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WO2020111888A1 - Composition de supplément de liquide synovial comprenant de l'acide hyaluronique - Google Patents

Composition de supplément de liquide synovial comprenant de l'acide hyaluronique Download PDF

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Publication number
WO2020111888A1
WO2020111888A1 PCT/KR2019/016778 KR2019016778W WO2020111888A1 WO 2020111888 A1 WO2020111888 A1 WO 2020111888A1 KR 2019016778 W KR2019016778 W KR 2019016778W WO 2020111888 A1 WO2020111888 A1 WO 2020111888A1
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Prior art keywords
synovial fluid
composition
hyaluronic acid
weight
mannitol
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Korean (ko)
Inventor
정현태
이현섭
장인석
김상은
소진언
김태협
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LG Chem Ltd
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LG Chem Ltd
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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
    • A61L27/20—Polysaccharides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
    • A61K31/728—Hyaluronic acid
    • 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
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • 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
    • 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
    • A61L27/54—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
    • A61M5/178—Syringes
    • A61M5/28—Syringe ampoules or carpules, i.e. ampoules or carpules provided with a needle
    • 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
    • A61L2400/00—Materials characterised by their function or physical properties
    • A61L2400/06—Flowable or injectable implant compositions
    • 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
    • A61L2430/24—Materials or treatment for tissue regeneration for joint reconstruction

Definitions

  • the present invention relates to a composition for supplementing synovial fluid containing hyaluronic acid, and more specifically, it comprises hyaluronic acid and satisfies certain conditions during a frequency sweep test and a rate sweep test. It relates to a composition for joint synovial fluid replenishment having a high stability and a high pain relief effect in terms of hyaluronic acid molecular weight and viscoelasticity, having a high average recovery rate and a small amount of deformation.
  • arthroscopic surgery is frequently performed as a method for the treatment of joint lesions such as osteoarthritis or synovitis.
  • Arthroscopic surgery refers to inserting an endoscope with a small camera into a joint by making a hole through a minimal incision less than 1 cm in diameter around the joint and performing surgery while viewing a high-resolution monitor.
  • Types of arthroscopic surgery include tendon, ligament reconstruction and suture-related surgery, meniscal resection and suture-related surgery, limb resection, vitrectomy, and cruciate ligament plastic surgery.
  • tendon As many as 330,000 patients received, a large number of patients are undergoing arthroscopic surgery (Judgment Evaluation and Assessment Service, Health and Medical Big Data Medical Opening System, and Statistical Practices).
  • the knee joint is the largest joint in the human body, and is not only surrounded by muscles in the front, but also has no important blood vessels or nerves, so it is known as the most suitable joint to perform arthroscopic surgery. Therefore, arthroscopic surgery performed on the knee joint is the most frequently performed during arthroscopic surgery, and the total occupied joint arthroscopic surgery is known to be about 80% (Samsung Seoul Hospital Orthopedic Surgery Ahn Jin-hwan, Korean doctor) Association magazine).
  • the arthroscopic procedures performed in the knee joint include partial or total meniscectomy, meniscal repair, removal of loose body, synovectomy, and exfoliative bone. Removal or fixation of osteochondritis dissecans, repair or reconstruction of cruciate ligament, and fracture fixation.
  • synovial fluid supplement made of a polymer solution such as hyaluronic acid is used to wash the physiological saline used for arthroscopic surgery, temporarily supplement and replace the lost joint synovial fluid to relieve pain.
  • the synovial fluid supplement is classified as a biomaterial (medical device) for grade 4 tissue repair, and was developed to replace synovial fluid that is lost after arthroscopic surgery. It reduces the risk of infection by coating the synovial cell layer of joint cartilage and reducing the functionality quickly. As for this, only the Viscoseal®, an isotonic solution based on hyaluronic acid, which has been approved by the Ministry of Food and Drug Safety in April 2016, is currently being used as the first joint synovial replacement in Korea.
  • Viscosil forms a layer of hyaluronic acid as the hyaluronic acid isotonic solution is coated, and this layer becomes active, which causes a masking effect on the joints and reduces the pain caused by this, reducing the discomfort the patient feels after joint surgery. It was developed for the purpose of prescribing. On the other hand, there are no domestic products currently approved for manufacturing, but it is estimated that there is a market size of about 40 to 60 billion.
