WO2017181979A1 - 贻贝粘蛋白产品及其抑制脏器炎症的应用 - Google Patents

贻贝粘蛋白产品及其抑制脏器炎症的应用 Download PDF

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WO2017181979A1
WO2017181979A1 PCT/CN2017/081309 CN2017081309W WO2017181979A1 WO 2017181979 A1 WO2017181979 A1 WO 2017181979A1 CN 2017081309 W CN2017081309 W CN 2017081309W WO 2017181979 A1 WO2017181979 A1 WO 2017181979A1
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mussel mucin
mussel
inflammation
mucin
mefp
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PCT/CN2017/081309
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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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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/56—Materials from animals other than mammals

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 inflammation of organs.
  • Organ inflammation is an adhesion or infection that is formed by irritation, infection, trauma, or surgery.
  • the treatment of organ inflammation is usually treated with oral or injection of a broad-spectrum non-steroidal anti-inflammatory drug.
  • These drugs mainly exert anti-inflammatory, anti-rheumatic, analgesic, antipyretic and anticoagulant effects by inhibiting the synthesis of prostaglandins.
  • FDA US Food and Drug Administration
  • 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). The cells and tissues of the human body are negatively charged. Mussel mucin is negatively charged by its own positive charge and human cells and tissues.
  • 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.
  • 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., so Conducive to the treatment of organ 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 may be a liquid agent, a gel, or a foaming agent.
  • 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 supplement or food may be a liquid, a gel, or a foam.
  • 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 present invention is to provide an application of mussel mucin products to inhibit inflammation of organs.
  • mussel mucin can alleviate various organ inflammations including heart, stomach, intestine, lung, liver, spleen, kidney, pancreas, bladder, ovary, prostatitis and the like.
  • Cardiac inflammation is an inflammatory disease caused by pathogenic microorganisms directly invading heart tissue, including pericarditis, myocarditis, and endocarditis. Antibiotics are the main measure to treat heart inflammation.
  • Gastritis is an acute and chronic inflammation of the stomach caused by a variety of causes, often accompanied by epithelial damage, mucosal inflammatory response and epithelial regeneration. Clinical manifestations include upper abdominal pain, bloating, warming, repeated bleeding, loss of appetite, acid reflux, nausea, vomiting, fatigue, constipation or diarrhea. Gastritis can be used in the onset of pain, atropine, probensin, belladonna mixture and the like.
  • Enteritis is inflammation caused by bacteria, viruses, fungi or parasites. Clinical manifestations include abdominal pain, diarrhea, septic flushing or mucus pus and bloody stools. Viral enteritis generally does not require pathogen treatment and can heal itself. Bacterial enteritis is based on the results of bacterial drug susceptibility testing.
  • Pneumonia refers to inflammation of the terminal airway, alveolar and interstitial lungs, and can be caused by pathogenic microorganisms such as bacteria, viruses, fungi, parasites, and physical and chemical factors such as radiation and inhalation foreign bodies.
  • the main clinical symptoms are fever, cough, cough, blood in the sputum, and may be accompanied by chest pain or difficulty breathing.
  • the main link is pneumonia treatment.
  • Treatment of bacterial pneumonia includes treatment for pathogens and empiric therapy.
  • the former selects sensitive antibacterial drugs in vitro according to the results of sputum culture and drug susceptibility test; the latter mainly selects antibiotics that may cover pathogens according to the epidemiological data of pneumonia pathogens in this region.
  • Hepatitis is a general term for inflammation of the liver. It usually refers to the destruction of liver cells caused by various causes such as viruses, bacteria, parasites, chemical poisons, drugs, alcohol, autoimmune factors, etc., and the function of the liver is damaged, causing the body to A series of discomfort symptoms, as well as abnormalities in liver function indicators.
  • the treatment of hepatitis is to protect the liver, while injecting interferon or oral nucleoside analog antiviral, the advantages are good curative effect, small side effects, the disadvantage is that it needs to be taken for a long time, and there is a risk of developing drug resistance.
