein, BMP protein, TGF-beta protein, IL-1 protein, aminobenzoates, amides, aminoketones, aminoethers or carbamic acid One of the esters.
  • the molecular weight of the hyaluronic acid is 500,000 to 21.5 million.
  • Hyaluronic acid that meets the above molecular weight can be used as a delivery carrier for small molecule drugs or large molecule drugs.
  • hyaluronic acid is prepared into a biogel preparation in the above manner to load the corresponding injectable drug, and is adjusted by sodium chloride, sodium phosphate dihydrogen dodecahydrate and sodium dihydrogen phosphate anhydrous.
  • the pH value and osmotic pressure of the injection prepared by dissolving the biogel preparation in water. Dissolving the biogel preparation in water can directly obtain the corresponding injection solution that meets the injection requirements for local bone and joint injection, which can form an effective local injection in the bone and joint. drug concentration to avoid gastric and renal damage caused by oral administration.
  • the biogel preparation of this embodiment is of great significance especially in local drug applications such as osteoarthritis prevention and treatment, osteoarthritis pain management and post-operative incision pain management and other subdivided fields.
  • the embodiments of the present application also provide a method for preparing a biogel preparation, which includes the following steps:
  • the above-mentioned second solution is filtered through a 0.22 ⁇ m filter membrane. Since the bacteria in the second solution cannot pass through the 0.22 ⁇ m filter membrane, when the second solution is filtered through the 0.22 ⁇ m filter membrane, the second solution is removed at the same time. The bacteria in the solution have a sterilizing effect; then the second solution is freeze-dried to obtain a sample of the biogel preparation.
  • the biogel preparation is a sterile preparation, also known as freeze-dried powder for injection, freeze-dried powder for injection
  • the sample is packaged in a glass bottle, butyl rubber stopper, and aluminum cap. When injection is required, dissolve the freeze-dried powder in water and inject into the bone joint.
  • a second solution is formed by mixing hyaluronic acid, sodium chloride, sodium dihydrogen phosphate dodecahydrate, anhydrous sodium dihydrogen phosphate and injection drugs.
  • the second solution is filtered, sterilized and freeze-dried.
  • a freeze-dried powder is formed. Each component of the freeze-dried powder can maintain its original activity when dissolved in water to form an injection solution, and can be directly injected as an injection solution.
  • the mass concentration of the hyaluronic acid is 2-50 mg/L, and the mass concentration of the sodium chloride is 1-20 mg/L parts by mass
  • the mass concentration of the sodium dihydrogen phosphate dodecahydrate is 0.01-0.9 mg/L
  • the mass concentration of the anhydrous sodium dihydrogen phosphate is 0.01-0.5 mg/L
  • the mass concentration of the injection drug is 0.05-0.8 mg/L.
  • the mass concentration of the hyaluronic acid is 15-40 mg/L
  • the mass concentration of the sodium chloride is 5-20 mg/L parts by mass
  • the phosphoric acid dodecahydrate is The mass concentration of sodium dihydrogen is 0.1-0.6 mg/L
  • the mass concentration of the anhydrous sodium dihydrogen phosphate is 0.1-0.4 mg/L
  • the mass concentration of the injection drug is 0.2-0.6 mg/L.
  • the molecular weight of the hyaluronic acid is 500,000 to 21.5 million.
  • the injection drug is amobarbital, pentobarbital, secobarbital, phenobarbital, metformin, metformin derivatives, nifedipine, Wnt pathway inhibitor SM04690, Wnt pathway inhibitor SM04690 derivatives, osteoarthritis drug KA34, osteoarthritis drug KA34 derivatives, Galapagos GLPG1972, disulfiram, oxalopapaverine, TGF-beta encoding DNA, FGF18 encoding DNA, IL-1 encoding DNA, TGF-beta encoding mRNA, FGF18 encoding mRNA, IL-1 encoding mRNA, FGF18 protein, BMP protein, TGF-beta protein, IL-1 protein, aminobenzoates, amides, aminoketones, aminoethers Or one of the carbamates.
  • the formula of blank medicated biogel preparation for injection is (unit: mg/L): hyaluronic acid 2-50; sodium chloride 1-20, sodium phosphate dihydrogen dodecahydrate 0.01-0.9, anhydrous diphosphate Sodium hydrogen 0.01-0.5.
