WO2017088177A1 - Produit à base de protéines adhésives de moule, et utilisation de ce dernier pour prévenir et inhiber l'inflammation neuronale - Google Patents

Produit à base de protéines adhésives de moule, et utilisation de ce dernier pour prévenir et inhiber l'inflammation neuronale Download PDF

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Publication number
WO2017088177A1
WO2017088177A1 PCT/CN2015/095798 CN2015095798W WO2017088177A1 WO 2017088177 A1 WO2017088177 A1 WO 2017088177A1 CN 2015095798 W CN2015095798 W CN 2015095798W WO 2017088177 A1 WO2017088177 A1 WO 2017088177A1
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Prior art keywords
mussel mucin
mussel
neuroinflammation
mucin
mefp
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PCT/CN2015/095798
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English (en)
Chinese (zh)
Inventor
高敏
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江阴市本特塞缪森生命科学研究院有限公司
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Priority to PCT/CN2015/095798 priority Critical patent/WO2017088177A1/fr
Publication of WO2017088177A1 publication Critical patent/WO2017088177A1/fr

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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
    • A61K9/06—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
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/12—Aerosols; Foams

Definitions

  • the present invention relates generally to the fields of pharmaceuticals, medical products, health care products, and food technology, and more particularly to mussel mucin products and their use in preventing and inhibiting neuroinflammation.
  • the nervous system is a functional regulation system that plays a leading role in the human body. It is composed of brain, spinal cord, cranial nerve, spinal nerve and vegetative nerve, and various ganglia. It can coordinate the activities of various organs and systems in the body and make it complete. Integrated and interacted with the external environment.
  • Neuroinflammation refers to the inflammation or deterioration of nerves or nerve groups.
  • the symptoms vary with the disease. There are many causes of neuroinflammation, including nerve injuries such as nearby fractures and direct blows; nerve infections such as diabetes and blood cancer. And gout, etc.; mercury, lead, methanol and other poisoning; lack of vitamin B group in the diet, the general symptoms of neuroinflammation are pain, tenderness, tingling, infected nerve itching and loss of consciousness, partial infection of redness and severe spasm.
  • Mussel adhesive protein also known as Mytilus edulis foot protein (Mefp)
  • Mefp Mytilus edulis foot protein
  • Mytilus coruscus A special protein secreted by Perna viridis. Mussels are usually attached in groups to the reefs on the coast or to the bottom of the ship, and have the ability to withstand wave impacts in the offshore. In fact, mussels can be attached extremely strongly to the substrate of any material, such as metal, wood, glass, and the like. The main reason for the above characteristics of mussels is that they can form and store this special mucin in the girth of the foot. The mussels release the mucin through the foot silk to a solid surface such as rock to form a water-resistant combination. Fix yourself.
  • Mussel mucin has two structural features: (1) containing lysine, which has a high loading of positive charge; and (2) containing 3,4 dihydroxyphenylalanine (DOPA, dopa). The cells and tissues of the human body are negatively charged.
  • Mussel mucin interacts with cells by electrostatic interaction between its own positive charge and the negative charge of human cells and tissues Closely integrated with the organization to play a protective and therapeutic role.
  • dopa oxidation produces ortho-dioxins, which can be cross-linked with unoxidized dopa to form a membrane or a network scaffold, which promotes the protein to adhere more closely and firmly to the surface of the human body, thereby protecting.
  • Mussel mucin is a macromolecular protein that is completely degraded in the human body for about 3-10 days. Its ability to attach to cell tissues is excellent, so that mussel mucin can be stabilized locally and continue to function.
  • mussel mucin has the above characteristics, its current application field is very limited.
  • Commercial mussel mucin products are Cell-Tak from BD Biosciences, MAP Trix from Kollodis, Korea, and Hydrogel from Biopolymer, Sweden. These products are either used directly in the mussel mucin solution state, or are stored as lyophilized powder formulations and dissolved prior to use. Their primary application is limited to microscopic cell adhesion and tissue adhesives. Mussel mucin has also been reported for use in the repair of fetal membranes, as a coating against seawater corrosion, and as a drug-loaded stent for the heart.