  • Spleenitis the inflammation of the spleen, is the most common pathological process of the spleen. It is often associated with various infectious diseases and is also seen in hematogenous diseases. Spleenitis can be divided into three types: acute inflammatory splenomegaly, necrotizing spleenitis and chronic spleenitis according to its pathological characteristics and rapid course of disease. Spleen inflammation is often treated with antibiotics.
  • Nephritis is a type of kidney disease caused by immune-mediated, inflammatory mediators that cause inflammatory changes in the kidney's intrinsic tissue and cause varying degrees of renal dysfunction. Clinical manifestations include fatigue, lumbar pain, gross hematuria, edema, hypertension, renal dysfunction, decreased urine output, and congestive heart failure. Nephritis for immune pathogenesis often includes glucocorticoids and immunosuppressive agents. Blood purification treatments such as plasma exchange, immunoadsorption, etc. effectively remove autoantibodies and antigen-antibody complexes in vivo.
  • Nephritis for non-immune pathogenesis including hypertension, hyperlipidemia, hyperglycemia, hyperuricemia, obesity, proteinuria, and intrarenal hypercoagulability, is treated with renin-angiotensin system activation, oxidative stress, and the like.
  • Pancreatitis is a disease caused by the self-digestion of trypsin in the pancreas. It is characterized by edema, congestion or hemorrhage, necrosis, etc. The clinical manifestations are abdominal pain, bloating, nausea, vomiting, fever and other symptoms. Analgesics and antispasmodic drugs can be given in the early stage of the disease, and gastric tube decompression, H2 receptor blockers, and anticholinergic drugs are used when the condition is severe.
  • Cystitis is an inflammation that occurs in the bladder and is mainly caused by specific and non-specific bacterial infections. Its clinical manifestations are acute and chronic. The former has a sudden onset, a burning sensation during urination, and pain in the urethra area. Sometimes there is urgency and severe urinary frequency. In severe cases, there are gross hematuria and blood clots. The symptoms of chronic cystitis are similar to those of acute cystitis, but there is no high fever. Symptoms can last for several weeks or intermittent attacks, making the patient weak and thin, and the waist, abdomen and bladder are not comfortable or painful. Antibacterial therapy is the main method of treatment of cystitis.
  • Ovarianitis is an inflammatory reaction caused by infection of the ovaries, resulting in ovarian adhesions, fallopian tube wrapping, abscesses or obstructions. Ovarianitis is usually divided into acute and chronic. In acute cases, there will be symptoms such as fever, abdominal pain, and anal sensation. In chronic cases, symptoms such as general weakness, poor mental function, irregular menstruation, and mass in the lower abdomen may occur. In the acute phase, antibiotics are often used.
  • Prostatitis is an inflammatory reaction caused by pathogen infection in the prostate.
  • the clinical manifestations include systemic symptoms such as chills, fever, fatigue and weakness, as well as perineal and suprapubic pain, and even acute urinary retention.
  • Prostatitis treatment usually uses prostatic fluid culture to find pathogenic pathogens, choose antibacterial drugs, or use non-steroidal anti-inflammatory drugs to improve symptoms.
  • mussel mucin can be used to treat organ inflammation including heart, stomach, intestine, lung, liver, spleen, kidney, pancreas, bladder, ovary, prostatic inflammation, and the like.
  • 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.
  • the mussel mucin application according to any one of embodiments 1 to 5, wherein the organ inflammation is selected from the group consisting of: heart, stomach, intestine, lung, liver, spleen, kidney, pancreas, bladder, ovary, prostate Inflammation, etc.
  • composition can be used by oral, spray, injection, targeted local sustained release, targeted administration.
  • a medicament for treating inflammation of an organ 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 inflammation of an organ comprising a 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 treating inflammation of an organ comprising mussel mucin and a health care product or a carrier acceptable for the food field, wherein the mussel mucin concentration may be from 0.1 to 15.0 mg/ml.
  • mussel mucin in a medicament for treating inflammation of an organ, wherein the inflammation of the organ can be selected from the group consisting of: heart, stomach, intestine, lung, liver, spleen, kidney, pancreas, bladder, ovary, prostate Inflammation, etc.
