WO2012079311A1 - 一种海参复方制品、制法及其剂型 - Google Patents

一种海参复方制品、制法及其剂型 Download PDF

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WO2012079311A1
WO2012079311A1 PCT/CN2011/071482 CN2011071482W WO2012079311A1 WO 2012079311 A1 WO2012079311 A1 WO 2012079311A1 CN 2011071482 W CN2011071482 W CN 2011071482W WO 2012079311 A1 WO2012079311 A1 WO 2012079311A1
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Prior art keywords
sea cucumber
powder
nano
sea
compound product
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PCT/CN2011/071482
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English (en)
French (fr)
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焦健
邵俊杰
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大连海晏堂生物有限公司
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Priority to US13/576,972 priority Critical patent/US8927008B2/en
Priority to EP11840702.2A priority patent/EP2514431B1/en
Priority to CA2787164A priority patent/CA2787164C/en
Publication of WO2012079311A1 publication Critical patent/WO2012079311A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/25—Araliaceae (Ginseng family), e.g. ivy, aralia, schefflera or tetrapanax
    • A61K36/258—Panax (ginseng)
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L17/00—Food-from-the-sea products; Fish products; Fish meal; Fish-egg substitutes; Preparation or treatment thereof
    • A23L17/50—Molluscs
    • 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
    • A61K35/616—Echinodermata, e.g. starfish, sea cucumbers or sea urchins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
    • A61K2236/30—Extraction of the material
    • A61K2236/39—Complex extraction schemes, e.g. fractionation or repeated extraction steps

Definitions

  • the present invention belongs to the technical field of pharmaceutical preparations derived from mollusc extracts and plants.
  • sea cucumber is one of the eight treasures of seafood in China, and its nourishing value is recognized by people.
  • sea cucumber polysaccharide is the most important active ingredient in sea cucumber, and has a variety of physiological activities. According to experimental research, sea cucumber polysaccharide has a significant effect on diseases against cardiovascular and cerebrovascular diseases. After the sea cucumber is nano-sized, it can be directly developed, and not only the important active ingredients such as sea cucumber polysaccharides can be fully utilized, but also components such as sea cucumber protein and lipid can be fully utilized.
  • Panax notoginseng is a special ginseng plant in southern Yunnan.
  • the roots are fleshy like ginger, which is used by folks to treat bruises, blood stasis and other diseases.
  • the main functional component of Panax notoginseng is Panax notoginseng saponins, which has been widely used in the field of medicine and health care.
  • Pharmaceutical companies have used the special effects of Sanqi to develop many such as Yunnan Baiyao, Xuesaitong series and compound Danshen dripping pills.
  • Well-known drugs such as Pien Tze Huang.
  • the drug made from the total saponins of Panax notoginseng is commonly known as "Blood Plug".
  • Xuesaitong is an essential Chinese patent medicine for emergency departments in national hospitals. It is also mainly used for cardiovascular and cerebrovascular diseases.
  • Sea cucumber compound preparation the market is still basically blank, only a few such as patent 200710114414.7 compound sea cucumber glycopeptide oral liquid, which is a compound sea cucumber oral liquid developed by using sea cucumber, with royal jelly and Chinese medicine extract, which is not targeted at the population. Clear, the effect is not clear.
  • the object of the present invention is to develop a compound preparation which is better than the sea cucumber or the notoginseng and its products by using the low molecular weight sea cucumber nano powder directly with the notoginsenoside extract.
  • the technical proposal of the present invention is that the sea cucumber is gelatinized, freeze-dried, pulverized to nano-sized particles, and then mixed with the notoginsenoside extract.
  • the specific steps are:
  • Raw material processing Cut the fresh sea cucumber, remove the internal organs, and wash them thoroughly. In order to use only the wall of sea cucumber, it can also be ground together with the internal organs of sea cucumber and placed in a closed container. Raw materials can also be used in various forms of sea cucumber products, such as dried sea cucumber, semi-dry sea cucumber, salted sea cucumber, etc., which are cleaned and placed in a closed container.
  • Raw fresh sea cucumber, dried sea cucumber, semi-dry sea cucumber or salted sea cucumber is a product of sea cucumber, leaf melon and other varieties.
  • Heating gelation heating, the temperature is 70 ⁇ 130 ° C, and the time is lmin ⁇ 20h. Preferably, it is 100 to 105 ° C, lh.
  • Coarse pulverization The sea cucumber after lyophilization is coarsely pulverized.
  • the equipment selected for coarse pulverization is preferably high in power, and the pulverization time is very short.
  • ginseng powder having a fineness of 10 to 300 mesh can be obtained within 1 to 20 minutes.
  • Ultrafine pulverization The coarsely pulverized sea cucumber powder is ultra-finely pulverized by a jet mill to pulverize the sea cucumber ultrafine powder having a fineness of 100 to 3000 mesh.
  • Nano-crushing The sea cucumber ultrafine powder which has been subjected to jet milling is subjected to nano-grinding by a high-energy ball mill, and the pulverization time is 4 to 20 hours, preferably 10 to 12 hours, and the fineness can reach 10 to: L000 nm.
  • the particle size distribution is detected by X-ray, and the average particle diameter is in the range of 0 to 300 nm, which is 100 to 200 nm.
  • the nano sea cucumber powder and the notoginsenoside extract are mixed according to the ratio of sea cucumber: Panax notoginseng, 99 ⁇ 80wt%: l ⁇ 20wt%.