  • the treatment of neuritis is mainly to prevent and relieve symptoms. It is usually treated according to the cause of inflammation of the nerves to relieve symptoms. However, the treatment of neuroinflammation is slow and the treatment effect is not obvious. The average cure rate is only about 40%.
  • the mussel mucin used herein may be Mytilus edulis Linnaeus, Mytilus coruscus or Perna viridis from the Mytilidae bivalve mollusc. 11 subclasses of mussel mucin, currently known as purified from marine mussels: mefp1, mefp-2, mefp-3, mefp-4, mefp-5, mefp-6, collagen pre-COL- A mixture of one or more of P, pre-COL-D, pre-COL-NG, foot silk matrix proteins PTMP and DTMP.
  • the mussel mucin of the natural source used herein may have a pH of 1.0 to 7.0 in an aqueous solution, and particularly may have a pH of 3.0 to 6.5 to make the therapeutic effect better.
  • the mussel mucin used herein may also be obtained by a method of biosynthesis, comprising a mixture of one or more of the known 11 mussel mucin subclasses.
  • the artificial biosynthesized mussel mucin used herein may have a pH of 1.0 to 7.0 in aqueous solution, and particularly may be in the range of pH 3.0 to 6.5 to make the therapeutic effect better.
  • the mussel mucin used herein may also be a hydrolyzed peptide obtained by hydrolysis of mussel mucin from a natural source or an artificial biosynthesis source, or a functional group-containing complex obtained by artificial synthesis. Form a peptide.
  • the mussel mucin hydrolyzed peptide or synthetic peptide used herein may have a pH of 1.0 to 7.0 in an aqueous solution, and particularly may be in the range of pH 3.0 to 6.5 to make the therapeutic effect better.
  • the mussel mucin used herein can be obtained by the following preparation method, for example, a method for separating and purifying mussel mucin using mixed adsorption chromatography in Chinese Patent No. ZL200710179491.0, a kind of carboxy using Chinese Patent No. ZL200710179492.5 A method for purifying mussel mucin by methyl ion exchange chromatography, a method for separating and purifying mussel mucin using salting out and dialysis, Chinese Patent No. ZL200910087567.6.
  • the mussel mucin used herein may be in the form of a solution or a lyophilized powder, in particular, the concentration of mussel mucin in the product may be 0.1-15.0 mg/ml, and when the concentration is too low, the effect of mussel mucin Not large, when the concentration is too high, it can cause cytotoxicity, skin irritation, etc., which is not conducive to the prevention and treatment of neuroinflammation.
  • the mussel mucin used herein can also be prepared as a liquid agent by combining it with an excipient.
  • An exemplary mussel mucin liquid preparation is prepared by dissolving or diluting mussel mucin solution mother liquor or lyophilized powder to a certain concentration or pH, and the solution for dissolving or diluting may be water, physiological saline, phosphate solution, vinegar. Acid solution, borate solution, and the like.
  • the pH of the mussel mucin in the final product may be pH 1.0-7.0, especially in the range of pH 3.0-6.5 to make the therapeutic effect better.
  • the mussel mucin used herein can also be prepared as a gelling agent in combination with an excipient.
  • An exemplary mussel mucin gel is prepared by mixing a mussel mucin solution or a lyophilized powder with a gel matrix material, which may be selected from the group consisting of cellulose derivatives, carbomers, and seaweeds. Acid salt, tragacanth, gelatin, pectin, carrageenan, gellan gum, starch, xanthan gum, cationic guar gum, agar, non-cellulosic polysaccharide, ethylene polymer, acrylic resin, polyvinyl alcohol or poly One of carboxyvinyl or any combination thereof.
  • the mussel mucin used herein can be used as a main raw material to prepare a medicine using a pharmaceutically acceptable carrier.
  • the drug may be a liquid agent or a gel.
  • the drug may be administered by oral, targeted topical sustained release, targeted administration, and may be administered at a low temperature or in a heated manner.
  • the mussel mucin used herein can be used as a main raw material to prepare a medical device.
  • the term medical device as used herein refers to materials that are used directly or indirectly to the human body and other similar or related items.
  • the medical device can be a liquid agent or a gel.
  • the medical device can be used by oral, targeted local sustained release, targeted administration, and can be administered at a low temperature or in a heated manner.
  • the mussel mucin used herein can be used as a main raw material, and a health care product or food can be prepared by using an excipient which is acceptable in the field of health care or food.
  • the health care product or food may be a liquid agent or a gel.
  • the health supplement or food may be administered by oral, targeted topical sustained release, targeted administration, and may be administered at a low temperature or in a heated manner.
  • Another object of the invention is to provide a mussel mucin product for the prevention and treatment of neuroinflammation.