  • Medicinal biogel preparations loaded with small molecule drugs such as barbiturates and derivatives preparation formula (unit: mg/L): hyaluronic acid 2-50; sodium chloride 1-20, sodium phosphate dihydrogen dodecahydrate 0.01-0.9, anhydrous sodium dihydrogen phosphate 0.01-0.5, amobarbital 0.05-0.8.
  • the formula of blank medicated biogel preparation for injection is (unit: mg/L): hyaluronic acid 2-50; sodium chloride 1-20, sodium phosphate dihydrogen dodecahydrate 0.01-0.9, anhydrous diphosphate Sodium hydrogen 0.01-0.5.
  • the blank biogel does not contain injection drugs and is used as a blank control.
  • MMT medial meniscus partial resection
  • Surgical modeling plan Preoperative medication and anesthesia. Before surgery, each animal was injected intramuscularly with a certain dose of antibiotics (gentamicin, 20mg/kg) and subcutaneously with atropine (0.05mg/kg); use 2.0-3.5 % isoflurane mixed with oxygen at a flow rate of 0.8–1.5 L/min was used to maintain the animal anesthesia during surgery.
  • antibiotics gentamicin, 20mg/kg
  • atropine 0.05mg/kg
  • isoflurane mixed with oxygen at a flow rate of 0.8–1.5 L/min was used to maintain the animal anesthesia during surgery.
  • the right knee joint was depilated before surgery and cleaned and disinfected with iodophor to prepare for surgery.
  • the medial side of the femoral-tibial joint will be incised, the medial meniscus will be exposed through blunt dissection, and a full-thickness incision will be made at the narrowest point of the meniscus.
  • the posterior joint will be reduced, the knee joint muscles, ligaments, and skin will be sutured, and the surgical site will be disinfect.
  • Figure 1 Pathological pictures of representative animals in each group.
  • Figure 1 A G1 group;
  • Figure 1 B G2;
  • Figure 1 C G3;
  • Figure 1 D G4,
  • Figure 1 E G5.

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Abstract

