WO2017181372A1 - 贻贝粘蛋白产品及其抑制血管炎症的应用 - Google Patents

贻贝粘蛋白产品及其抑制血管炎症的应用 Download PDF

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Publication number
WO2017181372A1
WO2017181372A1 PCT/CN2016/079767 CN2016079767W WO2017181372A1 WO 2017181372 A1 WO2017181372 A1 WO 2017181372A1 CN 2016079767 W CN2016079767 W CN 2016079767W WO 2017181372 A1 WO2017181372 A1 WO 2017181372A1
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Prior art keywords
vasculitis
mussel mucin
vascular inflammation
mussel
mucin
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PCT/CN2016/079767
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English (en)
French (fr)
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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/CN2016/079767 priority Critical patent/WO2017181372A1/zh
Priority to PCT/CN2017/081308 priority patent/WO2017181978A1/zh
Publication of WO2017181372A1 publication Critical patent/WO2017181372A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • 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
    • A61K9/06—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
    • 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 inhibiting vascular inflammation.
  • Blood vessels are a series of tubes through which blood flows. They are divided into arteries, veins, and capillaries according to their structural functions.
  • Vascular inflammation is an infiltration of inflammatory cells around the blood vessel wall and blood vessels, accompanied by vascular damage, including cellulose deposition, collagen fiber degeneration, endothelial cells and myocyte necrosis.
  • the clinical manifestations of vascular inflammation are multiple systemic damage, unexplained fever, pleomorphic skin lesions such as erythema, nodules, cyanosis, wheal, blood blisters, necrosis and ulcers.
  • vascular inflammation can be aimed at the cause and eliminate allergens; it can be the treatment of underlying diseases, such as connective tissue diseases, tumors; vasculitis confined to the skin, often using antihistamines, causing telangiectasia and permeability Increase; systemic vasculitis can be treated with prednisone, by inhibiting the proliferation of connective tissue, reducing the permeability of the capillary wall and cell membrane, reducing inflammatory exudation.
  • vascular inflammation is primarily achieved by increasing permeability to relieve symptoms for therapeutic purposes.
  • 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; (2) containing 3,4 dihydroxyphenylalanine (DOPA, dopa). Human cells and groups Weave with a negative charge.
  • Mussel mucin plays a protective and therapeutic role by tightly binding cells and tissues through the electrostatic interaction between its own positive charge and the negative charge of cells and tissues.
  • 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, and 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.
  • Mussel mucin used herein refers to 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 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 blood Treatment of tube inflammation.
  • 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 mussel mucin in the final product may be pH 1.0-7.0, and in particular, the therapeutic effect may be better in the range of pH 3.0-6.5.
  • 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, spray, injection, 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, spray, injection, 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, spray, injection, 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 an application of mussel mucin products to inhibit vascular inflammation.
  • mussel mucin can alleviate cellulose deposition, collagen fiber degeneration, endothelial cells and myocyte necrosis caused by various vascular inflammations.
  • Common vascular inflammation includes allergic leukocyte vasculitis, nodular polyarteritis, thrombotic vasculitis, granulomatous vasculitis, lymphocytic vasculitis, abnormal blood vessel vasculitis, and rheumatoid vasculitis. .
  • Allergic leukocyte rupture vasculitis is vascular inflammation caused by infection, drug or immune abnormalities, and clinical manifestations may include irregular fever, myalgia, joint pain and the like. Skin lesions are mostly distributed in the lower limbs, and the lesions are diverse. Purpura is the most common, characteristic, often higher than the leather surface, the pressure does not fade. There may be genital erythema, blistering, blood blister in severe cases. Pustules can also occur when neutrophils ooze out into surrounding tissues. Sometimes there are subcutaneous nodules of varying sizes. If the vascular endothelium is damaged, the stenosis of the lumen may cause local ulceration and necrosis, and occasionally reticular leukoplakia.
  • rash is sometimes accompanied by itching or pain, usually lasting 2-4 weeks, with pigmentation or residual atrophic scar after absorption.
  • Allergic leukocyte vasculitis is usually treated with glucocorticoids, which can inhibit telangiectasia, reduce exudation and edema, inhibit white blood cell infiltration and phagocytosis, thereby reducing inflammation symptoms.
  • glucocorticoids can inhibit telangiectasia, reduce exudation and edema, inhibit white blood cell infiltration and phagocytosis, thereby reducing inflammation symptoms.
  • long-term or large-scale administration can lead to hypercortical hyperplasia, induce or aggravate infection, induce or aggravate ulcers, induce hypertension and arteriosclerosis.
  • Nodular polyarteritis is a kind of necrotizing vasculitis involving the whole layer of small and medium arteries caused by viral infection. It can affect the blood vessels of various tissues and organs of the whole body. The clinical manifestations are diverse and can be limited to the skin and can affect multiple organs. Or system. Usually characterized by skin nodules, arranged along the superficial arteries or irregularly gathered near the blood vessels, pain and tenderness, rose red, bright red or near normal skin color, severe cases can cause death or disability. There are mainly systemic nodular polyarteritis, benign skin type nodular polyarteritis, and infant nodular polyarteritis. The treatment of nodular polyarteritis usually uses corticosteroids, which can cause full moon face, osteoporosis, gastric ulcer, buffalo shoulder, high blood pressure, cataract, hemorrhoids and mold infections.
  • Thrombotic vasculitis mainly involves small and medium arteries and veins, characterized by intravascular thrombosis and presents different clinical manifestations. There are mainly thromboangiitis obliterans, thrombophlebitis, malignant atrophic papulosis, reticular leukocytitis, thrombotic thrombocytopenic purpura and so on. Angiogenic vasculitis is often treated with vasodilators, anticoagulants or plasma expanders.