  • the use of mussel mucin in a medical device for treating inflammation of an organ wherein the organ inflammation can be selected from the group consisting of: heart, stomach, intestine, lung, liver, spleen, kidney, pancreas, bladder, ovary, Prostate inflammation and so on.
  • the use of mussel mucin in a health care product or food for treating inflammation of an organ wherein The organ inflammation may be selected from the group consisting of heart, stomach, intestine, lung, liver, spleen, kidney, pancreas, bladder, ovary, prostatitis, and the like.
  • a method of treating inflammation of an organ comprising formulating a liquid or gel containing the mussel mucin according to any one of embodiments 10-12 and administering to a subject in need thereof, wherein the mussel is sticky
  • the concentration of the protein may be from 0.1 to 15.0 mg/ml.
  • organ inflammation is selected from the group consisting of: heart, stomach, intestine, lung, liver, spleen, kidney, pancreas, bladder, ovary, prostatitis, and the like.
  • Example 1 Application of mussel mucin liquid medicine in the treatment of endocarditis.
  • a mussel mucin solution having a concentration of 10.0 mg/ml was added, and a 0.1% citric acid solution was added to prepare a mussel mucin aqueous solution drug having a concentration of 1.0 mg/ml.
  • Example 2 Application of mussel mucin lyophilized powder medicine in the treatment of gastritis.
  • Example 3 Application of mussel mucin drug in the treatment of enteritis.
  • Twenty patients with acute enteritis were enrolled. The clinical manifestations were nausea, vomiting, and diarrhea. After enteroscopy, they were diagnosed as acute enteritis by the digestive medicine doctor. Subjects were randomized to control or experimental groups, and the control group was treated with oral berberine 3 times daily. The patients in the experimental group were orally administered an enteric sustained-release preparation containing mussel mucin, one capsule once a day. After 2 days of treatment, the patients in the control group and the test group were all relieved of nausea, vomiting and diarrhea, which proved that mussel mucin liquid medicine can be used for the treatment of acute enteritis.
  • Example 4 Application of mussel mucin liquid medical device in the treatment of pneumonia.
  • a mussel mucin liquid having a concentration of 10.0 mg/ml was taken and diluted to 5.0 mg/ml with 0.005% acetic acid to form a mussel mucin liquid medical device.
  • Ten patients with acute pneumonia were enrolled. The clinical manifestations were high fever, chills, cough, chest pain, and difficulty in breathing. After blood tests, the doctors were diagnosed with pneumonia.
  • the patients were randomly assigned to the control group or the experimental group. The control group was treated with intravenous penicillin.
  • the patients in the experimental group were given aerosolized administration once a day, 10 ml each time. After 7 days of treatment, the body temperature of the control group and the test group returned to normal, but there were still symptoms of cough and cough.
  • the control group was switched to oral Kechuanning, 1 ml each time, 3 times a day.
  • the test group still inhaled mussel mucin by atomization, once a day, 10 ml each time. By the 14th day of treatment, the symptoms of cough and cough disappeared in all patients, and the blood tests were normal. In the control group, 2 patients still had cough. It is proved that mussel mucin liquid medical devices can be used for the treatment of pneumonia.
  • Example 5 Application of mussel mucin drug in the treatment of hepatitis.
  • the mussel mucin solution was taken and diluted to 0.5 mg/ml with 0.001% citric acid to obtain a mussel mucin liquid medicine.
  • hepatitis A Five patients with hepatitis A were collected. The clinical manifestations were yellowish skin, fever, pain in the liver area, loss of appetite, and abdominal distension. The patient was diagnosed with hepatitis A after the doctor was admitted to the group. The patient took 2 times a day, 1 ml each time. After 3 weeks of treatment, the patient's clinical symptoms disappeared and the serum total bilirubin was below 17umol/l, which proved that mussel mucin drugs can be used for the treatment of hepatitis.
  • Example 6 Application of mussel mucin drug in the treatment of cystitis.
  • a mussel mucin solution having a concentration of 10.0 mg/ml was diluted with 0.001% acetic acid to obtain a mussel mucin liquid medicine having a mussel mucin concentration of 2.0 mg/ml.
  • Example 7 Application of mussel mucin medical device in the treatment of ovarian inflammation.