  • the notoginsenoside extract is a commercially available product.
  • the product is a grayish white or light yellow powder.
  • the main active ingredients are sea cucumber polysaccharide and panax notoginseng saponin (calculated as the total content of Rl+Rbl+Rgl components), sea cucumber polysaccharide content is 2.5 ⁇ 8.1wt%, panax notoginseng saponins The content is from 0.3 to 14.0% by weight.
  • the pharmacodynamic experiment of the invention proves that the high and low dose groups of the compound sea cucumber products have obvious inhibitory effects on the venous thrombosis of the rats, and the inhibition rates thereof are 88.9% and 81.5%, respectively; the compound sea cucumber products can reduce the high and low cut of the rats.
  • the whole blood specific viscosity at variability, but no significant effect on plasma specific viscosity, indicating that the effect of sea cucumber powder on lowering blood viscosity mainly comes from the effect on red blood cells, which can reduce the aggregation of red blood cells and enhance the deformability of red blood cells.
  • the improvement of blood rheology by sea cucumber powder has become one of the main pharmacological foundations of its antithrombotic effect.
  • the invention utilizes the low molecular weight sea cucumber nano powder and directly is combined with Panax notoginseng (total saponin extract) to develop a health food with remarkable effects mainly for cardiovascular and cerebrovascular diseases.
  • Sea cucumber polysaccharide not only has anticoagulant function, but also can mobilize liver cells from the bone marrow.
  • Panax notoginseng saponins can promote the transformation or differentiation of mobilized stem cells into new cardiomyocytes or brain cells to replace Necrosis of myocardium or brain tissue caused by ischemia.
  • the combination of nano sea cucumber powder and Panax notoginseng saponin can complement and synergize pharmacologically.
  • the side effect of sea cucumber polysaccharide on platelet polycondensation can be eliminated by complexing with panax notoginseng saponins.
  • the combination of nano sea cucumber and panax notoginseng saponins can greatly enhance the pharmacological functions of sea cucumber or notoginseng, and can be used for various medicinal purposes.
  • the outstanding feature of the present invention is that the nano sea cucumber and the panax notoginseng saponins are rationally compounded, and some defects caused by the original single use are removed, and the health care is better than the original single use. effect.
  • Raw material processing Cut the fresh sea thorns, remove the internal organs, and thoroughly clean the sea cucumber body wall and place them in a closed container.
  • Vacuum freeze-drying The gelatinized sea cucumber is freeze-dried, and the water is divided into 0.1 wt%.
  • Coarse pulverization The sea cucumber after lyophilization is coarsely pulverized. A sea cucumber powder having a fineness of 10 to 300 mesh is obtained.
  • Ultrafine pulverization The coarsely pulverized sea cucumber powder is ultra-finely pulverized by a jet mill to obtain a sea cucumber ultrafine powder having a pulverization fineness of 100 to 3,000 mesh.
  • Nano-crushing The sea cucumber ultrafine powder which was pulverized by airflow was subjected to nanometer pulverization with a high-energy ball mill pulverizer, and the pulverization time was 4 hours.
  • Panax notoginseng saponin extract is produced by Nanjing Zelang Pharmaceutical Technology Co., Ltd.
  • the product is an off-white powder, the main active ingredient of which is sea cucumber polysaccharide 7.28wt%, panax notoginseng saponin (calculated as total content of Rl+Rbl+Rgl component) 0.3wt%.
  • the powder is mixed into a capsule. 0.3 grams per capsule.
  • the compound sea cucumber products of this formula were tested for the effects of thrombosis and hemorheology.
  • Vacuum freeze-drying The gelatinized sea cucumber is freeze-dried, and the water is divided into 3 wt%.
  • Coarse pulverization The sea cucumber after lyophilization is coarsely pulverized. A sea cucumber powder having a fineness of 10 to 300 mesh is obtained.
  • Ultrafine pulverization The coarsely pulverized sea cucumber powder is ultra-finely pulverized by a jet mill to obtain a sea cucumber ultrafine powder having a pulverization fineness of 100 to 3,000 mesh.
  • Nano-crushing The sea cucumber ultrafine powder that has been subjected to jet milling is subjected to nano-grinding with a high-energy ball mill, and the pulverization time is 10 hours.
  • the nano sea cucumber nano powder and the notoginsenoside extract are mixed according to the ratio of 80 wt%: 20 wt%.
  • the product is an off-white powder.
  • the main active ingredients are sea cucumber polysaccharide and panax notoginseng saponin (calculated as the total content of Rl+Rbl+Rgl).
  • the content of sea cucumber polysaccharide is 3.8%, and the total saponin content of panax notoginseng is 12.5%.
  • the product was tested for in vivo and in vitro platelet aggregation in animals. The results showed that the blood coagulation and antithrombotic effects of the sea cucumber compound preparations on the animals.
  • Vacuum freeze-drying The gelatinized sea cucumber is freeze-dried, and the water is divided into 3 wt%.
  • Coarse pulverization The sea cucumber after lyophilization is coarsely pulverized. A sea cucumber powder having a fineness of 10 to 300 mesh is obtained.
  • Ultrafine pulverization The coarsely pulverized sea cucumber powder is ultra-finely pulverized by a jet mill to obtain a sea cucumber ultrafine powder having a pulverization fineness of 100 to 3,000 mesh.