  • Granulomatous vasculitis is a multi-system disease involving large, medium and small blood vessels, characterized by the formation of granuloma inside and outside the vessel wall, and the course of disease is slow. Mainly Wegener's granulomatosis, allergic granulomatous vasculitis, Arteritis, aortitis, etc. Its pathology is characterized by inflammation of the blood vessel wall, mainly invading the upper and lower respiratory tract and the kidney, usually starting with focal granulomatous inflammation of the nasal mucosa and lung tissue, and then progressing to diffuse necrotizing granulomatous inflammation of the blood vessel. . Clinical manifestations of nasal and paranasal sinusitis, lung disease and progressive renal failure. It can also affect joints, eyes, skin, and can also invade the eyes, heart, nervous system and ears. Glucocorticoid vasculitis is often treated with glucocorticoids or immunosuppressive agents.
  • Lymphocytic vasculitis is characterized by infiltration of lymphocytes in the small blood vessels of the skin, the wall of the tube and surrounding tissues, and produces various types of skin lesions, mainly lymphoma-like papules and acute acne-like lichen-like pityriasis.
  • Glucocorticoids and cyclophosphamide are the main drugs for treatment.
  • Blood component abnormal vasculitis is a small vascular inflammatory disease caused by abnormal components in the blood, which is manifested as skin or visceral damage, mainly cryoglobulinemia, cold hyperglobulinemia, macroglobulinemia, etc. .
  • rheumatic vasculitis The typical feature of rheumatic vasculitis is peripheral vascular damage, which often occurs in patients with high rheumatoid factor titer and systemic complications.
  • the clinical manifestations are cutaneous vasculitis damage, localized palpation of purpura, non-specific erythema of the trunk, vascular infarction, large Blisters and ulcers, 20% of patients have finger mites.
  • Capillary vasodilation, infarct papules and nodules occur in nail folds. Treatment with salicylate or antimalarial drugs is generally used, and corticosteroids are available for severe cases.
  • vascular inflammation is often treated with glucocorticoids or corticosteroids, but long-term or large doses can lead to hypercortical hyperplasia, induce or aggravate infections, induce or aggravate ulcers, induce hypertension and arteriosclerosis.
  • the mussel mucin of the present invention can be used for the treatment of allergic leukocyte vasculitis, nodular polyarteritis, thrombotic vasculitis, granulomatous vasculitis, lymphocytic vasculitis, blood components Inflammation such as abnormal vasculitis and rheumatoid vasculitis.
  • the mussel mucin of the present invention can be used for inhibiting allergic leukocyte vasculitis, nodular polyarteritis, thrombotic vasculitis, granulomatous vasculitis, lymphocytic vasculitis, blood Vascular cancer caused by abnormal vasculitis and rheumatoid vasculitis.
  • the mussel mucin application according to embodiment 1, wherein the mussel mucin concentration may be from 0.1 to 15.0 mg/ml.
  • Mussel mucin application according to embodiment 1, wherein the mussel mucin in the final product may be in the range of pH 1.0-7.0, in particular in the range of pH 3.0-6.5.
  • vascular inflammation may be selected from the group consisting of: allergic leukocyte vasculitis, nodular polyarteritis, thrombotic vasculitis, Granulomatous vasculitis, lymphocytic vasculitis, abnormal blood component vasculitis, and rheumatic vasculitis.
  • vascular inflammation may be selected from the group consisting of: allergic leukocyte vasculitis, nodular polyarteritis, thrombotic vasculitis, Vascular vasculitis, lymphocytic vasculitis, abnormal blood vessel vasculitis, and vascular cancer caused by rheumatoid vasculitis.
  • composition can be administered by oral, spray, injection, targeted topical sustained release, targeted administration.
  • a medicament for the treatment of vascular inflammation comprising mussel mucin and a pharmaceutically acceptable carrier, wherein the concentration of mussel mucin may be from 0.1 to 15.0 mg/ml.
  • a medical device for treating vascular inflammation comprising a mussel mucin and a carrier acceptable for use in the field of medical devices, wherein the concentration of mussel mucin can be from 0.1 to 15.0 mg/ml.
  • a health care product/food for treating vascular inflammation comprising mussel mucin and a health care product or a carrier acceptable for the food field, wherein the concentration of mussel mucin may be from 0.1 to 15.0 mg/ml.
  • vasculitis Symptoms can be selected from: allergic leukocyte rupture vasculitis, nodular polyarteritis, thrombotic vasculitis, granulomatous vasculitis, lymphocytic vasculitis, abnormal blood component vasculitis, and rheumatic vasculitis .
  • vascular inflammation may be selected from the group consisting of: allergic leukocyte vasculitis, nodular polyarteritis, thrombotic vasculitis, granulation Tumor vasculitis, lymphocytic vasculitis, abnormal blood vessel vasculitis, and vascular cancer caused by rheumatoid vasculitis.
  • vascular inflammation can be selected from the group consisting of: allergic leukocyte vasculitis, nodular polyarteritis, thrombotic vasculitis, Granulomatous vasculitis, lymphocytic vasculitis, abnormal blood component vasculitis, and rheumatic vasculitis.
  • vascular inflammation can be selected from the group consisting of: allergic leukocyte vasculitis, nodular polyarteritis, thrombotic vasculitis, Vascular vasculitis, lymphocytic vasculitis, abnormal blood vessel vasculitis, and vascular cancer caused by rheumatoid vasculitis.