  • synovial fluid supplements are still insufficient compared to the market size.
  • the initial pain relief of patients with arthroscopic surgery is affected by the molecular weight and viscoelasticity of the polymer solution used as synovial fluid supplementation, it is important to improve the stability of the polymer solution to maintain the molecular weight and viscoelastic stability.
  • the present invention has been proposed to solve the above problems, and has a specific numerical range during a frequency sweep test and a rate sweep tset, thereby causing the hyaluronic acid molecular weight and the solution of the hyaluronic acid solution in the hyaluronic acid solution. It is an object of the present invention to provide a composition for synovial fluid supplements, which is stable and does not decrease in viscoelasticity, and has high stability and high pain relief when injecting into the human body.
  • the present invention was devised to solve the problems of the prior art as described above, storage modulus and phase angle measured according to the frequency change test, and relaxation time measured according to the shear rate change test.
  • the (relaxation time) and the shear thinning index indicate a specific range, the molecular weight of the hyaluronic acid in the hyaluronic acid solution and the viscoelasticity of the solution are maintained without loss, resulting in high stability when injecting the human body and a pain relief effect. It has been confirmed that a composition for a high synovial fluid supplement can be provided and the present invention has been completed.
  • the present invention includes hyaluronic acid or a salt thereof, and mannitol, and storage modulus and phase angle measured according to a frequency change test,
  • the relaxation time and shear thinning index measured according to the shear rate change test have a specific range, specifically, the storage modulus measured at 1 Hz according to the frequency change test is 3 Pa or more.
  • the phase angle may be 60° or less, or a storage elastic modulus measured at 2.5 Hz of 6 Pa or more and a phase angle of 50° or less.
  • the composition for synovial fluid supplements according to the present invention has a relaxation time measured according to a shear rate change test of 0.1 seconds or more and a shear thinning index of 0.35 or less. Characterized by, it relates to a composition for joint synovial fluid supplement containing hyaluronic acid.
  • the composition for joint synovial fluid replenishment is injected into a joint or a region around the joint, replacing synovial fluid that is lost during arthroscopic surgery by replenishing synovial fluid, rapid functional recovery due to frictional reduction in joints, and reducing the risk of infection in the joint surgery site , Or may be used to relieve joint pain in a patient.
  • Hyaluronic acid (hereinafter, also referred to as'HA') contained in the synovial fluid supplement composition of the present invention is a biopolymer material in which a repeating unit composed of N-acetyl-D-glucosamine and D-glucuronic acid is linearly connected, It is present in a lot of eye fluids, joint synovial fluid, chicken clumps, etc., and has excellent biocompatibility, so it is used for medical and medical or cosmetic applications such as ophthalmic surgical aids, joint function improvers, drug delivery substances, eye drops, wrinkle improving agents, etc. It is widely used.
  • the hyaluronic acid contained in the synovial fluid supplement composition of the present invention may include a salt thereof in addition to hyaluronic acid.
  • the salt of hyaluronic acid includes, for example, inorganic salts such as sodium hyaluronate, potassium hyaluronate, calcium hyaluronate, magnesium hyaluronate, zinc hyaluronate, cobalt hyaluronate, and organic salts such as tetrabutylammonium hyaluronate It is, but is not limited to.
  • the average molecular weight of hyaluronic acid used as a synovial fluid composition may be 1,800,000 Da or more, preferably 1,800,000 to 4,00,000 Da, and more preferably 2,500,000 to 3,500,000 Da.
  • composition for hyaluronic acid synovial fluid supplements according to the present invention may be 0.1 to 3.0% by weight, and preferably 0.3 to 1.0% by weight of hyaluronic acid.
  • composition for a synovial fluid supplement according to the present invention includes mannitol.
  • the mannitol may be included as a stabilizer for stabilizing hyaluronic acid contained in synovial fluid supplement.
  • synovial fluid supplement when mannitol is included in the synovial fluid supplement according to the present invention, even if hyaluronic acid of the polymer is used, it is possible to minimize the decrease in molecular weight due to sterilization or storage as described above, thereby providing a stable synovial fluid supplement. I can do it.