  • Eight patients with oophoritis were enrolled.
  • the clinical manifestations were fever, abdominal pain (dull pain, no radiation to it), lumbosacral pain, and anal bulge.
  • the gynecologic doctor was diagnosed with oophoritis and enrolled.
  • the selected patients were randomly assigned to the control group or the experimental group. After laparoscopic adhesion decomposition, the control group was intraperitoneally perfused with molecular dextran, and the experimental group was perfused intraperitoneally with mussel mucin medical device 100 ml. The clinical symptoms of the patients in the control group and the experimental group disappeared, and the examinations were normal. It was proved that the mussel mucin medical device can be used for the treatment of oophoritis.
  • Example 8 Application of mussel mucin drug in the treatment of prostatitis.
  • a mussel mucin solution having a concentration of 0.5 mg/ml was taken, diluted 5 times with 0.001% acetic acid, and the mussel mucin content was 0.1 mg/ml to obtain a mussel mucin liquid medicine.
  • Example 9 Mussel mucin treatment of gastric ulcer animal test.
  • the mussel mucin solution (MAP) was prepared by column chromatography with a protein concentration of 5.0 mg/ml and a purity of 90%. The above mussel mucin solution was taken and diluted with physiological saline to a mussel mucin content of 0.5 mg/ml to obtain a mussel mucin liquid. Each 100 ml mussel mucin product contains mussel mucin 0.5 mg, sodium chloride 0.9 g, and the rest is water for injection.
  • the mussel mucin solution was taken as a test sample, and omeprazole (Sichuan Kelun Pharmaceutical Co., Ltd.) was taken as a positive control, and physiological saline (Chenxin Pharmaceutical Co., Ltd.) was used as a negative control.
  • the dose administered was mussel mucin of 1.6 mg/kg and omeprazole (8 mg/kg).
  • the experiment used multiple gavage methods to observe the protective effect of MAP on acute gastric ulcer induced by absolute alcohol.