  • vascular inflammation may be selected from the group consisting of: allergic leukocyte vasculitis, nodular polyarteritis, thrombotic blood vessel Inflammation, granulomatous vasculitis, lymphocytic vasculitis, and abnormal vasculitis of blood components.
  • vascular inflammation may be selected from the group consisting of: allergic leukocyte vasculitis, nodular polyarteritis, thrombotic blood vessel Inflammation, granulomatous vasculitis, lymphocytic vasculitis, abnormal blood vessel vasculitis, and vascular cancer caused by rheumatoid vasculitis.
  • Example 1 Application of mussel mucin liquid medicine in the treatment of allergic cutaneous vasculitis.
  • the selected patients were randomly divided into the control group and the experimental group, and the control group was treated with 0.1% citric acid solution.
  • the experimental group was treated with the above-mentioned mussel mucin aqueous solution drug.
  • the two groups were used three times a day. After the meal, the affected area was sprayed, and each time it was sprayed 2-3 times, the affected area was completely covered.
  • the pain or itching of the affected area was significantly weakened within 10-30 minutes, from the visual analog VAS score of 5.0-7.0 before treatment to 1.0-3.0, and the analgesic or antipruritic time lasted for 2-7 hours. There was no change in the VAS score of the affected area before and after the control group. As the use time prolonged, the duration of analgesia was prolonged, and the interval of use was prolonged, showing no dependence.
  • Example 2 Application of mussel mucin gel medical device in the treatment of skin type nodular polyarteritis.
  • the skin of the patients in the control group was red and swollen, ulceration and exudation were not improved, and the pain was slightly relieved.
  • the skin and sore surface of the legs were regressed, ulceration, exudation, and pain were obvious. Reduced.
  • the redness and swelling of the sore surface of the control group slightly subsided, the ulceration surface was not reduced, and a small amount of exudate was still present; all the patients in the test group had dry sores and scarring. It can be seen that the mussel mucin gel medical device can be used for the treatment of skin type nodular polyarteritis, and the effect is better than the existing drugs prednisone and lamivudine.
  • Example 3 Application of mussel mucin liquid health care products in the treatment of thrombotic vasculitis.
  • the selected patients were orally administered with the above-mentioned mussel mucin liquid health care products, taken once a day, 10 ml each time, and reviewed monthly. After taking it for 2 months, the patient's lower extremity pain symptoms disappeared, intermittent claudication time and distance decreased, and the sputum index returned to 0.9. It can be seen that mussel mucin liquid health care products are beneficial for the treatment of thrombotic vasculitis.
  • Example 4 Application of mussel mucin liquid medicine in the treatment of granulomatous vasculitis.
  • the selected patients were assigned to the control group or the experimental group, and the control group was treated with oral 1.5 mg/kg.d prednisone.
  • the test group received the above mussel mucin liquid medicine twice a day, 1.0 mg each time. After 4 weeks of treatment, the symptoms of the patients in the control group and the test group were all relieved. The control group reduced the dose by 1.0 mg/kg.d. The test group reduced the dose to 0.5 mg/time to maintain, and no recurrence or exacerbation of symptoms occurred in the control group and the test group at 8 weeks. It can be seen that oral mussel mucin liquid medicine contributes to the treatment of granulomatous vasculitis.
  • Example 5 Application of mussel mucin liquid medical device in the treatment of lymphocytic vasculitis.
  • the selected patients were randomly assigned to the control group or the experimental group.
  • oral prednisone 50 mg/d in the test group, the affected area was sprayed with mussel mucin liquid medical device twice a day, with the amount of mussel mucin Can evenly cover the affected area.
  • the papules in the control group were significantly reduced and the exudation was reduced.
  • the papules in the experimental group were significantly reduced and the exudation was reduced.
  • the papules in the control group were exacerbated, the redness and swelling were aggravated, and the treatment effect was repeated; the papules in the experimental group subsided. It can be seen that mussel mucin liquid medical devices can be used for the treatment of lymphocytic vasculitis.
  • Example 6 Application of mussel mucin gel drug in the treatment of rheumatic vasculitis.
  • the selected patients were randomly assigned to the control group or the experimental group.
  • the patients in the control group were treated with oral prednisone 50 mg/d.
  • the patients in the experimental group were treated with mussel mucin gel drug, applied twice a day for each dose. In order to evenly cover the affected area. After 1 week of treatment, the exudation of the ulcer in the control group decreased and the area of the ulcer did not change; the exudation of the ulcer in the test group decreased, and the area of the ulcer decreased to varying degrees. After 2 weeks of treatment, the exudation of the ulcer in the control group was reduced, and the average healing rate was 32%. All the ulcers in the experimental group were basically healed, and the affected area was covered by the neonatal epithelium. It can be seen that mussel mucin gel drugs can be used for the treatment of rheumatoid vasculitis.