  • mussel mucin can prevent and alleviate sensory, dyskinesia and autonomic dysfunction caused by various neuroinflammatory diseases.
  • Symptoms caused by neuroinflammation often in the initial stage of the fingertip or toe end burning pain and numbness and other irritations such as paresthesia or hyperesthesia, gradually appearing sensation decline or even disappear, the distribution of sensory disturbances are gloves or socks, a small number of patients There may be deep sensory disturbances, gastrocnemius and other places often have tenderness.
  • Neurological dysfunction caused by neuroinflammation manifested as cold, pale, flushing or mild cyanosis of the extremities, less sweat or sweating, thinning of the skin, tenderness or roughness of the nails, loss of normal luster, angle Enhancement and so on.
  • the symptoms of the above three groups may be different.
  • the pain caused by nitrofurazone poisoning and arsenic poisoning is often severe; the muscle atrophy is sometimes significant in diabetic patients.
  • the severity of various clinical manifestations is also inconsistent. In the light, only the acral pain can be numb without sensory loss or dyskinesia, and the severe one can also have limb paralysis.
  • the mussel mucin of the present invention can be used to prevent sensory disorders, motor dysfunction, and autonomic dysfunction caused by neuroinflammation.
  • the mussel mucin of the invention can be used to treat sensory disorders, motor dysfunction, and autonomic dysfunction caused by neuroinflammation.
  • prevention refers to a process of intervention to relieve pain or change of a particular state of health.
  • treatment in the present invention means that countermeasures that may deviate from subjectively expected or objective general laws in the course of disease treatment are prevented in advance to avoid possible damage.
  • the mussel mucin application according to embodiment 1 or 2 wherein the mussel mucin may be obtained by extracting from mussels, comprising one of 11 known mussel mucin subclasses or Several mixtures.
  • mussel mucin application according to embodiment 1 or 2 wherein the mussel mucin is also a hydrolyzed peptide obtained by hydrolyzing mussel mucin from a natural source or an artificial biosynthesis source, or by artificial synthesis.
  • a functional peptide-containing synthetic peptide obtained in a manner.
  • the mussel mucin application according to any one of embodiments 1 to 5, wherein the mussel mucin is a liquid agent or a gel.
  • the mussel mucin application according to any one of embodiments 1 to 5, wherein the mussel mucin in the final product may be in the range of pH 1.0-7.0, particularly in the range of pH 3.0-6.5.
  • the mussel mucin application according to any one of embodiments 1-8, wherein the neuroinflammation may include sensory disturbances caused by neuroinflammation, motor dysfunction, and autonomic dysfunction.
  • composition for preventing and treating neuroinflammation, wherein the composition may be a liquid agent or a gel.
  • a medicament for preventing and treating neuroinflammation comprising mussel mucin and a pharmaceutically acceptable carrier, wherein the mussel mucin is present in a concentration of from 0.1 to 15.0 mg/ml.
  • a medical device for preventing and treating neuroinflammation comprising mussel mucin and a carrier acceptable for use in the field of medical devices, wherein the concentration of mussel mucin may be from 0.1 to 15.0 mg/ml.
  • a health care product/food for preventing and treating neuroinflammation comprising a mussel mucin and a health care product/food acceptable carrier, wherein the mussel mucin may be in a concentration of 0.1 to 15.0 mg/ml.
  • neuroinflammation comprises: peripheral nerve inflammation, facial nerve inflammation, peripheral nerve inflammation, subcutaneous neuroinflammation, ulnar neuritis, intercostal nerve inflammation, and the like.
  • neuroinflammation comprises: peripheral nerve inflammation, facial nerve inflammation, peripheral nerve inflammation, subcutaneous neuroinflammation, ulnar neuritis, intercostal nerve inflammation, and the like.
  • Example 1 Application of mussel mucin gel drug in the treatment of peripheral nerve inflammation.
  • Example 2 Application of mussel mucin liquid medical device in the treatment of peripheral neuritis.
  • Example 3 Application of mussel mucin liquid medicine in the treatment of facial neuritis.
  • a mussel mucin solution having a concentration of 5.0 mg/ml was taken and diluted 5 times with 0.001% acetic acid to a mussel mucin content of 1.0 mg/ml to obtain a mussel mucin liquid medicine.
  • Example 4 Application of mussel mucin gel drug in the treatment of facial neuritis.
  • Ten patients with acute facial neuritis diagnosed by neurologists were enrolled in the study.
  • the clinical manifestations of the patients were one-sided facial expression tendon accompanied by mandibular angle or pain behind the ear.