  • mice used SPF grade C57BL/6 mice (purchased from Shanghai Experimental Animal Resource Center), 5 in each group, all male. Each group was administered continuously for 5 days, and after 30 minutes of administration on the 6th day, absolute ethanol (0.2 ml/mouse) was administered by intragastric administration, and the mice were sacrificed 1 hour later. Visual observation of bloating, hyperemia, etc., and histopathological examination of gastric tissue to determine the effect of MAP to protect gastric ulcer.
  • mice were orally administered with absolute alcohol, different degrees of mucosal shedding, deformation, necrosis, fibrosis, inflammation and congestion were observed in the stomach of each group.
  • MAP can reduce flatulence and congestion in the stomach, and the effect is comparable to omeprazole. It indicates that MAP has a protective function against acute gastric ulcer induced by absolute alcohol.

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Abstract

本发明公开了贻贝粘蛋白或其制剂抑制脏器炎症的应用。具体地公开了贻贝粘蛋白或其制剂在治疗心、胃、肠、肺、肝、脾、肾、胰、膀胱、卵巢、前列腺炎症等中的应用。

Description

贻贝粘蛋白产品及其抑制脏器炎症的应用
本申请要求于2016年04月20日提交中国专利局的申请号为PCT/CN2016/079766、名称为“贻贝粘蛋白产品及其抑制脏器炎症的应用”的国际专利申请的优先权，其全部内容通过引用结合在本申请中。
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脏器炎症中的应用。
背景技术
脏器主要位于人体胸腔、腹腔和盆腔，包括心、胃、肠、肺、肝、脾、肾、胰、膀胱、卵巢、前列腺等器官。脏器炎症是脏器受到刺激、感染、创伤或手术后形成的粘连或感染。脏器炎症的治疗多采用口服或注射广谱非甾体类抗炎药物，这类药物主要是通过抑制前列腺素的合成发挥其抗炎、抗风湿、止痛、退热和抗凝血等作用。最近美国食品药品监督管理局(FDA)认为非甾体抗炎药物存在潜在的心血管和消化道出血风险，同时可引起不同程度的胃肠道、肝脏、神经系统、泌尿系统等不良反应。
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，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 利于脏器炎症的治疗。
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、泡沫剂。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、泡沫剂。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脏器炎症的应用。
出人意料地，本发明人发现贻贝粘蛋白可缓解各种脏器炎症，包括心、胃、肠、肺、肝、脾、肾、胰、膀胱、卵巢、前列腺炎症等。
心脏炎症是病原微生物直接侵袭心脏组织而引起的炎症性疾病，包括心包炎、心肌炎、心内膜炎等。抗生素是治疗心脏炎症的主要措施。
胃炎是由多种病因引起的胃急性和慢性炎症，常伴有上皮损伤、粘膜炎症反应和上皮再生。临床表现为上腹痛、腹胀、暖气、反复出血、食欲不振、反酸、恶心、呕吐、乏力、便秘或腹泻等。胃炎在疼痛发作时可用阿托品、普鲁本辛、颠茄合剂等。