Abstract

本发明公开了贻贝粘蛋白或其制剂抑制血管炎症的应用。具体地公开了贻贝粘蛋白或其制剂在治疗变应性白细胞破碎性血管炎、结节性多动脉炎、血栓形成性血管炎、肉芽肿性血管炎、淋巴细胞性血管炎、血液成分异常性血管炎、风湿性血管炎和血管炎引起的血管癌中的应用，可以抑制血管炎症引发的红、肿、热、痛等症状。

Description

贻贝粘蛋白产品及其抑制血管炎症的应用 技术领域
本发明大体涉及药品、医疗产品、保健品及食品技术领域，更具体地，涉及贻贝粘蛋白产品及其在抑制血管炎症中的应用。
相关技术讨论
血管是指血液流过的系列管道，按照血管的构造功能不同，分为动脉、静脉和毛细血管三种。血管炎症是血管壁及血管周围有炎性细胞浸润，并伴有血管损伤，包括纤维素沉积、胶原纤维变性、内皮细胞及肌细胞坏死等。血管炎症临床表现为多系统损害，不明原因发热，多形性皮肤损害如红斑、结节、紫癜、风团、血疱、坏死及溃疡等。血管炎症的治疗可以是针对于病因，消除过敏原；可以是治疗基础疾病，如结缔组织病、肿瘤；局限于皮肤的血管炎，常使用抗组胺类药，引起毛细血管扩张及通透性增加；全身性血管炎可用泼尼松治疗，通过抑制结缔组织的增生、降低毛细管壁和细胞膜的通透性、减少炎性渗出。血管炎症主要是通过增加通透性缓解症状达到治疗目的。
贻贝粘蛋白(Mussel adhesive protein，MAP)，也称作贻贝足丝蛋白(Mytilus edulis foot protein，Mefp)，是海洋贝类紫贻贝(Mytilus edulis Linnaeus)、厚壳贻贝(Mytilus coruscus)、翡翠贻贝(Perna viridis)等分泌的一种特殊的蛋白质。贻贝通常成群地附着在海岸边的礁石上或者轮船的底部，有在近海耐受波浪冲击的能力。实际上贻贝几乎可以极其牢固地附着在任何材料的基底上，如金属、木材、玻璃等。贻贝具有上述特性的主要原因是其足丝腺内可生成并储存这种特殊的粘蛋白，贻贝通过足丝释放粘蛋白到岩石一类的固体表面上，形成抗水的结合，从而将自己固定。
目前从贻贝中鉴定得到11种粘蛋白亚类，包括mefp1、mefp-2、mefp-3、mefp-4、mefp-5、mefp-6、胶原蛋白pre-COL-P、pre-COL-D、pre-COL-NG、足丝基质蛋白PTMP和DTMP(朱曜曜等，海洋科学进展，2014，32(4)：560-568)。贻贝粘蛋白具有2个结构特点：(1)含有赖氨酸，使蛋白带有高载量正电荷；(2)含3，4二羟基苯丙氨酸(DOPA，多巴)。人体的细胞和组 织带有负电荷。贻贝粘蛋白通过自身正电荷与人体的细胞和组织负电荷之间的静电相互作用与细胞和组织紧密结合，发挥防护和治疗的作用。此外，多巴氧化生成邻位二醌，可以和未被氧化的多巴相互交联形成膜或是网状支架，促使蛋白质更加紧密、稳固地附着在人体表面，起到保护作用。贻贝粘蛋白是大分子蛋白质，在人体内完全降解的时间约为3-10天，其附着于细胞组织的能力优异，使贻贝粘蛋白可以稳固于局部，持续发挥作用。
虽然贻贝粘蛋白具有以上特点，但目前其产品应用领域非常有限。商品化的贻贝粘蛋白产品有美国BD Biosciences的Cell-Tak，韩国Kollodis的MAP Trix和瑞典Biopolymer的Hydrogel。这些产品或者是以贻贝粘蛋白溶液状态直接使用，或者是以冻干粉制剂保存而在使用前溶解，并且它们的主要应用限于微观的细胞粘附和组织粘合剂。也有报道贻贝粘蛋白用于胎膜修复、作为抗海水腐蚀涂层、心脏载药支架等应用。
发明内容
本发明的一个目的是提供贻贝粘蛋白产品。
在本文中使用的贻贝粘蛋白是指从贻贝科(Mytilidae)双壳类软体动物中的紫贻贝(Mytilus edulis Linnaeus)、厚壳贻贝(Mytilus coruscus)或翡翠贻贝(Perna viridis)等海洋贻贝中纯化获得的、目前已知的贻贝粘蛋白11个亚类：mefp1、mefp-2、mefp-3、mefp-4、mefp-5、mefp-6、胶原蛋白pre-COL-P、pre-COL-D、pre-COL-NG、足丝基质蛋白PTMP和DTMP中的一种或几种的混合物。在本文中使用的贻贝粘蛋白在水溶液中的酸碱度可以是pH 1.0-7.0，特别是可以在pH 3.0-6.5的范围内以使其治疗效果更佳。
在本文中使用的贻贝粘蛋白可以采用以下制备方法获得，例如中国专利号ZL200710179491.0的一种使用混合吸附色谱分离纯化贻贝粘蛋白的方法，中国专利号ZL200710179492.5的一种使用羧甲基离子交换色谱纯化贻贝粘蛋白的方法，中国专利号ZL200910087567.6的一种使用盐析和透析分离纯化贻贝粘蛋白的方法等。