一种生物凝胶制剂、其制备方法及应用，原料包括透明质酸、氯化钠、十二水合磷酸二氢钠、无水磷酸二氢钠以及注射药物，并且，该生物凝胶制剂为冻干粉剂；通过上述方式，将透明质酸制备成生物凝胶制剂载荷相应的注射药物，并通过氯化钠、十二水合磷酸二氢钠以及无水磷酸二氢钠调节该生物凝胶制剂溶于水制备的注射液的pH值及渗透压，将该生物凝胶制剂溶于水可以直接得到符合临床应用注射要求的对应无菌注射液进行局部骨关节注射，能够在骨关节局部形成有效药物浓度，避免口服给药方式出现的胃肾损害，克服生物凝胶难以灭菌技术难题。

Description

生物凝胶制剂、其制备方法及应用 技术领域
本申请涉及生物医药技术领域，尤其涉及一种生物凝胶制剂、其制备方法及应用。
背景技术
骨关节炎是欧美第三大和中国第四大致残疾病，会导致身体机能和生活质量下降，并增加全因死亡的风险。现有技术中，一般采用口服非甾体抗炎药(NSAID)，扑热息痛(对乙酰氨基酚)或阿片类药物的药物治疗方式，但是骨关节炎为慢性疾病，长期口服上述药物会出现胃肾损害和上瘾等并发症，加上骨关节组织依赖组织液营养，口服药物难以在骨关节局部形成有效药物浓度。因此，制备非口服递送途径的药物制剂成为本领域亟待解决的技术问题。
发明内容
本申请的目的在于提供一种生物凝胶制剂、其制备方法及应用，以解决现有技术中口服给药不利于提高有效药物浓度和全身并发症及生物凝胶难以灭菌的技术问题。
本申请的技术方案如下：提供一种生物凝胶制剂，所述生物凝胶制剂的原料包括透明质酸、氯化钠、十二水合磷酸二氢钠、无水磷酸二氢钠以及注射药物，所述生物凝胶制剂为冻干粉剂。
可选地，所述生物凝胶制剂的原料包括2～50质量份的透明质酸、1～20质量份的氯化钠、0.01～0.9质量份的十二水合磷酸二氢钠、0.01～0.5质量份的无水磷酸二氢钠以及0.05～0.8质量份的注射药物。
可选地，所述生物凝胶制剂的原料包括15～40质量份的透明质酸、5～20质量份的氯化钠、0.1～0.6质量份的十二水合磷酸二氢钠、0.1～0.4质量份的无水磷酸二氢钠以及0.2～0.6质量份的注射药物。
可选地，所述注射药物为异戊巴比妥、戊巴比妥、司可巴比妥、苯巴比妥、 二甲双胍、二甲双胍衍生物、硝苯地平、Wnt通路抑制剂SM04690、Wnt通路抑制剂SM04690衍生物、骨关节炎药物KA34、骨关节炎药物KA34衍生物、Galapagos GLPG1972、双硫仑、氧海罂粟碱、TGF-beta编码DNA、FGF18编码DNA、IL-1编码DNA、TGF-beta编码mRNA、FGF18编码mRNA、IL-1编码mRNA、FGF18蛋白、BMP蛋白、TGF-beta蛋白、IL-1蛋白、氨基苯甲酸酯类、酰胺类、氨基酮类、氨基醚类或氨基甲酸酯类中的一种。
可选地，所述透明质酸的分子量为50万～2150万。
本申请的另一技术方案如下：提供一种生物凝胶制剂的制备方法，包括：
将透明质酸进行浸泡溶胀，得到第一溶液；
在所述第一溶液中加入氯化钠、十二水合磷酸二氢钠、无水磷酸二氢钠以及注射药物，得到第二溶液；
将所述第二溶液用微孔滤膜进行过滤灭菌；
将过滤后灭菌的所述第二溶液进行冷冻干燥，得到所述生物凝胶制剂。
可选地，在所述第二溶液中，所述透明质酸的质量浓度为2～50mg/L，所述氯化钠的质量浓度为1～20mg/L质量份的，所述十二水合磷酸二氢钠的质量浓度为0.01～0.9mg/L、所述无水磷酸二氢钠的质量浓度为0.01～0.5mg/L，所述注射药物的质量浓度为0.05～0.8mg/L。
可选地，所述透明质酸的分子量为50万～2150万。
可选地，所述注射药物为异戊巴比妥、戊巴比妥、司可巴比妥、苯巴比妥、二甲双胍、二甲双胍衍生物、硝苯地平、Wnt通路抑制剂SM04690、Wnt通路抑制剂SM04690衍生物、骨关节炎药物KA34、骨关节炎药物KA34衍生物、Galapagos GLPG1972、双硫仑、氧海罂粟碱、TGF-beta编码DNA、FGF18编码DNA、IL-1编码DNA、TGF-beta编码mRNA、FGF18编码mRNA、IL-1编码mRNA、FGF18蛋白、BMP蛋白、TGF-beta蛋白、IL-1蛋白、氨基苯甲酸酯类、酰胺类、氨基酮类、氨基醚类或氨基甲酸酯类中的一种。
本申请的另一技术方案如下：提供一种上述的生物凝胶制剂在治疗骨关节炎中的应用。