肠炎是细菌、病毒、真菌或寄生虫引起的炎症，临床表现主要有腹痛、腹泻、稀水便或粘液脓血便。病毒性肠炎一般不需病原治疗，可自愈。细菌性肠炎根据细菌药物敏感试验结果选用抗菌药。
肺炎是指终末气道、肺泡和肺间质的炎症，可由细菌、病毒、真菌、寄生虫等致病微生物以及放射线、吸入性异物等理化因素引起。临床症状主要为发热、咳嗽、咳痰、痰中带血，可伴有胸痛或呼吸困难等。肺炎治疗除了卧床休息、大量饮水、吸氧、积极排痰外，最主要环节是抗感染。细菌性肺炎的治疗包括针对病原体治疗和经验性治疗。前者根据痰培养和药物敏感试验结果，选择体外试验敏感的抗菌药物；后者主要根据本地区肺炎病原体流行病学资料，选择可能覆盖病原体的抗菌药物。
肝炎是肝脏炎症的统称，通常是指由多种致病因如病毒、细菌、寄生虫、化学毒物、药物、酒精、自身免疫因素等使肝脏细胞受到破坏，肝脏的功能受到损害，引起身体一系列不适症状，以及肝功能指标的异常。肝炎的治疗是在保肝的同时，注射干扰素或口服核苷类似物抗病毒，优点是疗效好、副作用小，缺点是需长期服用，并有产生耐药性的风险。
脾炎即脾脏的炎症，是脾脏最常见的一种病理过程，多伴发于各种传染病，也见于血原虫病。脾炎根据其病变特征和病程急缓可分为急性炎性脾肿、坏死性脾炎和慢性脾炎三种类型。脾脏炎症多采用抗生素治疗。
肾炎是由免疫介导的、炎症介质参与的，导致肾固有组织发生炎性改变，引起不同程度肾功能减退的一类肾脏疾病。临床主要表现为乏力、腰部疼痛、肉眼血尿、水肿、高血压、肾功能异常、尿量减少、充血性心力衰竭等。针对免疫发病机制的肾炎，常包括糖皮质激素及免疫抑制剂治疗。 血液净化治疗如血浆置换、免疫吸附等有效清除体内自身抗体和抗原-抗体复合物。针对非免疫发病机制的肾炎，包括高血压、高血脂、高血糖、高尿酸血症、肥胖、蛋白尿及肾内高凝状态，采用肾素-血管紧张素系统激活、氧化应激等治疗。
胰腺炎是胰腺因胰蛋白酶的自身消化作用而引起的疾病，表现为水肿、充血或出血、坏死等，临床表现为腹痛、腹胀、恶心、呕吐、发热等症状。发病早期可给予止痛药和解痉药，病情较严重时采用胃管减压、H2受体阻滞剂、抗胆碱药等。
膀胱炎是发生在膀胱的炎症，主要由特异性和非特异性细菌感染引起，其临床表现有急性与慢性两种。前者发病突然，排尿时有烧灼感，并在尿道区有疼痛，有时有尿急和严重的尿频，严重时有肉眼血尿和血块排出。慢性膀胱炎的症状与急性膀胱炎相似，但无高热，症状可持续数周或间歇性发作，使病者乏力、消瘦，出现腰腹部及膀胱会阴区不舒适或隐痛。抗菌药物治疗是膀胱炎治疗的主要方法。
卵巢炎是卵巢受到感染产生的炎症反应，产生卵巢粘连、输卵管包裹、脓肿或梗阻等。卵巢炎通常分为急性和慢性两种，急性者会出现发热、腹痛、肛门有坠胀感等症状；慢性者会出现全身无力、精神差、月经不调、下腹部发生包块等症状。急性期多采用抗生素治疗。
前列腺炎是前列腺受到病原体感染产生的炎症反应，临床表现为寒战、发热、疲乏无力等全身症状，及会阴部和耻骨上疼痛，甚至急性尿潴留。前列腺炎治疗通常采用前列腺液培养发现致病病原体后选择抗菌药物，或是采用非甾体类抗炎药物改善症状。
出人意料地，本发明人发现并证实了贻贝粘蛋白可用于治疗包括心、胃、肠、肺、肝、脾、肾、胰、膀胱、卵巢、前列腺炎症等脏器炎症。
具体实施方式
本发明的实施方式包括：
1、贻贝粘蛋白在治疗脏器炎症中的应用。
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，其中所述脏器炎症可以选自：心、胃、肠、肺、肝、脾、肾、胰、膀胱、卵巢、前列腺炎症等。
7、贻贝粘蛋白作为活性成分在用于治疗脏器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。
8、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。
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以低温或加热方式使用。
10、一种用于治疗脏器炎症的药品，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。
11、一种用于治疗脏器炎症的医疗器械，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。
12、一种用于治疗脏器炎症的保健品/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。
13、贻贝粘蛋白在用于治疗脏器炎症的药品中的应用，其中所述脏器炎症可以选自：心、胃、肠、肺、肝、脾、肾、胰、膀胱、卵巢、前列腺炎症等。
14、贻贝粘蛋白在用于治疗脏器炎症的医疗器械中的应用，其中所述脏器炎症可以选自：心、胃、肠、肺、肝、脾、肾、胰、膀胱、卵巢、前列腺炎症等。