在本文中使用的贻贝粘蛋白可以是溶液或冻干粉形式，特别是贻贝粘蛋白在产品中的浓度可以是0.1-15.0mg/ml，当浓度过低时，贻贝粘蛋白的功效不大，当浓度过高时，可引起细胞毒性、皮肤刺激等作用，从而不利于血 管炎症的治疗。
在本文中使用的贻贝粘蛋白也可以与辅料结合而制备成液体剂。示例性的贻贝粘蛋白液体剂是将贻贝粘蛋白溶液母液或冻干粉溶解或稀释至一定浓度或pH值制得，溶解或稀释用溶液可以是水、生理盐水、磷酸盐溶液、醋酸盐溶液、硼酸盐溶液等等。最终产品中贻贝粘蛋白的酸碱度可以是pH 1.0-7.0，特别是可以在pH 3.0-6.5的范围内治疗效果更佳。
在本文中使用的贻贝粘蛋白也可以与辅料结合而制备成凝胶剂。示例性的贻贝粘蛋白凝胶剂是将贻贝粘蛋白溶液或冻干粉与凝胶基质材料混合制得，所述凝胶基质材料可以是选自纤维素衍生物、卡波姆和海藻酸盐、西黄蓍胶、明胶、果胶、卡拉胶、结冷胶、淀粉、黄原胶、阳离子瓜尔胶、琼脂、非纤维素多糖、乙烯聚合物、丙烯酸树脂、聚乙烯醇或聚羧乙烯中之一或其任意组合。
本领域技术人员可以根据不同病期的临床适应症的特点来选择使用上述剂型或其他合适的剂型。
以上所有制剂都可以采用本领域周知的方法制备，详细的操作步骤可以参照例如《制剂学》。
在本文中使用的贻贝粘蛋白可以作为主要原料，采用药学上可接受的载体制备药品。所述药品可以是液体剂、凝胶剂。所述药品可通过口服、喷涂、注射、定向局部缓释、靶向给药的方式使用，并且可以以低温或者加热的方式给予。
在本文中使用的贻贝粘蛋白可以作为主要原料，制备医疗器械。本文中使用的术语医疗器械是指直接或间接用于人体的材料及其他类似或相关的物品。所述医疗器械可以是液体剂、凝胶剂。所述医疗器械可通过口服、喷涂、注射、定向局部缓释、靶向给药的方式使用，并且可以以低温或加热方式给予。
在本文中使用的贻贝粘蛋白可以作为主要原料，采用保健品或食品领域可接受的辅料制备保健品或食品。所述保健品或食品可以是液体剂、凝胶剂。所述保健品或食品可通过口服、喷涂、注射、定向局部缓释、靶向给药的方式使用，并且可以以低温或加热方式给予。
本发明的另一个目的是提供贻贝粘蛋白产品抑制血管炎症的应用。
出人意料地，本发明人发现贻贝粘蛋白可缓解各种血管炎症引起的纤维素沉积、胶原纤维变性、内皮细胞及肌细胞坏死等。
常见血管炎症包括变应性白细胞破碎性血管炎、结节性多动脉炎、血栓形成性血管炎、肉芽肿性血管炎、淋巴细胞性血管炎、血液成分异常性血管炎和风湿性血管炎等。
变应性白细胞破碎性血管炎是由感染、药物或免疫异常引起的血管炎症，临床表现可有不规则发热、肌痛、关节痛等。皮肤损害多分布于下肢，皮损呈多样性。紫癜性瘀斑最常见，具特征性，常高出皮面、压之不褪色。可有风团样红斑，严重时有水疱、血疱。中性粒细胞渗出到周围组织时还可以出现脓疱。有时有大小不等的皮下结节。若血管内皮损伤，导致管腔狭窄可出现局部溃疡和坏死，偶见网状青斑。皮疹有时伴有瘙痒或疼痛，一般持续2-4周，吸收后有色素沉着或遗留萎缩性瘢痕。变应性白细胞破碎性血管炎治疗通常采用糖皮质激素，可抑制毛细血管扩张、减轻渗出和水肿、抑制白血细胞的浸润和吞噬，从而减轻炎症症状。但长期或大量服用可导致皮质功能亢进综合症、诱发或加重感染、诱发或加重溃疡、诱发高血压和动脉硬化等。
结节性多动脉炎是由病毒感染引起的一种累及中、小动脉全层的坏死性血管炎，可累及全身各组织器官血管，临床表现多样，可仅限于皮肤，也可以波及多个器官或系统。通常以皮肤结节为特征，沿浅表动脉排列或不规则地聚集在血管近旁，有痛及压痛，呈玫瑰红、鲜红或接近正常皮色，病情严重者可致死亡或致残。主要有系统性结节性多动脉炎、良性皮肤型结节性多动脉炎、婴儿结节性多动脉炎等。结节性多动脉炎的治疗通常采用皮质类固醇，长期使用易引发满月脸、骨质疏松、胃溃疡、水牛肩、高血压、白内障、痤疮及霉菌感染。
血栓形成性血管炎主要累及中、小动脉和静脉，以血管腔内血栓形成为特征，并呈现不同的临床表现。主要有血栓闭塞性脉管炎、血栓性静脉炎、恶性萎缩性丘疹病、网状青斑性血管炎、血栓性血小板减少性紫癜等。血管形成性血管炎治疗常使用血管扩张剂、抗凝剂或血浆扩容剂治疗。