本申请的生物凝胶制剂、其制备方法及应用，原料包括透明质酸、氯化钠、 十二水合磷酸二氢钠、无水磷酸二氢钠以及注射药物，并且，该生物凝胶制剂为冻干粉剂；通过上述方式，将透明质酸制备成生物凝胶制剂载荷相应的注射药物，并通过氯化钠、十二水合磷酸二氢钠以及无水磷酸二氢钠调节该生物凝胶制剂溶于水制备的注射液的pH值及渗透压，将该生物凝胶制剂溶于水可以直接得到符合临床应用注射要求的对应无菌的注射液进行局部骨关节注射，能够在骨关节局部形成有效药物浓度，避免口服给药方式出现的胃肾损害，实现了对生物凝胶的灭菌处理。
附图说明
图1为本申请应用例中各组实验效果图。
具体实施方式
下面结合附图和实施方式对本申请作进一步说明。
本申请实施例提供一种生物凝胶制剂，该生物凝胶制剂的原料包括透明质酸、氯化钠、十二水合磷酸二氢钠、无水磷酸二氢钠以及注射药物，该生物凝胶制剂为冻干粉剂。
本实施例的生物凝胶制剂被制成冻干粉剂，透明质酸被制备为含药生物凝胶成为注射药物的递送载体，其中，注射药物为小分子药物或大分子药物，在需要使用时，将该冻干粉剂溶于水得到注射液，该注射液无需进一步调节pH值及渗透压，该注射液可以直接进行局部骨关节注射，使用方便。透明质酸作为注射药物的递送载体，可以控制注射药物在局部骨关节的释放速度，进一步增加注射药物的药效。
在一个可选的实施方式中，所述生物凝胶制剂的原料包括2～50质量份的透明质酸、1～20质量份的氯化钠、0.01～0.9质量份的十二水合磷酸二氢钠、0.01～0.5质量份的无水磷酸二氢钠以及0.05～0.8质量份的注射药物。
进一步地，所述生物凝胶制剂的原料包括15～40质量份的透明质酸、5～20质量份的氯化钠、0.1～0.6质量份的十二水合磷酸二氢钠、0.1～0.4质量份的无水磷酸二氢钠以及0.2～0.6质量份的注射药物。
在本实施例中，所述注射药物为异戊巴比妥、戊巴比妥、司可巴比妥、苯巴比妥、二甲双胍、二甲双胍衍生物、硝苯地平、Wnt通路抑制剂SM04690、Wnt 通路抑制剂SM04690衍生物、骨关节炎药物KA34、骨关节炎药物KA34衍生物、Galapagos GLPG1972、双硫仑、氧海罂粟碱、TGF-beta编码DNA、FGF18编码DNA、IL-1编码DNA、TGF-beta编码mRNA、FGF18编码mRNA、IL-1编码mRNA、FGF18蛋白、BMP蛋白、TGF-beta蛋白、IL-1蛋白、氨基苯甲酸酯类、酰胺类、氨基酮类、氨基醚类或氨基甲酸酯类中的一种。
在本实施例中，所述透明质酸的分子量为50万～2150万。满足上述分子量的透明质酸可以作为小分子药物或大分子药物的递送载体。
本实施例的生物凝胶制剂通过上述方式，将透明质酸制备成生物凝胶制剂载荷相应的注射药物，并通过氯化钠、十二水合磷酸二氢钠以及无水磷酸二氢钠调节该生物凝胶制剂溶于水制备的注射液的pH值及渗透压，将该生物凝胶制剂溶于水可以直接得到符合注射要求的对应注射液进行局部骨关节注射，能够在骨关节局部形成有效药物浓度，避免口服给药方式出现的胃肾损害。本实施例的生物凝胶制剂特别在局部药物应用例如骨关节炎防治，骨关节炎疼痛处理和手术后切口疼痛处理等细分领域具有重大意义。
本申请实施例还提供了一种生物凝胶制剂的制备方法，包括如下步骤：
S10，将透明质酸进行浸泡溶胀，得到第一溶液；
其中，先称取配方量的透明质酸，加水使其完全溶胀。
S20，在所述第一溶液中加入氯化钠、十二水合磷酸二氢钠、无水磷酸二氢钠以及注射药物，得到第二溶液；
其中，再加入处方量的注射药物、氯化钠、十二水合磷酸二氢钠、无水磷酸二氢钠，充分搅拌溶解混匀，定容至所需体积。
S30，将所述第二溶液用微孔滤膜进行过滤灭菌；
S40，将过滤灭菌后的所述第二溶液进行冷冻干燥，得到所述生物凝胶制剂。
其中，搅拌混匀后再将上述第二溶液经0.22μm滤膜过滤，由于第二溶液中的细菌无法通过0.22μm滤膜，因此，第二溶液经0.22μm滤膜过滤时同时去除了第二溶液中的细菌，具有灭菌的效果；随后将第二溶液冻干后即得生物凝胶制剂的样品，该生物凝胶制剂为无菌制剂，又称为冻干粉针剂，冻干粉针剂样品用玻璃瓶、丁基胶塞、铝盖包装，需要进行注射时，用水溶解冻干粉后，骨关节注 射。
本实施例中，通过将透明质酸、氯化钠、十二水合磷酸二氢钠、无水磷酸二氢钠以及注射药物进行配伍形成第二溶液，第二溶液经过过滤灭菌以及冷冻干燥后形成冻干粉剂，该冻干粉剂在溶解于水形成注射液中各成分还能保持原有活性，可以直接作为注射液进行注射。