  • the selected patients were randomly divided into the control group and the experimental group.
  • the control group was treated with a blank gel without mussel mucin.
  • the test group was treated with the above mussel mucin gel drug.
  • the two groups were used 3 times a day for external use, so that the affected area could be evenly covered.
  • Example 5 Application of mussel mucin liquid medicine in the treatment of peripheral neuritis.
  • a mussel mucin solution having a concentration of 20.0 mg/ml was prepared and diluted 10 times with 0.05% citric acid to a mussel mucin content of 2.0 mg/ml to obtain a mussel mucin liquid medicine.
  • the control group was treated with 0.05% citric acid.
  • the test group was treated with the above mussel mucin liquid medicine. The two groups were used 3 times a day for external use, so that the affected area could be evenly covered.
  • Example 6 Application of mussel mucin gel health supplement in the treatment of peripheral neuritis.
  • mice Ten patients with peripheral neuritis diagnosed by neurologists were enrolled in the study.
  • the clinical manifestations were sympathetic abnormalities (pain, numbness, allergies) in the distal part of the limb.
  • the dyskinesia included hypotonia, hypotonia, and decreased tendon reflex. Or disappear, autonomic dysfunction, including cold skin and pale skin.
  • the selected patients were randomly divided into the control group and the experimental group.
  • the control group was treated with a gel without mussel mucin
  • the experimental group was treated with the above mussel mucin liquid medicine.
  • the two groups were used 3 times a day for external use, so that the affected area could be evenly covered.
  • Example 7 Application of mussel mucin liquid medical device in the treatment of subcutaneous neuritis.
  • the mussel mucin solution was taken, diluted with physiological saline, and the pH was adjusted to pH 6.0 with acetic acid to obtain a mussel mucin liquid medical device, wherein the mussel mucin concentration was 3 mg/ml.
  • Example 8 Application of mussel mucin gel medical device in the treatment of subcutaneous neuritis.
  • a mussel mucin solution Taking a mussel mucin solution, mixing the preparation with hydroxypropylmethylcellulose and glycerol at a mass ratio of 3:2:1, and adjusting the pH to pH 6.2 with citric acid to obtain a mussel mucin gel medical device.
  • the mussel mucin concentration was 3 mg/ml.
  • Example 9 Application of mussel mucin liquid medical device in the treatment of ulnar neuritis.
  • the mussel mucin solution was mixed with propylene glycol in a ratio of 2:1 by volume, and the pH was adjusted to pH 5.0 with acetic acid to obtain mussel mucin liquid health care product, wherein the mussel mucin concentration was 2.0 mg/ml.
  • Example 10 Application of mussel mucin gel drug in the treatment of intercostal neuritis.
  • a mussel mucin solution was taken, and carboxymethylcellulose and glycerin were added in a volume ratio of 2:1:1 to obtain a mussel mucin hydrogel drug, wherein the mussel mucin concentration was 2.5 mg/ml.
  • a total of 12 patients with intercostal neuritis diagnosed by neurologists were enrolled in the study.
  • the clinical manifestations of the patients were along the chest ribs, from the back through the flank, to the painful mass and tenderness at the costal cartilage in the chest.
  • the selected patients were randomly divided into the control group and the experimental group.
  • the control group was treated with a blank gel without mussel mucin.
  • the test group was treated with the above mussel mucin gel drug.
  • the two groups were used 3 times a day for external use, so that the affected area could be evenly covered.
  • Example 11 Application of mussel mucin liquid health care products in the protection of neuritis.
  • the mussel mucin solution was taken and diluted with physiological saline to prepare a mussel mucin liquid health care product, and the mussel mucin concentration was 1.0 mg/ml.
  • Myelin basic protein is extracted from the fresh sciatic nerve of cattle, and the extracted myelin basic protein is identified for biochemical and biological activity.
  • the control group was only immunized with the extracted bovine myelin basic protein, and the clinical manifestations were observed along with the pathological examination.
  • the experimental group was orally administered with mussel mucin liquid health care products every day, 2-3 ml each time, 3 times a day.
  • the inflammatory cell infiltration of the rabbits in the experimental group was caused by cervical nerve root, lumbar nerve root and cauda equina nerve damage, and the sciatic nerve was separated. The single nerve fibers were separated. The semi-thin sections and electron microscopy showed that the demyelination was the main change. No axis was found. Degeneration and lesions in the brain parenchyma. It is proved that mussel mucin liquid health care products can prevent neuroinflammation.