肉芽肿性血管炎是大、中、小血管受累及的多系统疾病，以血管壁内外肉芽肿形成为特征，病程慢。主要有韦格纳氏肉芽肿、变应性肉芽性血管炎、 颞动脉炎、大动脉炎等。其病理以血管壁的炎症为特征，主要侵犯上、下呼吸道和肾脏，通常以鼻黏膜和肺组织的局灶性肉芽肿性炎症为开始，继而进展为血管的弥漫性坏死性肉芽肿性炎症。临床常表现为鼻和副鼻窦炎、肺病变和进行性肾功能衰竭。还可累及关节、眼、皮肤，亦可侵及眼、心脏、神经系统及耳等。肉芽肿性血管炎的治疗常采用糖皮质激素或免疫抑制剂。
淋巴细胞性血管炎以皮肤细小血管、管壁及其周围组织内淋巴细胞浸润为特征，产生不同类型的皮肤损害，主要有淋巴瘤样丘疹病、急性痘疮样苔藓样糠疹等。糖皮质激素和环磷酰胺是治疗的主要药物。
血液成分异常性血管炎是由于血液中甘些成分异常引起的细小血管炎性疾病，表现为皮肤或内脏损害，主要有冷球蛋白血症、冷高球蛋白血症、巨球蛋白血症等。
风湿性血管炎的典型特征是周围血管损害，常发生在风湿因子滴度高及有全身并发症者，临床表现为皮肤血管炎损害，局限性可触及紫癜，躯干非特异红斑，血管梗塞，大疱和溃疡，20％患者发生指(趾)坏疽。甲皱襞发生毛细血管扩张、梗塞性丘疹和结节。治疗一般用水杨酸盐或抗疟药，重症者可用皮质类固醇。
总体而言，血管炎症的治疗多采用糖皮质激素或皮质类固醇，但长期或大量服用可导致皮质功能亢进综合症、诱发或加重感染、诱发或加重溃疡、诱发高血压和动脉硬化等。
在一个方面，本发明的贻贝粘蛋白可用于治疗变应性白细胞破碎性血管炎、结节性多动脉炎、血栓形成性血管炎、肉芽肿性血管炎、淋巴细胞性血管炎、血液成分异常性血管炎及风湿性血管炎等炎症。
在另一个方面，本发明的贻贝粘蛋白可用于抑制变应性白细胞破碎性血管炎、结节性多动脉炎、血栓形成性血管炎、肉芽肿性血管炎、淋巴细胞性血管炎、血液成分异常性血管炎及风湿性血管炎引起的血管癌。
具体实施方式
本发明的实施方式包括：
1、贻贝粘蛋白在治疗血管炎症中的应用。
2、根据实施方式1的贻贝粘蛋白应用，其中所述贻贝粘蛋白是来自亚类： mefp1、mefp-2、mefp-3、mefp-4、mefp-5、mefp-6、胶原蛋白pre-COL-P、pre-COL-D、pre-COL-NG、足丝基质蛋白PTMP和DTMP中的一种或几种的混合物。
3、根据实施方式1的贻贝粘蛋白应用，其中所述贻贝粘蛋白浓度可以是0.1-15.0mg/ml。
4、根据实施方式1的贻贝粘蛋白应用，其中所述贻贝粘蛋白可以是以液体剂、凝胶剂使用。
5、根据实施方式1的贻贝粘蛋白应用，其中最终产品中的贻贝粘蛋白可以是在pH 1.0-7.0的范围内，特别是在pH 3.0-6.5的范围内。
6、根据实施方式1-5中任一项的贻贝粘蛋白应用，其中所述血管炎症可以选自：变应性白细胞破碎性血管炎、结节性多动脉炎、血栓形成性血管炎、肉芽肿性血管炎、淋巴细胞性血管炎、血液成分异常性血管炎及风湿性血管炎。
7、根据实施方式1-5中任一项的贻贝粘蛋白应用，其中所述血管炎症可以选自：变应性白细胞破碎性血管炎、结节性多动脉炎、血栓形成性血管炎、肉芽肿性血管炎、淋巴细胞性血管炎、血液成分异常性血管炎及风湿性血管炎引起的血管癌。
8、贻贝粘蛋白作为活性成分在用于治疗血管炎症的组合物中的应用，其中所述组合物可以是以液体剂、凝胶剂使用。
9、根据实施方式7的贻贝粘蛋白应用，其中所述组合物可以是通过口服、喷涂、注射、定向局部缓释、靶向给药的方式使用。
10、根据实施方式7的贻贝粘蛋白应用，其中所述组合物可以以低温或加热方式使用。
11、一种用于治疗血管炎症的药品，包括贻贝粘蛋白和药学上可接受的载体，其中贻贝粘蛋白的浓度可以是0.1-15.0mg/ml。
12、一种用于治疗血管炎症的医疗器械，包括贻贝粘蛋白和医疗器械领域可接受的载体，其中贻贝粘蛋白的浓度可以是0.1-15.0mg/ml。
13、一种用于治疗血管炎症的保健品/食品，包括贻贝粘蛋白和保健品或食品领域可接受的载体，其中贻贝粘蛋白的浓度可以是0.1-15.0mg/ml。
14、贻贝粘蛋白在用于治疗血管炎症的药品中的应用，其中所述血管炎 症可以选自：变应性白细胞破碎性血管炎、结节性多动脉炎、血栓形成性血管炎、肉芽肿性血管炎、淋巴细胞性血管炎、血液成分异常性血管炎及风湿性血管炎。
15、贻贝粘蛋白在用于治疗血管炎症的药品中的应用，其中所述血管炎症可以选自：变应性白细胞破碎性血管炎、结节性多动脉炎、血栓形成性血管炎、肉芽肿性血管炎、淋巴细胞性血管炎、血液成分异常性血管炎及风湿性血管炎引起的血管癌。
16、贻贝粘蛋白在用于治疗血管炎症的医疗器械中的应用，其中所述血管炎症可以选自：变应性白细胞破碎性血管炎、结节性多动脉炎、血栓形成性血管炎、肉芽肿性血管炎、淋巴细胞性血管炎、血液成分异常性血管炎及风湿性血管炎。