作为一种可选的实施方式，在所述第二溶液中，所述透明质酸的质量浓度为2～50mg/L，所述氯化钠的质量浓度为1～20mg/L质量份的，所述十二水合磷酸二氢钠的质量浓度为0.01～0.9mg/L、所述无水磷酸二氢钠的质量浓度为0.01～0.5mg/L，所述注射药物的质量浓度为0.05～0.8mg/L。
进一步地，在所述第二溶液中，所述透明质酸的质量浓度为15～40mg/L，所述氯化钠的质量浓度为5～20mg/L质量份的，所述十二水合磷酸二氢钠的质量浓度为0.1～0.6mg/L、所述无水磷酸二氢钠的质量浓度为0.1～0.4mg/L，所述注射药物的质量浓度为0.2～0.6mg/L。
作为一种可选的实施方式，所述透明质酸的分子量为50万～2150万。
作为一种可选的实施方式，所述注射药物为异戊巴比妥、戊巴比妥、司可巴比妥、苯巴比妥、二甲双胍、二甲双胍衍生物、硝苯地平、Wnt通路抑制剂SM04690、Wnt通路抑制剂SM04690衍生物、骨关节炎药物KA34、骨关节炎药物KA34衍生物、Galapagos GLPG1972、双硫仑、氧海罂粟碱、TGF-beta编码DNA、FGF18编码DNA、IL-1编码DNA、TGF-beta编码mRNA、FGF18编码mRNA、IL-1编码mRNA、FGF18蛋白、BMP蛋白、TGF-beta蛋白、IL-1蛋白、氨基苯甲酸酯类、酰胺类、氨基酮类、氨基醚类或氨基甲酸酯类中的一种。
实施例1
本实施例提供一种生物凝胶制剂制备方法及制备所得生物凝胶制剂
1，注射用空白含药生物凝胶制剂配方为(单位为mg/L)：透明质酸2-50；氯化钠1-20，十二水合磷酸二氢钠0.01-0.9，无水磷酸二氢钠0.01-0.5。
2，含药生物凝胶制剂载荷小分子药物例如巴比妥及衍生物制剂配方(单位为mg/L)：透明质酸2-50；氯化钠1-20，十二水合磷酸二氢钠0.01-0.9，无水磷酸二氢钠0.01-0.5，异戊巴比妥0.05-0.8。
3，制备用含药生物凝胶冻干制剂制备：
先称取配方量的透明质酸，加水使其完全溶胀。再加入处方量的异戊巴比妥钠、氯化钠、十二水合磷酸二氢钠、无水磷酸二氢钠，充分搅拌溶解混匀，定容至所需体积。搅拌混匀后再将上述药液经0.22μm滤膜过滤，冻干后即得样品，冻干粉针剂样品用玻璃瓶、丁基胶塞、铝盖包装，注射用水溶解冻干粉后(具体见下)，骨关节注射。
表1不同冻干阶段参数表
Figure PCTCN2022093861-appb-000001
对比例1：空白生物凝胶制备
1，注射用空白含药生物凝胶制剂配方为(单位为mg/L)：透明质酸2-50；氯化钠1-20，十二水合磷酸二氢钠0.01-0.9，无水磷酸二氢钠0.01-0.5。
2，制备空白生物凝胶冻干制剂制备：
先称取配方量的透明质酸，加水使其完全溶胀。再加入处方量的氯化钠、十二水合磷酸二氢钠、无水磷酸二氢钠，充分搅拌溶解混匀，定容至所需体积。搅拌混匀后再将上述药液经0.22μm滤膜过滤，冻干后即得样品，冻干粉针剂样品用玻璃瓶、丁基胶塞、铝盖包装，注射用水溶解冻干粉后，骨关节注射。
其中，空白生物凝胶中不含注射药物，作为空白对照使用。
应用例
建立内侧半月板局部切除(MMT)诱导骨关节炎模型
1，手术造模方案：术前给药及麻醉术前每只动物分别肌肉注射一定剂量的抗生素(庆大霉素，20mg/kg)，皮下注射阿托品(0.05mg/kg)；使用2.0-3.5％异氟烷混合0.8–1.5L/min流速的氧气用于维持动物在手术中麻醉。
2，手术过程
动物麻醉后，对行前右侧膝关节进行脱毛，并用碘伏清洁消毒，做好手术准 备。股骨-胫骨关节内侧将被切开，通过钝性分离显露内侧半月板，并在半月板最窄的处进行全厚度切割，完成后关节复位，缝合膝关节肌肉、韧带及皮肤，并对手术部位消毒。
3，术后护理
所有动物术后连续3天给予一定量的镇痛剂痛立定(8-10mg/kg，i.m.)，每日一次。所有动物手术结束后给予一定量的抗生素(庆大霉素，20mg/kg，i.m.)。
麻醉恢复期动物允许自由的活动及完全负重，动物实验人员在麻醉恢复期须密切监控所有动物。
空白含药生物凝胶和荷载巴比妥生物凝胶给药治疗
手术后第二天(24小时内)所有动物采用关节腔注射方式给予测试物，一星期后再注射一次，共2次，给药方案见表2所示。
表2不同组给药方案表
Figure PCTCN2022093861-appb-000002
Figure PCTCN2022093861-appb-000003
实验结果及分析：
图1各分组代表性动物的病理图片图1中A：G1组；图1中B：G2；图1中C：G3；图1中D：G4，图1中E：G5。