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Abstract

La présente invention concerne l'utilisation de protéines adhésives de moule ou d'une préparation de ces dernières pour prévenir et inhiber l'inflammation neuronale, et en particulier concerne l'utilisation de protéines adhésives de moule ou d'une préparation de ces dernières dans des troubles sensoriels, des troubles moteurs, des troubles du système nerveux autonome, et analogues, liés à une inflammation neuronale.
PCT/CN2015/095798 2015-11-27 2015-11-27 Produit à base de protéines adhésives de moule, et utilisation de ce dernier pour prévenir et inhiber l'inflammation neuronale WO2017088177A1 (fr)

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PCT/CN2015/095798 WO2017088177A1 (fr) 2015-11-27 2015-11-27 Produit à base de protéines adhésives de moule, et utilisation de ce dernier pour prévenir et inhiber l'inflammation neuronale

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PCT/CN2015/095798 WO2017088177A1 (fr) 2015-11-27 2015-11-27 Produit à base de protéines adhésives de moule, et utilisation de ce dernier pour prévenir et inhiber l'inflammation neuronale

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020143744A1 (fr) * 2019-01-10 2020-07-16 Jiangyin Mucocare Pharmaceutical Co., Ltd. Nouvelles formulations contenant des antagonistes des récepteurs des leucotriènes

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
YU , FENGBIN ET AL.: "Reconstructing Spinal Dura-like Tissue Using Electrospun Poly (lactide-co-glycolide) Membranes and Dermal Fibroblasts to Seamlessly Repair Spinal Dural Defects in Goats", J BIOMATER APPL, vol. 30, no. 3, 30 September 2015 (2015-09-30), pages 311 - 326 *
ZHU, YAOYAO ET AL.: "The Research Progress on Mussel Adhesive Proteins", ADVANCES IN MARINE SCIENCE, vol. 32, no. 4, 31 October 2014 (2014-10-31), pages 560 - 570 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020143744A1 (fr) * 2019-01-10 2020-07-16 Jiangyin Mucocare Pharmaceutical Co., Ltd. Nouvelles formulations contenant des antagonistes des récepteurs des leucotriènes

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