  • Nano-crushing The sea cucumber ultrafine powder that has been subjected to jet milling is nano-sized and pulverized by a high-energy ball mill, and the pulverization time is 12 hours.
  • the nano-cucurbita powder and the notoginsenoside extract are mixed at a ratio of 90 wt%: 10 wt%.
  • the product is a light yellow powder, the main active ingredients of which are sea cucumber polysaccharide and panax notoginseng saponin (calculated as the total content of Rl+Rbl+Rgl components), the sea cucumber polysaccharide content is 4.7%, and the total saponin content of panax notoginseng is 6.3%. .
  • Raw material treatment Cut the salted sea thorns, soften them with water, cut the body walls, clean them, and place them in a closed container.
  • Vacuum freeze-drying The gelatinized sea cucumber is freeze-dried, and the water is divided into 5 wt%.
  • Coarse pulverization The sea cucumber after lyophilization is coarsely pulverized. A sea cucumber powder having a fineness of 10 to 300 mesh is obtained.
  • Ultrafine pulverization The coarsely pulverized sea cucumber powder is ultra-finely pulverized by a jet mill to obtain a sea cucumber ultrafine powder having a pulverization fineness of 100 to 3,000 mesh.
  • Nano-crushing The sea cucumber ultrafine powder which has been subjected to jet milling is subjected to nano-grinding with a high-energy ball mill, and the pulverization time is 16 hours.
  • the product is a light yellow powder, the main active ingredients of which are sea cucumber polysaccharide and panax notoginseng saponin
  • the total content of Rl+Rbl+Rgl components was calculated), the sea cucumber polysaccharide content was 5.1 wt%, and the panax notoginseng total saponin content was 2.3 wt%.
  • the tablets were prepared according to the ratio of the raw materials: the excipients were 2:1. 0.2 g per tablet.
  • Raw material processing Dry the dried melon seeds and soften them. After cleaning, the water is sprayed and placed in a closed container.
  • Coarse pulverization The sea cucumber after lyophilization is coarsely pulverized. A sea cucumber powder having a fineness of 10 to 300 mesh is obtained.
  • Ultrafine pulverization The coarsely pulverized sea cucumber powder is ultra-finely pulverized by a jet mill to obtain a sea cucumber ultrafine powder having a pulverization fineness of 100 to 3,000 mesh.
  • Nano-crushing The nano-powder is prepared by high-energy ball mill pulverizer Broken, crushing time is 18h.
  • nano-leaf ginseng nano powder and the notoginsenoside extract are mixed according to the ratio of sea cucumber: Panax notoginseng 85 wt%: 15%.
  • the product is a light yellow powder
  • the main active ingredients are sea cucumber polysaccharide and panax notoginseng saponin (calculated as the total content of Rl+Rbl+Rgl components), sea cucumber polysaccharide content is 2.56wt%, and panax notoginseng total saponin content is 3.9wt %.
  • the ratio of the auxiliary material is 1:1, and the granule is prepared.
  • Raw material processing Cut the sea thorns and place them in a closed container.
  • Coarse pulverization The sea cucumber after lyophilization is coarsely pulverized. A sea cucumber powder having a fineness of 10 to 300 mesh is obtained.
  • Ultrafine pulverization The coarsely pulverized sea cucumber powder is ultra-finely pulverized by a jet mill to obtain a sea cucumber ultrafine powder having a pulverization fineness of 100 to 3,000 mesh.
  • Nano-crushing The sea cucumber ultrafine powder that has been subjected to jet milling is subjected to nanometer pulverization with a high-energy ball mill pulverizer, and the pulverization time is 20 hours.
  • the product is a light yellow powder, the main active ingredients of which are sea cucumber polysaccharide and panax notoginseng saponin
  • the total content of Rl+Rbl+Rgl component is calculated), the sea cucumber polysaccharide content is 3.9 wt%, and the panax notoginseng total saponin content is l.lwt%.
  • the ratio of the auxiliary material is 1:1, and the granule is prepared.
  • NS normal saline
  • compound sea cucumber high-dose group compound sea cucumber high-dose group
  • compound sea cucumber low-dose group 20% urethane ip lg.kg- 1 anesthesia.
  • the abdominal wall was cut in the middle, the inferior vena cava was separated, and the silk thread was placed under the left renal vein for ligation.
  • the high- and low-dose groups of NS group and compound sea cucumber capsules were intragastrically administered with NS and drugs for two weeks, and the inferior vena cava was ligated 1 hour after the last administration, and the abdominal cavity was closed.
  • thrombosis 4 hours after ligation, reopen the abdominal cavity, clamp the blood vessel 2 cm below the ligature line, and clamp the main vein side branch in the segment and use the syringe to remove the residual blood in the vein, and cut the lumen longitudinally to observe the presence or absence of thrombosis. If there is thrombosis, it is baked in the oven at 60 ° C. The dry weight was weighed in 20 minutes, and the number of thrombotic animals and the dry weight of the thrombus were recorded. The rate of thrombosis (number of thrombotic animals/number of animals tested) and percent inhibition of dry weight of thrombus were calculated.
  • Rats were grouped and administered as above. Except for the same amount of NS in the NS group, the other groups were intragastrically administered for two weeks, and the abdominal aorta was collected 1 hour after the last administration, and 3.8% sodium citrate was added for anticoagulation (blood and anticoagulant volume).
  • the platelet-rich blood plasma (PRP) was prepared by centrifugation at 200 xg for 10 minutes at a ratio of 9:1), and the remaining blood was centrifuged at 1200 x g for 10 minutes to prepare a platelet-poor blood plasma paddle (PPP).