17、贻贝粘蛋白在用于治疗血管炎症的医疗器械中的应用，其中所述血管炎症可以选自：变应性白细胞破碎性血管炎、结节性多动脉炎、血栓形成性血管炎、肉芽肿性血管炎、淋巴细胞性血管炎、血液成分异常性血管炎及风湿性血管炎引起的血管癌。
18、贻贝粘蛋白在用于治疗血管炎症的保健品或食品中的应用，其中所述血管炎症可以选自：变应性白细胞破碎性血管炎、结节性多动脉炎、血栓形成性血管炎、肉芽肿性血管炎、淋巴细胞性血管炎及血液成分异常性血管炎。
19、贻贝粘蛋白在用于治疗血管炎症的保健品或食品中的应用，其中所述血管炎症可以选自：变应性白细胞破碎性血管炎、结节性多动脉炎、血栓形成性血管炎、肉芽肿性血管炎、淋巴细胞性血管炎、血液成分异常性血管炎及风湿性血管炎引起的血管癌。
下面将结合具体实施例对本发明作进一步说明。需要指出的是，由本发明中的贻贝粘蛋白或贻贝粘蛋白的各种制剂形成的药品、医疗器械、保健品或食品在施用于受试者后，都可以应用于上文所述的适应症并展现出上文所述的功能，在本发明范围内的所有剂型均已测试，下文中，仅仅是为说明，只在实施例中描述了其中一少部分，然而不应将其理解为对本发明的限制。
除非特殊说明，否则本发明中所使用的试剂都是市售可购买的。
实施例1：贻贝粘蛋白液体药品在变应性皮肤血管炎治疗中的应用。
取浓度为10.0mg/ml的贻贝粘蛋白溶液1ml，加入9ml 0.1％柠檬酸溶液，配制浓度为1.0mg/ml的贻贝粘蛋白水溶液药品。收集经血管外科专家确诊的变应性皮肤血管炎患者6例，入选病患临床表现皮肤红斑、丘疹、荨麻疹，伴有疼痛或瘙痒症状。
入选病患随机分为对照组和试验组，对照组采用0.1％柠檬酸溶液治疗，试验组采用上述贻贝粘蛋白水溶液药品治疗。两组使用方法均为每日3次，饭后喷涂患处，每次喷涂2-3次至患处完全被覆盖。喷涂贻贝粘蛋白水溶液药品组中，10-30分钟内患处疼痛或瘙痒明显减弱，从治疗前视觉模拟VAS评分5.0-7.0下降到1.0-3.0，止痛或止痒时间可持续2-7小时。对照组喷涂前后患处疼痛VAS评分无变化。随着使用时间延长，止痛持续时间延长，使用间隔延长，未表现出任何依赖性。
连续喷涂7天后，试验组1例病患部位痊愈，对照组3例均未痊愈；连续喷涂14天后，试验组剩余2例患者均痊愈，对照组3例患者均未痊愈(参见表1)。
表1：
观察指标 对照组 试验组
平均起效时间(min) - 18.6±5.2
使用前VAS平均评分 5.3±1.0 5.5±0.9
使用后VAS平均评分 5.1±0.8 1.9±0.8
平均止痛持续时间(h) - 5.2±1.0
平均愈合时间(天) 15.7±0.5 10.3±3.5
实施例2：贻贝粘蛋白凝胶医疗器械在皮肤型结节性多动脉炎治疗中的应用。
取羧甲基纤维素钠10g，加入20ml去离子水，90℃温浴30min至完全溶解得到凝胶基质，另取浓度为10.0mg/ml的贻贝粘蛋白溶液2.5ml，边搅拌边加入到凝胶基质中，混合均匀后形成贻贝粘蛋白凝胶医疗器械，贻贝粘蛋白浓度为1.0mg/ml。
收集经免疫内科专家确诊的皮肤型节结性多动脉炎患者6例，入选病患 临床表现体重下降、乏力、肌痛、双下肢压痛，双腿皮肤溃烂、渗液，疮面周围红肿发热、伴有疼痛症状。入选患者随机分配至对照组或试验组，对照组治疗时，口服泼尼松50mg/d及拉米夫定100mg/d；试验组治疗时采用贻贝粘蛋白凝胶医疗器械喷涂双腿皮肤患处，每日2次，用量以贻贝粘蛋白凝胶能均匀覆盖患处。治疗2周后，对照组病患双腿部皮肤疮面红肿，溃烂、渗液未见好转，疼痛略有减轻；试验组病患双腿部皮肤疮面红肿消退，溃烂、渗液、疼痛明显减轻。治疗3周后，对照组疮面红肿略有消退，溃烂面未减小，仍有少量渗液；试验组全部病患疮面干燥、结痂。可以看出，贻贝粘蛋白凝胶医疗器械可用于皮肤型结节性多动脉炎的治疗，且效果相较于现有药物泼尼松和拉米夫定更好。
实施例3：贻贝粘蛋白液体保健品在血栓形成性血管炎治疗中的应用。
取浓度为5.0mg/ml的贻贝粘蛋白溶液100ml，加入9ml 0.1％柠檬酸溶液，配制浓度为0.1mg/ml的贻贝粘蛋白水溶液保健品。
收集经免疫科专家确诊的血栓形成性血管炎患者2例，入选病患临床表现下肢疼痛、活动后间歇性跛行、踝肱指数0.8，肢体抬高试验呈阳性。
入选病患口服上述贻贝粘蛋白液体保健品，每日服用1次，每次10ml，每月复查。服用2个月后，患者下肢疼痛症状消失，间歇性跛行时间和距离减低，踝肱指数恢复至0.9。可以看出，贻贝粘蛋白液体保健品有利于血栓形成性血管炎的治疗。
实施例4：贻贝粘蛋白液体药品在肉芽肿性血管炎治疗中的应用。