  • the content of mannitol contained in the synovial fluid supplement composition according to the present invention is 3% by weight or more, preferably 3% by weight or more and 10% by weight or less, more preferably 3% by weight or more, based on the total synovial fluid supplement weight. 7% by weight or less.
  • the composition for hyaluronic acid-based synovial fluid supplements according to the present invention exhibits excellent stability in terms of the molecular weight and viscoelasticity of hyaluronic acid, and specifically, the storage elastic modulus measured at 1 Hz according to the frequency change test is 3 Pa or more and the phase angle is 60°. It is characterized in that the storage modulus measured at 2.5 Hz or less is 6 Pa or more and the phase angle is 50° or less.
  • the measured storage elastic modulus at 1 Hz may be 2 Pa or more and 20 Pa or less, more preferably 3 Pa or more and 15 Pa or less, and the measured storage elastic modulus at 2.5 Hz may be 5 Pa or more and 25 Pa or less, more preferably 6 Pa or more.
  • the measured phase angle at 1 Hz may be 20° or more to 60° or less, more preferably 40° or more to 60° or less, and the measured phase angle at 2.5 Hz may be 20° or more to It may be 50° or less, more preferably 30° or more to 50° or less.
  • the frequency sweep test (oscillation) is to determine the change in rheological properties according to the shear rate in order to measure the viscoelastic properties according to the frequency change, shear storage modulus (G', storage modulus), shear Loss modulus (G", loss modulus), phase angle ( ⁇ , phase angle) can be measured, etc.
  • the numerical value according to the frequency change test according to the present invention is measured at 1Hz and 2.5Hz, 1Hz is The walking condition, 2.5 Hz, is defined as the frequency corresponding to the running condition.
  • the frequency change test can be performed by loading a sample at room temperature in a circular parallel plate geometry, increasing the frequency from 0.01 to 100 Hz, and measuring rheological properties according to shear in the linear region. .
  • a rate sweep test (roatation) is intended to confirm changes in rheological properties such as viscosity due to changes in shear rate, and relaxation time using an application according to a viscosity model based on viscosity results. ), shear thinning index, etc. can be calculated.
  • the shear rate change test can be performed by loading the sample at room temperature into a circular parallel plate geometry and then increasing the shear rate from 0.01 to 500/s to measure viscosity.
  • composition for synovial fluid supplement according to the present invention may further include a hyaluronic acid and mannitol, as well as a buffer, an isotonic agent, or a combination thereof.
  • a hyaluronic acid and mannitol as well as a buffer, an isotonic agent, or a combination thereof.
  • mannitol and/or an isotonic agent may be mixed with the buffer and mixed with hyaluronic acid or a salt thereof.
  • the buffer solution can be used without limitation as long as it is used for the production of hyaluronic acid.
  • preferred buffers include citric acid, sodium monohydrogen phosphate, sodium dihydrogen phosphate, acetic acid, diethyl barbituric acid, sodium acetate, and TAPS (tris(hydroxymethyl)methylamino)propane.
  • the isotonic agent may be used without limitation as long as it is used for the production of hyaluronic acid, and may be included in a buffer solution.
  • a preferred isotonic agent sodium chloride may be used, but is not limited thereto.
  • the content of the isotonic agent may be appropriately adjusted as needed, and may be, for example, 0.1 to 9.0 g/L with respect to the buffer solution, but is not limited thereto.
  • the composition according to the present invention may further include, in addition to the above components, acceptable components that may be included in the preparation of a composition for synovial fluid supplementation.
  • the composition may include one or more components selected from the group consisting of non-steroidal anti-inflammatory drugs, anesthetics, opioid analgesics, corticosteroids, anti-neoplastic agents, monoclonal antibodies, chimeric monoclonal antibodies, vitamins and minerals. .