  • PPP was used to adjust the number of platelets in PRP to 4-5xl0 12 .mL.
  • Platelet-poor plasma (PPP) and platelet-rich blood plasma (PRP) were prepared according to the method of platelet aggregation in vivo. ), take PRP 20 ( ⁇ L, add the above prepared sea cucumber M powder and N powder aqueous extract 1 (L, then add the inducer ADP (final concentration 2 mol. L-, according to the Bron's method to determine the platelet aggregation rate.
  • Nano-sea cucumber powder 200mg: ImL, lOOmg: ImL has the effect of promoting platelet aggregation in vitro, the percentage of pro-aggregation is 23.6% and 11.2%, compound sea cucumber products 200mg: lmL, lOOmg: ImL water extracts outside the platelet aggregation reaction is not obvious , the results are shown in Table 3:
  • nano-sea cucumber powder After two weeks of intragastric administration of nano-sea cucumber powder and compound sea cucumber powder, nano-sea cucumber powder has the effect of promoting platelet aggregation.
  • the platelet aggregation rates in the high and low dose groups were 47.1% and 24.3%, respectively.
  • the co-aggregation reaction of compound sea cucumber products is not obvious. The results are shown in Table 4:
  • Nano-leaf ginseng powder 0.5g/kg .56+0.43*** 60.84+9.98***
  • mice 60 male Kunming mice were randomly divided into 6 groups: blank control group, thrombus model group, 0.5g/kg nano-cucurbita powder group, and 0.5g/kg nano-stab Powder group. The mice were intragastrically administered with 0.5 g/kg of different kinds of sea cucumbers twice a day, and the blank control group and the thrombus model group were given the stomach. Rat subcutaneously injected into the lower back
  • mice can significantly reduce the length of the black tail (%, p ⁇ 0.001), indicating that it has the effect of inhibiting carrageenan.
  • the tail thrombosis of mice is antithrombotic.

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Description

一种海参复方制品、 制法及其剂型
技术领域
本发明属于来源于软体动物的提取物和植物的医药配制品技术领域。
背景技术
海参， 是我国的海味八珍之一， 其滋补价值为人们所公认。 其中海参多糖 是海参中最为重要的活性成分， 具有多种生理活性， 根据实验研究表明， 海参 多糖在对抗心脑血管方面疾病的效果显著。 将海参纳米化后， 直接进行开发， 不仅可充分利用海参多糖等重要的活性成分， 同时， 可将海参蛋白、 脂质等成 分共同进行充分利用。