15、贻贝粘蛋白在用于治疗脏器炎症的保健品或食品中的应用，其中 所述脏器炎症可以选自：心、胃、肠、肺、肝、脾、肾、胰、膀胱、卵巢、前列腺炎症等。
16、一种治疗脏器炎症的方法，包括配制含有根据实施方式10-12中任一项的贻贝粘蛋白的液体剂或凝胶剂，并给予有需要的受试者，其中贻贝粘蛋白的浓度可以是0.1-15.0mg/ml。
17、根据实施方式16的方法，其中所述脏器炎症可以选自：心、胃、肠、肺、肝、脾、肾、胰、膀胱、卵巢、前列腺炎症等。
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心脏内膜炎治疗中的应用。
取浓度为10.0mg/ml的贻贝粘蛋白溶液，加入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。
收集心内科专家确诊的5例心脏内膜炎病患进行试验，入选病患临床表现全身高热、寒战、全身毒血症症状明显。入选患者口服贻贝粘蛋白液体药品，每日2次，每次1mg。口服1周后，患者发热症状减退，至4周时，取血样培养呈阴性。可以看出，贻贝粘蛋白液体药品可用于心脏内膜炎的治疗。
实施例2：贻贝粘蛋白冻干粉药品在胃炎治疗中的应用。
取贻贝粘蛋白冻干粉1mg，并将贻贝粘蛋白冻干粉水包裹在胃溶性包衣材料中形成胃溶性缓释制剂。
收集10例胃炎病患进行试验，病患经消化内科大夫胃镜检查确诊后入组。入选病患随机分配至对照组或试验组，对照组采用米索前列醇治疗， 口服200mg/次，每日4次；试验组口服包含贻贝粘蛋白冻干粉药品的胃溶性缓释给药制剂，每日1次，每次1粒。治疗3周后胃镜检查，对照组受试者胃部溃疡平均愈合率46.3％，试验组受试者胃部溃疡平均愈合率68.9％。治疗6周后胃镜检查，对照组受试者胃部溃疡愈合率达到68.9％，试验组受试者胃部溃疡面全部愈合。可以看出，贻贝粘蛋白冻干粉药品可用于胃炎治疗且效果优异。
实施例3：贻贝粘蛋白药品在肠炎治疗中的应用。
取贻贝粘蛋白冻干粉1mg，并将贻贝粘蛋白冻干粉水包裹在肠溶性包衣材料中形成肠溶性缓释制剂。
收集20例急性肠炎病患，临床表现为恶心、呕吐、腹泻，经肠镜检查后由消化内科大夫确诊为急性肠炎后入组。受试者被随机分配至对照组或试验组，对照组采用口服黄连素治疗，每日3次。试验组入组病患口服包含贻贝粘蛋白的肠溶性缓释给药制剂，每日1次，每次1粒。治疗2天后，对照组和试验组病患恶心、呕吐、腹泻情况均得到缓解，证明贻贝粘蛋白液体药品可用于急性肠炎的治疗。
实施例4：贻贝粘蛋白液体医疗器械在肺炎治疗中的应用。
取浓度为10.0mg/ml的贻贝粘蛋白液体，用0.005％乙酸稀释至5.0mg/ml，形成贻贝粘蛋白液体医疗器械。
收集10例急性肺炎病患，临床表现为高热、寒战、咳嗽、胸痛、呼吸困难，经血液检查后由内科大夫确诊为肺炎后入组。病患随机分配至对照组或试验组，对照组采用静滴青霉素治疗，试验组入组病患采用雾化给药方式，每日1次，每次10ml。治疗7天后，对照组和试验组患者体温均恢复正常，但仍有咳嗽和咳痰症状。对照组改用口服咳喘宁，每次1ml，每日3次，试验组仍采用雾化给药方式吸入贻贝粘蛋白，每日1次，每次10ml。至治疗14天试验组全部病患咳嗽和咳痰症状消失，血液检查各指标均正常；对照组有2例病患仍有咳嗽现象。证明贻贝粘蛋白液体医疗器械可用于肺炎的治疗。
实施例5：贻贝粘蛋白药品在肝炎治疗中的应用。
取贻贝粘蛋白溶液，用0.001％柠檬酸稀释至0.5mg/ml，获得贻贝粘蛋白液体药品。
收集5例甲性肝炎病患，临床表现为皮肤黄染、发热、肝区隐痛、食欲减退、腹胀，由内科大夫确诊为甲型肝炎后入组，患者每日服用2次，每次1ml。治疗3周后，病患临床症状消失，血清总胆红素在17umol/l以下，证明贻贝粘蛋白药品可用于肝炎的治疗。
实施例6：贻贝粘蛋白药品在膀胱炎治疗中的应用。
取浓度为10.0mg/ml的贻贝粘蛋白溶液，用0.001％乙酸稀释，得到贻贝粘蛋白液体药品，其中贻贝粘蛋白浓度为2.0mg/ml。
收集6例膀胱炎病患，临床表现为尿频、尿急、尿痛，尿液常规检查可见红细胞、脓细胞，尿细胞培养阳性，由泌尿科大夫确诊为膀胱炎后入组。患者随机分配至对照组或试验组，对照组采用口服氯霉素治疗，每日2次，试验组患者每日服用2次，每次1ml。治疗3周后，对照组和试验组病患临床症状消失，尿液检查正常，证明贻贝粘蛋白液体药品可用于膀胱炎的治疗。
实施例7：贻贝粘蛋白医疗器械在卵巢炎治疗中的应用。
取羟丙基甲基纤维素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，其中贻贝粘蛋白浓度为1.0mg/ml。