  • non-steroidal anti-inflammatory drugs eg diclofenac, ibuprofen, piroxicam
  • Anesthetics eg lidocaine and bupivacaine
  • Opioid analgesics eg codeine and morphine
  • Corticosteroids eg dexamethasone and prednisone
  • Anti-neoplastic agents eg methotrexate
  • Antiviral agents eg acyclovir and vidarabine
  • composition for synovial fluid supplements according to the present invention is formulated in a suitable dosage form known in the art, and may be administered to a joint or a peripheral portion of the joint.
  • the composition for synovial fluid supplement according to the present invention may be administered in a dosage form suitable for such use, and may be preferably an injection.
  • the present invention provides a method for treating arthritis or reducing joint pain, comprising administering the composition for synovial fluid supplementation.
  • the present invention provides a synovial fluid supplementation method comprising the step of administering the composition for synovial fluid supplements.
  • the method of administration may include single or multiple intra-articular injection or implantation of the supplement in an amount sufficient to provide a desired physiological effect to the composition for a lubricant supplement prepared according to the present invention.
  • Intra-articular injection or implantation is performed directly into the bone and/or cartilage defect of a human or non-human mammal, for example by arthroscopy or by an injection device such as a syringe.
  • Examples of administration sites include knee, shoulder, ankle, tempo-mandibular and carpal tunnel, elbow, hip, wrist, and spinal discs.
  • the present invention provides a prefilled disposable syringe (pre-filled syringe) having a single dose of synovial fluid composition.
  • the present invention relates to a composition for the reduction or treatment of pain and discomfort associated with joint damage, or joint disease, including joint disorders, osteoarthritis and traumatic cartilage lesions, comprising the composition for synovial supplements.
  • joint diseases include osteoarthritis (primary (idiopathic) or secondary), rheumatoid arthritis, joint damage (e.g. traumatic or repetitive movement damage), cartilage pathology (e.g. chondroccalconsis, cartilage) Softening, and septic arthritis.
  • the composition for hyaluronic acid-based synovial fluid supplements according to the present invention includes a specific range of mannitol as a stabilizer, and at the same time, storage modulus and phase angle measured according to a characteristic frequency change test. It has a relaxation time and a shear thinning index calculated according to the shear rate change test, thereby suppressing the decrease in molecular weight that can occur when sterilizing high molecular weight hyaluronic acid and maintaining viscoelasticity. It not only improves the stability of the preparation, but also satisfies the osmotic pressure and pH range similar to normal joint synovial fluid, significantly reducing pain that can occur to patients.It is a composition for synovial fluid supplements used in arthritis surgery as well as arthritis patients. useful.
  • the storage modulus measured at 1 Hz is 3 Pa or more, and the phase angle is 60° or less, the storage modulus measured at 2.5 Hz is 6 Pa or more, and the phase angle is 50 Stability, characterized in that it is determined whether or not to indicate below, and whether the relaxation time measured according to the shear rate change test is 0.1 seconds or more, and the shear thinning index is 0.35 or less. And it provides a method for selecting a composition for supplementing synovial fluid with high pain relief.
  • the frequency change test and the shear rate change test may be performed according to a known frequency change test and a shear rate change test method. As an example of each of these tests, the items described in the synovial fluid supplement composition may be applied as it is. In the case of a synovial fluid supplement composition having a storage elastic modulus, phase angle, relaxation time, and shear thinning index within the range, even if it contains a polymer hyaluronic acid, it has a low stability and a high probability of reducing molecular weight and viscoelasticity due to sterilization. The composition for replenishing synovial fluid can be clearly selected.
  • the composition for synovial fluid supplement according to the present invention includes hyaluronic acid, a salt or mannitol thereof, and the frequency change test and the shear rate change test are unique storage elastic modulus and phase angle by a known frequency change test and shear rate change test method.
  • the frequency change test and the shear rate change test are unique storage elastic modulus and phase angle by a known frequency change test and shear rate change test method.
  • the decrease in hyaluronic acid molecular weight is suppressed and the viscoelasticity is maintained to increase the stability of the formulation, and pain that may occur to patients by satisfying an osmotic pressure and pH range similar to that of a normal joint synovial fluid. It can be significantly reduced, so it is useful for replacement of synovial fluid lost during arthroscopic surgery, rapid functional recovery due to friction reduction of joints, reduction of the risk of infection in the joint surgery area, and pain relief for patients.