三七为云南南部特产的人参属植物， 根茎肉质如姜块状， 民间用于治疗跌 打损伤、 活血祛瘀等疾患。 三七的主要功能成分是三七总皂苷， 在医药保健领 域有广泛的应用， 医药企业利用三七这种特殊的功效， 研制开发了很多如云南 白药、 血塞通系列、 复方丹参滴丸、 片仔癀等知名药品。 其中， 以三七总皂苷 为原料制成的药物通称"血塞通"， 目前市场上有血塞通粉针、血塞通片、血塞通 胶囊、 血塞通颗粒等。 血塞通是全国医院急诊科室必备中成药， 也主要用于心 脑血管方面的疾病。
现代科技发展已经确定了海参和三七的活性成分和对人体的作用， 而且有 相当数量的药品、 保健品生产和上市。 但是目前对于利用海参和三七等各自的 特点进行复配能否起到更为有利人体健康作用， 是当前重要研究课题。
海参复方制剂， 目前市场基本还属于空白， 仅有少数如专利 200710114414.7 复方海参糖肽口服液， 其是利用海参， 配以蜂王浆以及中药提取液而开发的一 种复方海参口服液， 其针对人群不清， 效果不明确。
发明内容
本发明的目的在于利用低分子化后的海参纳米粉， 直接配以三七皂苷提取 物， 开发一种比单用海参或三七及其制品更好治疗和保健效果的复方制品。
本发明的技术方案是将海参经胶化、 冷冻干燥、 粉碎至纳米级颗粒， 而后 与三七皂甙提取物混合而成。 具体步骤为：
( 1 ) 原料处理： 将鲜活海参剪开， 取出内脏， 将其分别充分清洗干净， 可 以仅是用海参体壁， 也可以连同海参内脏一起绞碎， 置于密闭容器中。 原料也 可以采用各种形式的海参制品， 如干海参、 半干海参、 盐渍海参等， 将其发制 好清洗干净置于密闭容器中。 原料鲜活海参、 干海参、 半干海参或盐渍海参为 海刺参、 叶瓜参等品种的制品。
(2)加热胶化：加热，温度为 70〜130°C，时间为 lmin〜20h。优选 100〜105°C， lh。
(3 )冷冻干燥： 将胶化后的海参进行冷冻干燥， 水分小于 10wt%。 为了利于 后续的粉碎过程， 干燥后得水分越低越好， 优选水分小于 3wt%。
(4 ) 粗粉碎： 将冷冻干燥后的海参进行粗粉碎。 粗粉碎选择的设备以功率 大的为佳， 粉碎时间很短， 一般在 l〜20min内可以得到细度为 10〜300目不等的 海参粉。
(5 ) 超微粉碎： 将粗粉碎的海参粉用气流粉碎机进行超微粉碎， 粉碎细度 为 100〜3000目的海参超微粉。
(6 ) 纳米粉碎： 将经过气流粉碎的海参超微粉用高能球磨粉碎机进行纳米 化粉碎， 粉碎时间为 4〜20h， 优选 10〜12h， 细度可达到 10〜： L000nm。 其中用 X-射线检测粒度分布， 在 0〜300nm范围， 它的平均粒径是 100〜200nm。
(7 ) 纳米海参粉与三七皂甙提取物按照海参： 三七为 99~80wt% : l~20wt% 的比例进行混合。 三七皂甙提取物为市售的商品。
(8 ) 混合后即可制成各种制剂， 如胶囊、 片剂、 冲剂等。
产品为一种灰白色或浅黄色粉末， 其主要活性成分为海参多糖和三七总皂 甙 （以 Rl+Rbl+Rgl成分总含量来计算）， 海参多糖含量为 2.5~8.1wt%， 三七总 皂甙含量为 0.3~14.0wt%。
本发明药效实验证明： 复方海参制品高、 低剂量组对大鼠静脉血栓形成均 有明显的抑制作用， 其抑制率分别为 88.9%和 81.5%; 复方海参制品能降低大鼠 高、 低切变率时的全血比黏度， 但对血浆比黏度无明显影响， 说明海参粉降低 血液黏度的作用主要来自对红细胞的影响， 它既可降低红细胞的聚集性， 又可 增强红细胞的变形能力， 海参粉对血液流变学的改善作用成为它的抗血栓作用 的主要药理学基础之一。
复方海参制品与单纯纳米海参粉相比较进行体内、 体外血小板聚集试验显 示： 单纯纳米海参粉有促进血小板聚集的作用； 而复方海参制品对促进血小板 聚集的作用不明显。 本发明实验还证实： 不同品种海参的抗凝血活性和抗栓活 性的比较没有显著差异。
本发明利用低分子化后的海参纳米粉， 直接配以三七 （总皂甙提取物）， 开 发一种主要针对心脑血管疾病的一种效果显著的保健食品。 目前的研究显示， 海参多糖不仅具有抗凝功能， 同时可以从骨髓动员肝细胞的能力， 而三七总皂 甙则可促进被动员的干细胞转化或分化为新生的心肌细胞或脑细胞， 以替代因 缺血而引发的心肌或脑组织的坏死。 纳米海参粉和三七总皂甙复合制剂在药理 作用上可起到互补和协同， 海参多糖对血小板促聚的副作用， 可以通过与三七 总皂甙的复合剂而得以消除。 纳米海参和三七总皂甙的复合制剂， 能够大大提 高海参或三七单一组方的药理功能， 并可用于多种药用用途。
因此， 与现有技术比较， 本发明将的突出特点是将纳米海参和三七总皂甙 合理的复配， 去掉了原来单一使用所带来的一些缺陷， 而取得比原来单一使用 更好的保健效果。
具体实施方式
一. 海参复方制品的制备
实施例 1
( 1 )原料处理： 将鲜活海刺参剪开， 取出内脏， 将海参体壁分别充分清洗干净， 置于密闭容器中。
(2) 胶化： 将上述容器于 70〜80°C， 加热 20h。
(3 ) 真空冷冻干燥： 将胶化后的海参进行冷冻干燥， 水分为 0.1wt%
(4) 粗粉碎： 将冷冻干燥后的海参进行粗粉碎。 得到细度为 10〜300目不等的 海参粉。
(5 ) 超微粉碎： 将粗粉碎的海参粉用气流粉碎机进行超微粉碎， 得到粉碎细度 为 100〜3000目的海参超微粉。