组织病理学评价结果显示，与G2组(图B)相比，G5组(图E)显著地减缓半月板切除诱导的大鼠骨性关节炎软骨退行性变，对骨性关节炎的软骨细胞集聚，骨刺形成也均有减缓效果。同时，G4(图D)给药后42天对月板切除诱导的大鼠骨性关节炎退行性变也有一定减缓趋势。
以上所述的仅是本申请的实施方式，在此应当指出，对于本领域的普通技术人员来说，在不脱离本申请创造构思的前提下，还可以做出改进，但这些均属于本申请的保护范围。

Claims (10)

  1. 一种生物凝胶制剂，其特征在于，所述生物凝胶制剂的原料包括透明质酸、氯化钠、十二水合磷酸二氢钠、无水磷酸二氢钠以及注射药物，所述生物凝胶制剂为冻干粉剂。
  2. 根据权利要求1所述的生物凝胶制剂，其特征在于，所述生物凝胶制剂的原料包括2～50质量份的透明质酸、1～20质量份的氯化钠、0.01～0.9质量份的十二水合磷酸二氢钠、0.01～0.5质量份的无水磷酸二氢钠以及0.05～0.8质量份的注射药物。
  3. 根据权利要求2所述的生物凝胶制剂，其特征在于，所述生物凝胶制剂的原料包括15～40质量份的透明质酸、5～20质量份的氯化钠、0.1～0.6质量份的十二水合磷酸二氢钠、0.1～0.4质量份的无水磷酸二氢钠以及0.2～0.6质量份的注射药物。
  4. 根据权利要求1～3任一项所述的生物凝胶制剂，其特征在于，所述注射药物为异戊巴比妥、戊巴比妥、司可巴比妥、苯巴比妥、二甲双胍、二甲双胍衍生物、硝苯地平、Wnt通路抑制剂SM04690、Wnt通路抑制剂SM04690衍生物、骨关节炎药物KA34、骨关节炎药物KA34衍生物、Galapagos GLPG1972、双硫仑、氧海罂粟碱、TGF-beta编码DNA、FGF18编码DNA、IL-1编码DNA、TGF-beta编码mRNA、FGF18编码mRNA、IL-1编码mRNA、FGF18蛋白、BMP蛋白、TGF-beta蛋白、IL-1蛋白、氨基苯甲酸酯类、酰胺类、氨基酮类、氨基醚类或氨基甲酸酯类中的一种。
  5. 根据权利要求1～3任一项所述的生物凝胶制剂，其特征在于，所述透明质酸的分子量为50万～2150万。
  6. 一种生物凝胶制剂的制备方法，其特征在于，包括：
    将透明质酸进行浸泡溶胀，得到第一溶液；
    在所述第一溶液中加入氯化钠、十二水合磷酸二氢钠、无水磷酸二氢钠以及注射药物，得到第二溶液；
    将所述第二溶液用微孔滤膜进行过滤灭菌；
    将过滤后灭菌的所述第二溶液进行冷冻干燥，得到所述生物凝胶制剂。
  7. 根据权利要求6所述的生物凝胶制剂的制备方法，其特征在于，在所述第二溶液中，所述透明质酸的质量浓度为2～50mg/L，所述氯化钠的质量浓度为1～20mg/L质量份的，所述十二水合磷酸二氢钠的质量浓度为0.01～0.9mg/L、所述无水磷酸二氢钠的质量浓度为0.01～0.5mg/L，所述注射药物的质量浓度为0.05～0.8mg/L。
  8. 根据权利要求6所述的生物凝胶制剂的制备方法，其特征在于，所述透明质酸的分子量为50万～2150万。
  9. 根据权利要求6所述的生物凝胶制剂的制备方法，其特征在于，所述注射药物为异戊巴比妥、戊巴比妥、司可巴比妥、苯巴比妥、二甲双胍、二甲双胍衍生物、硝苯地平、Wnt通路抑制剂SM04690、Wnt通路抑制剂SM04690衍生物、骨关节炎药物KA34、骨关节炎药物KA34衍生物、Galapagos GLPG1972、双硫仑、氧海罂粟碱、TGF-beta编码DNA、FGF18编码DNA、IL-1编码DNA、TGF-beta编码mRNA、FGF18编码mRNA、IL-1编码mRNA、FGF18蛋白、BMP蛋白、TGF-beta蛋白、IL-1蛋白、氨基苯甲酸酯类、酰胺类、氨基酮类、氨基醚类或氨基甲酸酯类中的一种。
  10. 权利要求1至5任一项所述的生物凝胶制剂在治疗骨关节炎中的应用。
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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2000230001A (ja) * 1999-02-15 2000-08-22 Denki Kagaku Kogyo Kk ヒアルロン酸ゲルスラリー及びその用途