  • 1 is a graph showing the measurement of the storage modulus and phase angle as a result of the frequency change test of 1 Hz (walking condition) of the compositions for synovial fluid supplements of Examples 1 to 3 and Comparative Examples 1 to 6 according to the present invention.
  • Figure 2 is a graph showing the measurement of the storage modulus and phase angle as a test result of the frequency change of 2.5Hz (run condition) of Comparative Examples 1 to 6 and the composition for synovial fluid supplements of Examples 1 to 3 according to the present invention.
  • Figure 3 is a graph showing the relaxation time (s) and the shear thinning index calculated through the results of the shear rate change test results of Comparative Examples 1 to 6 and the composition for synovial fluid supplements of Examples 1 to 3 according to the present invention.
  • Example 1 Preparation of a composition for synovial fluid supplement comprising a polymer hyaluronic acid and 3% by weight of mannitol
  • the following manufacturing method was performed to obtain a composition.
  • hyaluronic acid (average molecular weight: about 2.5 to 3.5 million Da) was dissolved in a buffer solution containing 3% by weight of mannitol, 0.35% by weight of sodium chloride and 0.043% by weight of sodium hydrogen phosphate at a concentration of 0.5% by weight. Did. The completely melted mixture was filled in a plastic syringe and sterilized for 10 minutes using a high-temperature and moist heat sterilizer to prepare a composition for synovial fluid supplements containing hyaluronic acid and mannitol as a stabilizer.
  • Example 2 Preparation of a composition for synovial fluid supplement comprising a polymer hyaluronic acid and 4% by weight of mannitol
  • hyaluronic acid (average molecular weight: about 2.5 to 3.5 million Da) is dissolved in a buffer solution containing 4% by weight of mannitol, 0.16% by weight of sodium chloride and 0.043% by weight of sodium hydrogen phosphate at a concentration of 0.5% by weight.
  • the completely melted mixture was filled in a plastic syringe and sterilized for 10 minutes using a high-temperature and moist heat sterilizer to prepare a composition for synovial fluid supplements containing hyaluronic acid and mannitol as a stabilizer.
  • Example 3 Preparation of a composition for synovial fluid supplement comprising a polymer hyaluronic acid and 5% by weight of mannitol
  • hyaluronic acid (average molecular weight: about 2.5 to 3.5 million Da) was dissolved at a concentration of 0.5% by weight in a buffer solution containing 5% by weight of mannitol and 0.043% by weight of sodium hydrogen phosphate.
  • the completely melted mixture was filled in a plastic syringe and sterilized for 10 minutes using a high-temperature and moist heat sterilizer to prepare a composition for synovial fluid supplements containing hyaluronic acid and mannitol as a stabilizer.
  • Comparative Example 1 Composition for polymer hyaluronic acid synovial fluid supplement that does not contain mannitol
  • composition for synovial fluid supplement was prepared by the following method.
  • hyaluronic acid (average molecular weight: about 2.5 to 3.5 million Da) was dissolved at a concentration of 0.5% in a buffer solution in which 0.9% by weight of sodium chloride and 0.043% by weight of sodium hydrogen phosphate were dissolved.
  • the completely melted mixture was filled in a plastic syringe and sterilized for 10 minutes using a high-temperature and moist heat sterilizer to prepare a composition for synovial fluid supplements containing hyaluronic acid and mannitol as a stabilizer.
  • Viscosil® a product licensed as a synovial fluid supplement, was used as a comparative example.
  • Comparative Example 3 Composition for low molecular weight hyaluronic acid synovial fluid supplement that does not contain mannitol
  • hyaluronic acid (average molecular weight: about 1.2 million to 1.8 million Da) was dissolved at a concentration of 0.5% by weight in a buffer solution in which 0.9% by weight of sodium chloride and 0.043% by weight of sodium hydrogen phosphate were dissolved.
  • the completely melted mixture was filled in a plastic syringe and sterilized for 10 minutes using a high-temperature and moist heat sterilizer to prepare a composition for synovial fluid supplements containing hyaluronic acid and mannitol as a stabilizer.