(6) 纳米粉碎： 将经过气流粉碎的海参超微粉用高能球磨粉碎机进行纳米化粉 碎， 粉碎时间为 4h。
(7)纳米海刺参纳米粉与三七皂甙提取物 99%: 1%的质量比例进行混合。 三七 皂甙提取物为南京泽朗医药科技有限公司生产。
产品为一种灰白色粉末， 其主要活性成分为海参多糖 7.28wt%， 三七总皂甙 (以 Rl+Rbl+Rgl成分总含量来计算） 0.3wt%。 混合后粉剂制成胶囊。 每囊 0.3 克。
该配方的复方海参制品进行了对血栓及血液流变学的影响的实验， 结果见 下部分海参复方制品对动物的凝血、 抗栓效果。
实施例 2
( 1 ) 原料处理： 将鲜活叶瓜参剪开， 取出内脏， 将其分别充分清洗干净， 叶瓜 参体壁和内脏一起绞碎置于密闭容器中。
(2) 胶化： 将上述容器于 90〜95°C， 加热 6h。
(3 ) 真空冷冻干燥： 将胶化后的海参进行冷冻干燥， 水分为 3wt%
(4) 粗粉碎： 将冷冻干燥后的海参进行粗粉碎。 得到细度为 10〜300目不等的 海参粉。
(5 ) 超微粉碎： 将粗粉碎的海参粉用气流粉碎机进行超微粉碎， 得到粉碎细度 为 100〜3000目的海参超微粉。
(6) 纳米粉碎： 将经过气流粉碎的海参超微粉用高能球磨粉碎机进行纳米化粉 碎， 粉碎时间为 10h。
(7 ) 纳米海刺参纳米粉与三七皂甙提取物按照： 80wt%: 20wt%的比例进行混 合。 产品为一种灰白色粉末， 其主要活性成分为海参多糖和三七总皂甙 （以 Rl+Rbl+Rgl成分总含量来计算）， 海参多糖含量为 3.8% , 三七总皂甙含量为 12.5%。
(8 ) 混合后粉剂制成胶囊。 每囊 0.3克。
产品进行了对动物体内和体外血小板聚集试验， 结果见下部分海参复方制 品对动物的凝血、 抗栓效果。
实施例 3
( 1 ) 原料处理： 将鲜活叶瓜参剪开， 取出内脏， 将其分别充分清洗干净， 叶瓜 参体壁和内脏一起绞碎置于密闭容器中。
(2) 胶化： 将上述容器于 100〜105°C， 加热 lh。
(3 ) 真空冷冻干燥： 将胶化后的海参进行冷冻干燥， 水分为 3wt%
(4) 粗粉碎： 将冷冻干燥后的海参进行粗粉碎。 得到细度为 10〜300目不等的 海参粉。
(5 ) 超微粉碎： 将粗粉碎的海参粉用气流粉碎机进行超微粉碎， 得到粉碎细度 为 100〜3000目的海参超微粉。
(6) 纳米粉碎： 将经过气流粉碎的海参超微粉用高能球磨粉碎机进行纳米化粉 碎， 粉碎时间为 12h。 (7) 纳米叶瓜参粉与三七皂甙提取物按照 90wt%: 10wt%的比例进行混合。
(8 ) 混合后制成胶囊。 每囊 0.3克
该产品为一种浅黄色粉末， 其主要活性成分为海参多糖和三七总皂甙 （以 Rl+Rbl+Rgl成分总含量来计算）， 海参多糖含量为 4.7% , 三七总皂甙含量为 6.3%。
实施例 4
( 1 ) 原料处理： 将盐渍海刺参剪开， 用水浸泡软化后， 剪开体壁， 并清洗干净 后， 置于密闭容器中。
(2) 胶化： 将上述容器于 105〜110°C， 加热 0.8h。
(3 ) 真空冷冻干燥： 将胶化后的海参进行冷冻干燥， 水分为 5wt%
(4) 粗粉碎： 将冷冻干燥后的海参进行粗粉碎。 得到细度为 10〜300目不等的 海参粉。
(5 ) 超微粉碎： 将粗粉碎的海参粉用气流粉碎机进行超微粉碎， 得到粉碎细度 为 100〜3000目的海参超微粉。
(6) 纳米粉碎： 将经过气流粉碎的海参超微粉用高能球磨粉碎机进行纳米化粉 碎， 粉碎时间为 16h。
(7) 纳米海刺参纳米粉与三七皂甙提取物按照 95wt%: 5wt%的比例进行混合。
产品为一种浅黄色粉末， 其主要活性成分为海参多糖和三七总皂甙 （以
Rl+Rbl+Rgl成分总含量来计算）， 海参多糖含量为 5.1wt%， 三七总皂甙含量为 2.3wt%。
混合后按照原料： 辅料为 2: 1的比例， 制成片剂。 每片 0.2克。
实施例 5
( 1 ) 原料处理： 将干制叶瓜参泡软后剪开， 清洗干净后， 水发， 置于密闭容器 中。
(2) 胶化： 将上述容器于 110〜120°C， 加热 0.6h。
(3 ) 真空冷冻干燥： 将胶化后的海参进行冷冻干燥， 水分为 7wt%。
(4) 粗粉碎： 将冷冻干燥后的海参进行粗粉碎。 得到细度为 10〜300目不等的 海参粉。
(5 ) 超微粉碎： 将粗粉碎的海参粉用气流粉碎机进行超微粉碎， 得到粉碎细度 为 100〜3000目的海参超微粉。
(6) 纳米粉碎： 将经过气流粉碎的海参超微粉用高能球磨粉碎机进行纳米化粉 碎， 粉碎时间为 18h。
(7 ) 纳米叶瓜参纳米粉与三七皂甙提取物按照海参： 三七为 85wt%: 15^%的 比例进行混合。
产品为一种浅黄色粉末， 其主要活性成分为海参多糖和三七总皂甙 （以 Rl+Rbl+Rgl成分总含量来计算）， 海参多糖含量为 2.56wt%， 三七总皂甙含量为 3.9wt%。
混合后按照原料： 辅料为 1 : 1的比例， 制成冲剂。
实施例 6
( 1 ) 原料处理： 将水发海刺参剪开， 置于密闭容器中。
(2) 胶化： 将上述容器于 120〜130°C， 加热 0.2h。