CN1864662A (zh) * 2006-06-12 2006-11-22 中国人民解放军第三军医大学第一附属医院 一种关节腔内注射治疗骨关节炎的雷公藤内酯醇复方制剂
CN103254448A (zh) * 2013-05-17 2013-08-21 成都金凯生物技术有限公司 一种医用透明质酸钠凝胶及其制备方法
CN114010640A (zh) * 2015-08-19 2022-02-08 爱荷华大学研究基金会 创伤后骨关节炎的预防性治疗

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1321692C (zh) * 2005-08-16 2007-06-20 广东天普生化医药股份有限公司 一种治疗关节炎的药物组合物
WO2014096257A1 (en) * 2012-12-19 2014-06-26 Novozymes Biopharma Dk A/S Freeze-dried cross-linked hyaluronic acid sponge
CN108403628B (zh) * 2018-05-21 2021-01-08 北京和舆医药科技有限公司 一种地塞米松磷酸钠注射剂

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2000230001A (ja) * 1999-02-15 2000-08-22 Denki Kagaku Kogyo Kk ヒアルロン酸ゲルスラリー及びその用途
CN1864662A (zh) * 2006-06-12 2006-11-22 中国人民解放军第三军医大学第一附属医院 一种关节腔内注射治疗骨关节炎的雷公藤内酯醇复方制剂
CN103254448A (zh) * 2013-05-17 2013-08-21 成都金凯生物技术有限公司 一种医用透明质酸钠凝胶及其制备方法
CN114010640A (zh) * 2015-08-19 2022-02-08 爱荷华大学研究基金会 创伤后骨关节炎的预防性治疗

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
HE, ZHIWEI ET AL..: "An Overview of Hydrogel-Based Intra-Articular Drug Delivery for the Treatment of Osteoarthritis.", COLLOIDS AND SURFACES B: BIOINTERFACES., vol. 154, 6 March 2017 (2017-03-06), XP085001965, DOI: 10.1016/j.colsurfb.2017.03.003 *
QIN GAO, CHEN JIAN-YING, LIU WEN-GUAN: "Study on Stability of Sinomenine Hydrochloride Hyaluronic Acid Composite Gel for Injection", JOURNAL OF SHANDONG MEDICAL COLLEGE, vol. 40, no. 3, 2 July 2018 (2018-07-02), pages 167 - 169, XP093099270 *
ZHANG ZHIWEI, WEI XIAOCHUN, GAO JIZONG, ZHAO YU, ZHAO YAMIN, GUO LI, CHEN CHONGWEI, DUAN ZHIQING, LI PENGCUI, WEI LEI: "Intra-Articular Injection of Cross-Linked Hyaluronic Acid-Dexamethasone Hydrogel Attenuates Osteoarthritis: An Experimental Study in a Rat Model of Osteoarthritis", INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, vol. 17, no. 4, 15 April 2016 (2016-04-15), pages 411, XP093099267, DOI: 10.3390/ijms17040411 *

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