  • Comparative Example 4 Preparation of composition for synovial fluid supplement containing low molecular weight hyaluronic acid and 3% by weight of mannitol
  • hyaluronic acid (average molecular weight: about 1.2 million to 1.8 million Da) was dissolved in a buffer solution containing 3% by weight of mannitol, 0.35% by weight of sodium chloride, and 0.043% by weight of sodium hydrogen phosphate at a concentration of 0.5% by weight. Did. The completely melted mixture was filled in a plastic syringe and sterilized for 10 minutes using a high-temperature and high-temperature heat sterilizer to prepare a composition for synovial fluid supplements containing hyaluronic acid and mannitol as a stabilizer.
  • Comparative Example 5 Preparation of composition for synovial fluid supplement comprising low molecular weight hyaluronic acid and 4% by weight of mannitol
  • hyaluronic acid (average molecular weight: about 1.2 million to 1.8 million Da) was dissolved in a buffer solution containing 4% by weight of mannitol, 0.16% by weight of sodium chloride, and 0.043% by weight of sodium hydrogen phosphate at a concentration of 0.5% by weight. Did. The completely melted mixture was filled in a plastic syringe and sterilized for 10 minutes using a high-temperature and high-temperature heat sterilizer to prepare a composition for synovial fluid supplements containing hyaluronic acid and mannitol as a stabilizer.
  • Comparative Example 6 Preparation of composition for synovial fluid supplement comprising low molecular weight hyaluronic acid and 5% by weight of mannitol
  • hyaluronic acid (average molecular weight: about 1.2 million to 1.8 million Da) was dissolved at a concentration of 0.5% by weight in a buffer solution containing 5% by weight of mannitol and 0.043% by weight of sodium hydrogen phosphate.
  • the completely melted mixture was filled in a plastic syringe and sterilized for 10 minutes using a high-temperature and high-temperature heat sterilizer to prepare a composition for synovial fluid supplements containing hyaluronic acid and mannitol as a stabilizer.
  • the sample is loaded into a circular parallel plate geometry with a diameter of 40 mm in diameter of DHR (Discovery Hybrid Rhemeter, manufactured by TA), the frequency is increased from 0.01 to 100 Hz, and the strain in the linear region is 1 Hz and 2.5 Hz.
  • DHR Discovery Hybrid Rhemeter, manufactured by TA
  • the storage modulus and phase angle were measured at room temperature (25°C).
  • the contents of mannitol were 3% by weight, 4% by weight, and 5% by weight, respectively, compared to the total composition, and the above Examples 1 to 3 including the polymer hyaluronic acid, and the polymer hyaluronic acid not containing mannitol as the control group,
  • Commercially available hyaluronic acid-based synovial fluid supplements, Viscoseal®, low-molecular-weight hyaluronic acid and mannitol-free mannitol respectively, compared to the total composition of 3% by weight, 4% by weight, and 5% by weight of low-molecular hyaluronic acid.
  • the comparative examples 1 to 6 were used, and the results are shown in Table 1 and FIGS. 1 and 2 below.
  • Examples 1 to 3 which are hyaluronic acid-based synovial fluid supplement compositions containing hyaluronic acid of the polymer and containing mannitol in a concentration of 3% by weight or more based on the total composition weight, are the control Comparative example 1, which is a hyaluronic acid-based synovial fluid supplement composition containing a high-molecular-weight and low-molecular-weight hyaluronic acid that does not contain a commercially available preparation, bisoxyl or mannitol, and contains mannitol at a concentration of 3% by weight or more based on the total composition weight.
  • the storage elastic modulus (G') is large and the phase angle is small at both 1 Hz and 2.5 Hz, assuming walking and running situations.
  • composition for synovial fluid supplements that satisfies the conditions of storage elastic modulus and phase angle according to the frequency change test is high in stability and has a large pain relief effect.
  • the storage elastic modulus measured at 1 Hz in the test described above is 3 Pa or more and the phase angle is 60 It is preferable that the storage elastic modulus measured at 2.5 Hz is 6 Pa or more and the phase angle is 50 or less.
  • the sample was loaded into a 40 mm diameter circular parallel plate geometry of DHR (Discovery Hybrid Rhemeter, manufactured by TA), the shear rate was increased from 0.01 to 500/s, and the viscosity was measured at room temperature (25°C). The measured viscosity results were substituted into the Carreau-Yasuda Model to calculate relaxation time and shear thinning index.