(3 ) 真空冷冻干燥： 将胶化后的海参进行冷冻干燥， 水分为 9wt%
(4) 粗粉碎： 将冷冻干燥后的海参进行粗粉碎。 得到细度为 10〜300目不等的 海参粉。
(5 ) 超微粉碎： 将粗粉碎的海参粉用气流粉碎机进行超微粉碎， 得到粉碎细度 为 100〜3000目的海参超微粉。
(6) 纳米粉碎： 将经过气流粉碎的海参超微粉用高能球磨粉碎机进行纳米化粉 碎， 粉碎时间为 20h。
(7) 纳米海刺参粉与三七皂甙提取物按照 97wt%: 3wt%的比例进行混合。
产品为一种浅黄色粉末， 其主要活性成分为海参多糖和三七总皂甙 （以
Rl+Rbl+Rgl成分总含量来计算）， 海参多糖含量为 3.9wt%， 三七总皂甙含量为 l.lwt%。
混合后按照原料： 辅料为 1 : 1的比例， 制成冲剂。
二.海参复方制品对动物的凝血、 抗栓效果
1.复方海参制品对大鼠下腔静脉血栓形成的影响：
SD大鼠 30只， 雄性， 体重 180~220g， 随机分为 3组， 即生理盐水 （NS ) 组、 复方海参制品高剂量组、 复方海参制品低剂量组。 20%乌拉坦 ip lg.kg— 1麻醉。 按 Rayers氏法， 于正中切开腹壁， 分离下腔静脉， 并于左肾静脉下方预置丝线备 结扎用。 NS组、 复方海参胶囊高、 低剂量组分别灌胃给予 NS和药物两周， 并于 末次给药 1小时后结扎下腔静脉， 关闭腹腔。 结扎后 4小时重新打开腹腔， 于结 扎线下方 2厘米处夹闭血管， 同时夹住段内主要静脉侧枝并用注射器吸尽静脉内 残血， 纵行剖开管腔， 观察有无血栓形成， 若有血栓形成， 则于烤箱内 60°C烘 20分钟称其干重， 记录血栓形成动物数和血栓干重。 计算血栓形成率 （血栓形 成动物数 /受试动物数） 及血栓干重抑制百分率。
复方海参制品高、 低剂量组均有明显的抑制大鼠静脉血栓形成作用， 其抑 制率分别为 88.9%和 81.5%。 结果见表 1 :
表 1 复方海参制品抗大鼠静脉血栓形成实验结果 （n=10)
血栓形成率 抑制百分 剂量 血栓干重
组别 (血栓形成动物数 /受试动物
(mg/Kg) (mg)
数） (%)
NS 10/10 2·7±0·4
复方海参制 900
Π 8/10 0.3+0.3 88.9 复方海参制 100
8/10 0.5+0.3 81.5
*" Ρ<0.001 与生理盐水组比较
2.复方海参制品对血液流变学的影响：
SD大鼠 30只， 雄性， 体重 180~220g， 随机分为 3组， 即生理盐水 （NS ) 组、 复方海参制品高剂量组、 复方海参制品低剂量组。 除 NS组灌胃等量 NS外， 其余 给药组灌胃给药两周， 末次给药后 1小时， 乙醚麻醉动物， 腹主动脉采血 4.9ml， 置于加有 1.25 %肝素 0.1ml的硅化试管内， 立刻用血流变仪测定高切变率与低切 变率下的全血比粘度、 血桨比粘度等血液流变学指标。
本研究表明复方海参制品能降低大鼠高、 低切变率时的全血比黏度， 但对 血桨比黏度无明显影响， 说明海参粉降低血液黏度的作用主要来自对红细胞的 影响， 它既可降低红细胞的聚集性， 又可增强红细胞的变形能力， 海参粉对血 液流变学的改善作用成为它的抗血栓作用的主要药理学基础之一。 结果见表 2 表 2 复方海参制品对大鼠血液流变学的影响 （n=10)
剂量 全血比黏度
组别
(mg/Kg) 20S- 1 80S"1 血浆比黏度
NS 一 33·27±3·29 13.74+1.31 2.127±0.185
复方海参制品 900 9.99+0.14* 5.62+0.27* 2.082±0.204 复方海参制品 100 10.51±0.19* 6.00+0.23* 2.133±0.142
Ρ<0.05 ， 与生理盐水组比较
3.复方海参制品与单纯的纳米海参粉相比较进行体内血小板聚集试验： (1)试验设计：
大鼠分组及给药同上。 除 NS组灌胃等量 NS外， 其余给药组灌胃给药两周， 末次给药 1小时后腹主动脉采血， 分别加入 3.8 %枸橼酸鈉抗凝（血与抗凝剂体积 比 9 ： 1 )， 以 200xg离心 10分钟， 制备富血小板血桨（PRP), 剩余血液经 1200xg 离心 10分钟， 制备贫血小板血桨（PPP)。用 PPP调 PRP中血小板数至 4-5xl012.mL 分别取 PRP 20(^L， 加入诱导剂 ADP (终浓度 2μιηο11— ， 按 Bran提出的比 浊法测定血小板聚集率， 并按下式计算对血小板的促聚率 （％)。 血小板聚集测 定均在 3小时内完。
给药管血小板聚集％ -对照管血小板聚集％
血小板聚集促聚率 = - <100
对照管血小板聚集％
分别按 200mg: ImL和 lOOmg: ImL配制高、 低浓度的 M粉和 N粉混悬液， 涡旋混合 1分钟， 提取其中水溶性活性成分， 然后经 3500rpm离心 lOmin, 取上清 液， 即水提液备用。
家兔心脏采血， 加入 3.8%枸橼酸鈉抗凝 （血与抗凝剂体积比 9 : 1 )， 按体 内血小板聚集试验中方法分别制备贫血小板血桨（PPP)和富血小板血桨（PRP) , 取 PRP 20(^L， 加入上述配制的海参 M粉及 N粉水提液 1( L， 再加入诱导剂 ADP (终浓度 2 mol.L— ， 按 Bron氏法测定血小板聚集率。