取浓度为10.0mg/ml的贻贝粘蛋白溶液10ml，加入9ml 0.1％乙酸溶液，配制浓度为1.0mg/ml的贻贝粘蛋白液体药品。
收集经免疫科专家确诊的早期肉芽肿性血管炎患者2例，入选病患临床表现发热、体重下降、关节痛症状，并伴有鼻粘膜溃疡、鼻出血、上呼吸道阻塞和疼痛。
入选病患分别分配为对照组或试验组，对照组采用口服1.5mg/kg.d泼尼松治疗；试验组口服上述贻贝粘蛋白液体药品，每日2次，每次1.0mg。治疗4周后，对照组和试验组病患症状均出现缓解。对照组降低剂量1.0mg/kg.d， 试验组降低剂量至0.5mg/次维持，至8周对照组和试验组均未出现复发或症状加重情况。可以看出，口服贻贝粘蛋白液体药品有助于肉芽肿性血管炎的治疗。
实施例5：贻贝粘蛋白液体医疗器械在淋巴细胞性血管炎治疗中的应用。
取浓度为10.0mg/ml的贻贝粘蛋白溶液1ml，加入9ml 0.1％柠檬酸溶液，配制浓度为1.0mg/ml的贻贝粘蛋白水溶液医疗器械。
收集经免疫科专家确诊的淋巴细胞性血管炎患者8例，入选病患临床表现皮肤红色丘疹，丘疹水疱性、脓疱性或出血性。
入选患者随机分配至对照组或试验组，对照组治疗时，口服泼尼松50mg/d；试验组治疗时采用贻贝粘蛋白液体医疗器械喷涂患处，每日2次，用量以贻贝粘蛋白能均匀覆盖患处。治疗2周后，对照组病患丘疹明显减少、渗出减少；试验组丘疹明显减少、渗出减少。治疗3周后，对照组病患丘疹渗出加重、红肿情况加重，治疗效果出现反复；试验组丘疹消退。可以看出，贻贝粘蛋白液体医疗器械可以用于淋巴细胞性血管炎的治疗。
实施例6：贻贝粘蛋白凝胶剂药品在风湿性血管炎治疗中的应用。
取羧甲基纤维素钠8g，加入20ml去离子水，90℃温浴30min至完全溶解得到凝胶基质，另取浓度为5.0mg/ml的贻贝粘蛋白溶液10ml，边搅拌边加入到凝胶基质中，混合均匀后形成贻贝粘蛋白凝胶剂药品，贻贝粘蛋白浓度为0.6mg/ml。
收集经免疫科专家确诊的风湿性血管炎患者6例，入选病患临床表现皮肤溃疡及周围神经病变。
入选患者随机分配至对照组或试验组，对照组病患治疗时，口服泼尼松50mg/d；试验组病患采用贻贝粘蛋白凝胶剂药品治疗，每日涂抹2次，每次用量以能均匀覆盖患处。治疗1周后，对照组溃疡处渗出减少、溃疡面积均无变化；试验组溃疡处渗出减少，溃疡面积出现不同程度的减少。治疗2周后，对照组溃疡处渗出减少，平均愈合率为32％；试验组全部病患溃疡基本愈合，表现为患处被新生上皮所覆盖。可以看出，贻贝粘蛋白凝胶剂药品可以用于风湿性血管炎的治疗。

Claims (11)

  1. 贻贝粘蛋白在治疗血管炎症中的应用。
  2. 根据权利要求1的贻贝粘蛋白应用，其中所述贻贝粘蛋白是来自亚类：mefp1、mefp-2、mefp-3、mefp-4、mefp-5、mefp-6、胶原蛋白pre-COL-P、pre-COL-D、pre-COL-NG、足丝基质蛋白PTMP和DTMP中的一种或几种的混合物。
  3. 根据权利要求1的贻贝粘蛋白应用，其中所述贻贝粘蛋白浓度为0.1-15.0mg/ml。
  4. 根据权利要求1的贻贝粘蛋白应用，其中所述贻贝粘蛋白是以液体剂、凝胶剂使用。
  5. 根据权利要求1的贻贝粘蛋白应用，其中最终产品中的贻贝粘蛋白是在pH1.0-7.0的范围内，特别是在pH3.0-6.5的范围内。
  6. 根据权利要求1-5中任一项的贻贝粘蛋白应用，其中所述血管炎症选自：变应性白细胞破碎性血管炎、结节性多动脉炎、血栓形成性血管炎、肉芽肿性血管炎、淋巴细胞性血管炎、血液成分异常性血管炎及风湿性血管炎。
  7. 根据权利要求1-5中任一项的贻贝粘蛋白应用，其中所述血管炎症选自：变应性白细胞破碎性血管炎、结节性多动脉炎、血栓形成性血管炎、肉芽肿性血管炎、淋巴细胞性血管炎、血液成分异常性血管炎及风湿性血管炎引起的血管癌。
  8. 贻贝粘蛋白作为活性成分在用于治疗血管炎症的组合物中的应用，其中所述组合物是以液体剂、凝胶剂使用。
  9. 贻贝粘蛋白作为活性成分在用于治疗血管炎症的药品中的应用。
  10. 贻贝粘蛋白作为活性成分在用于治疗血管炎症的医疗器械中的应用。
  11. 贻贝粘蛋白作为活性成分在用于治疗血管炎症的保健品或食品中的应用。
PCT/CN2016/079767 2016-04-20 2016-04-20 贻贝粘蛋白产品及其抑制血管炎症的应用 WO2017181372A1 (zh)

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