  • DHR Discovery Hybrid Rhemeter, manufactured by TA
  • the contents of mannitol were 3% by weight, 4% by weight, and 5% by weight, respectively, compared to the total composition, and the above Examples 1 to 3 including the polymer hyaluronic acid, and the polymer hyaluronic acid not containing mannitol as the control group,
  • Commercially available hyaluronic acid-based synovial fluid supplements, Viscoseal®, low-molecular-weight hyaluronic acid and mannitol-free mannitol respectively, compared to the total composition of 3% by weight, 4% by weight, and 5% by weight of low-molecular hyaluronic acid.
  • the comparative examples 1 to 6 were used, and the results are shown in Tables 2 and 3 below.
  • Examples 1 to 3 which are hyaluronic acid-based synovial fluid supplement compositions containing hyaluronic acid of the polymer and containing mannitol in a concentration of 3% by weight or more based on the total composition weight, are commercially available as controls
  • Comparative examples 1 to 6 which are hyaluronic acid-based synovial fluid supplement compositions containing a high-molecular and low-molecular-weight hyaluronic acid, or a low-molecular-weight hyaluronic acid, containing mannitol at a concentration of 3% by weight or more based on the total composition weight
  • the viscosity is high, the relaxation time is long, and the shear thinning index is small.
  • composition for synovial fluid supplements satisfying the conditions of relaxation time and shear thinning index according to the shear rate change test has high stability and a large relief effect of pain.

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Abstract

La présente invention concerne une composition de supplément de liquide synovial comprenant de l'acide hyaluronique. La composition de supplément de liquide synovial supprime une diminution du poids moléculaire de l'acide hyaluronique et préserve la viscoélasticité en satisfaisant des conditions uniques dans un test de balayage de fréquence et un test de balayage de vitesse, ce qui augmente la stabilité des préparations, et réduit significativement la douleur qui peut survenir chez des patients en satisfaisant la pression osmotique et la plage de pH similaires à un liquide synovial normal. Par conséquent, la composition de supplément de liquide synovial est utile pour reconstituer le liquide synovial perdu pendant une chirurgie arthroscopique, accélérer la récupération fonctionnelle en raison d'un frottement réduit dans des articulations, réduire le risque d'infections de site chirurgical lors d'une chirurgie articulaire, et soulager la douleur chez les patients.
PCT/KR2019/016778 2018-11-30 2019-11-29 Composition de supplément de liquide synovial comprenant de l'acide hyaluronique Ceased WO2020111888A1 (fr)

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KR20110084510A (ko) * 2008-11-07 2011-07-25 앙테이스 에스.아. 히알루론산 또는 그의 염 중 하나, 폴리올 및 리도카인의 가열 멸균된 주사용 조성물
KR20150079786A (ko) * 2012-10-24 2015-07-08 테옥산 피부 주사가능한 멸균 조성물
US20170354761A1 (en) * 2014-12-15 2017-12-14 Teoxane Process for preparing hydrogels
KR20180004256A (ko) * 2015-05-11 2018-01-10 라보라뚜와 비바시 적어도 하나의 폴리올 및 적어도 하나의 마취제를 포함하는 조성물

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FR2918276B1 (fr) * 2007-07-02 2010-01-22 Anteis Sa "utilisation d'un gel de polysaccharide(s)naturel(s)pour la preparation d'une formulation injectable de traitement des degenerescences articulaires"
KR20090011021A (ko) * 2008-12-10 2009-01-30 산드라 고보 히알루론산 이원 혼합물 및 그의 치료적 용도
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KR20150079786A (ko) * 2012-10-24 2015-07-08 테옥산 피부 주사가능한 멸균 조성물
US20170354761A1 (en) * 2014-12-15 2017-12-14 Teoxane Process for preparing hydrogels
KR20180004256A (ko) * 2015-05-11 2018-01-10 라보라뚜와 비바시 적어도 하나의 폴리올 및 적어도 하나의 마취제를 포함하는 조성물

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