收集8例卵巢炎病患，临床表现为发热、腹痛(呈钝痛，无向它处放射)、腰骶部疼痛、肛门坠胀感，由妇科大夫确诊为卵巢炎后入组。入选病患被随机分配到对照组或试验组，患者腹腔镜下粘连分解术后，对照组腹腔灌注中分子右旋糖酐，试验组腹腔内灌注贻贝粘蛋白医疗器械100ml。术后对照组和试验组病患临床症状消失，各项检查正常，证明贻贝粘蛋白医疗器械可用于卵巢炎的治疗。
实施例8：贻贝粘蛋白药品在前列腺炎治疗中的应用。
取浓度为0.5mg/ml的贻贝粘蛋白溶液，用0.001％的乙酸稀释5倍，至贻贝粘蛋白含量为0.1mg/ml，得到贻贝粘蛋白液体药品。
收集10例前列腺炎病患，临床表现为发热、寒战、疲乏无力、伴有会阴部和耻骨上疼痛、尿潴留，由泌尿外科大夫确诊为前列腺炎后入组。入选患者随机分配至对照组或试验组，对照组病患口服氧氟沙星治疗，每日2次；试验组患者口服贻贝粘蛋白药品，每日2次，每次3ml。服用3周后，对照组及试验组患者临床症状消失，证明贻贝粘蛋白药品可用于前列腺炎的治疗。
实施例9：贻贝粘蛋白治疗胃溃疡动物试验。
采用柱层析法制备贻贝粘蛋白溶液(MAP)，蛋白浓度为5.0mg/ml，纯度90％。取上述贻贝粘蛋白溶液，用生理盐水稀释，至贻贝粘蛋白含量为0.5mg/ml，得到贻贝粘蛋白液体。每100ml贻贝粘蛋白产品中含有贻贝粘蛋白0.5mg，氯化钠0.9g，其余为注射用水。
取贻贝粘蛋白溶液作为试验样品，另取奥美拉唑(四川科伦药业股份有限公司)作为阳性对照，生理盐水(辰欣药业股份有限公司)作为阴性对照。给药剂量，贻贝粘蛋白为1.6mg/kg，奥美拉唑(8mg/kg)。实验采用多次灌胃方式，观察MAP对无水酒精诱导的急性胃溃疡的保护作用。
本次实验动物采用SPF级C57BL/6小鼠(购自上海实验动物资源中心)，每组5只，均为雄性。各组别连续给药5天，第6天给药30min后，分别灌胃给予无水乙醇(0.2ml/只)，1h后脱臼处死小鼠。肉眼观察胃胀、充血等情况，并对胃组织进行组织病理学检查，以确定MAP保护胃溃疡的效果。
结果显示：小鼠经无水酒精灌胃后，各组小鼠胃部可见不同程度的粘膜脱落、变形、坏死、纤维增生、炎症和充血现象。MAP可以减轻胃部胀气和充血，效果与奥美拉唑相当。表明MAP对无水酒精诱导的急性胃溃疡有保护功能。

Claims (10)

  1. 贻贝粘蛋白在治疗脏器炎症中的应用。
  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或凝胶剂使用。
  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，其中所述脏器炎症选自：心、胃、肠、肺、肝、脾、肾、胰、膀胱、卵巢、前列腺炎症等。
  7. 贻贝粘蛋白作为活性成分在用于治疗脏器炎症的组合物中的应用，其中所述组合物是以液体剂或凝胶剂使用。
  8. 贻贝粘蛋白作为活性成分在用于治疗脏器炎症的药品中的应用。
  9. 贻贝粘蛋白作为活性成分在用于治疗脏器炎症的医疗器械中的应用。
  10. 贻贝粘蛋白作为活性成分在用于治疗脏器炎症的保健品或食品中的应用。
PCT/CN2017/081309 2016-04-20 2017-04-20 贻贝粘蛋白产品及其抑制脏器炎症的应用 WO2017181979A1 (zh)

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CN103520766A (zh) * 2013-09-25 2014-01-22 高敏 贻贝粘蛋白液体产品、其制备方法及其应用
CN104645313A (zh) * 2015-01-28 2015-05-27 南京航空航天大学 一种修复止痒贻贝粘蛋白凝胶剂及其制备方法

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US20020018787A1 (en) * 1999-05-21 2002-02-14 Roger V. Kendall Methods and compositions for modulating immune response and for the treatment of inflammatory disease
CN105392468A (zh) * 2013-05-20 2016-03-09 高敏 贻贝粘蛋白凝胶的制备方法、贻贝粘蛋白凝胶及其应用

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CN104645313A (zh) * 2015-01-28 2015-05-27 南京航空航天大学 一种修复止痒贻贝粘蛋白凝胶剂及其制备方法

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