(2)试验结果：
①体外血小板聚集试验结果
纳米海参粉 200mg: ImL, lOOmg: ImL体外均有促进血小板聚集的作用， 其 促聚百分率分别为 23.6%和 11.2%, 复方海参制品 200mg: lmL、 lOOmg: ImL水 提物体外血小板聚集反应不明显， 结果见表 3 :
表 3 纳米海参粉、 复方海参制品水提物体外血小板聚集实验结果 （n=10)
组别 水提物浓度 血小板聚集率 （％) 促聚百分率 e¾)
NS 67.77+1.29
纳米海参粉 200mg: ImL 83.79±2.30*" 23.6
纳米海参粉 lOOmg: ImL 75.37+0.78*Δ 11.2
复方海参制品 200mg: ImL 73.29+0.39*Δ 8.1
复方海参制品 lOOmg: ImL 68.57+0.56* 1.2
P<0.05 ， 与生理盐水组比较
Δ Ρ<0.05 ， 与纳米海参粉 200mg: ImL组比较
②体内血小板聚集试验结果：
用纳米海参粉、 复方海参制品粉末分别灌胃给药两周后， 纳米海参粉具有 促进血小板聚集的作用。 高低剂量组的血小板促聚率分别为 47.1%和 24.3%。 而 复方海参制品促聚反应不明显， 结果见表 4:
表 4 纳米海参粉、 复方海参制品体内血小板聚集实验结果 （n=10)
剂量 血小板聚集率 促进百分率
Figure imgf000009_0001
(mg/Kg) ( ) (%) NS 一 50.84+1.57 一
纳米海 i ,粉 900 74.79+0.56* 47.1
纳米海 i ,粉 100 63.19±1.80*Δ 24.3
复方海参 ^制品 900 58.48+1.11*Δ 15.0
复方海参 ^制品 100 52.74+1.68* 3.7
Ρ<0.05 ， 与生理盐水组比较
Δ Ρ<0.05 ， 与纳米海参粉 900 mg/Kg组比较
4.不同品种海参的抗凝血活性和抗栓活性的比较：
(1)抗凝血活性的比较： 雄性昆明种小鼠 50只， 随机分为 5组： NS空白对照 组、 0.5g/kg纳米海刺参粉组、 0.5g/kg纳米叶瓜参粉组。 小鼠每日灌胃 0.5g/kg不 同种海参 2次， NS空白对照组灌胃给予等容量 NS, 连续给药 3日后， 应用生物测 定法测定凝血酶时间 （TT) 及复钙时间 （RT) , 进而比较纳米海刺参粉及纳米 叶瓜参粉的抗凝活性。 结果见下表 5:
表 5.小鼠灌胃不同海参粉 3天后对 TT及 RT的影响 （n=10， x±s) 组别 TT (s) TT延长％ RT (s) RT延长％
NS 5.80+0.61 10.66+3.08
纳米叶瓜参粉 0.5g/kg .56+0.43*** 60.84+9.98***
30.34 470.73 纳米海剌参粉 0.5g/kg .69+0.62*** 65.87+9.00***
32.59 517.92 注： P<0.001与 NS组比较
由表 5可知， 小鼠灌胃给予 0.5g/kg上述两种不同纳米海参粉均能明显延长凝血酶 时间 (TT) (p<0.001 )和复钙时间 (RT) (p<0.001 )， 说明上述两种纳米海参粉 均具有明显抗凝活性。
(2)抗栓活性的比较： 雄性昆明种小鼠 60只， 随机分为 6组： 空白对照组、 血栓模型组、 0.5g/kg 纳米叶瓜参粉组、 和 0.5g/kg 纳米海刺参粉组。 小鼠 每日灌胃给予 0.5g/kg不同种海参 2次，空白对照组和血栓模型组小鼠灌胃给
Figure imgf000010_0001
鼠于腰背部皮下注射
0.4%角叉菜胶 O.lmL/lOg复制血栓模型， 继续给药至造模后 48h测量鼠尾全 长及黑尾长度， 计算黑尾长度％。 以模型组黑尾长度％为基准， 计算各给 药组黑尾长度％抑制％ (血栓形成抑制％)， 比较不同海参粉的抗栓作用。 结果见下表 6:
表 6. 小鼠灌胃不同品种纳米海参粉对角叉菜胶诱发的尾部血栓形成的影响 (n=10， X土 s) 组别 黑尾长度％ 血栓形成抑制％ 空白对照组
模型组 67.58+8.66 纳米叶瓜参粉 24.04土 14.46***
64.43
纳米海剌参粉 14.36土 10.98***
78.75
注： P<O.OOI与模型组比较
由表 6可知， 与模型组相比， 小鼠灌胃给予 0.5g/kg上述两种纳米海参粉均能 明显降低黑尾长度％ (p<0.001 )， 说明其具有抑制角叉菜胶所致的小鼠尾部血栓 形成作用， 即抗栓作用。
结论： 不同的海参品种， 在制得纳米制剂之后， 在效果上没有明显的差别。

Claims

权 利 要 求 书
1、 一种海参复方制品， 其特征在于是一种灰白色或浅黄色粉末， 由纳米海 参粉与三七皂甙提取物按照 99~80wt% : l~20wt%的比例进行混合， 其中海参多 糖含量为 2.5~8.1wt%， 三七总皂甙含量为 0.3~14.0wt%;
所述三七总皂甙是以 Rl+Rbl+Rgl成分总含量来计算的。
2、 如权利要求 1所述一种海参复方制品的制备方法， 其特征在于具体步骤 为：
( 1 ) 原料处理： 将鲜活海参剪开， 取出内脏， 将其分别充分清洗干净， 置 于密闭容器中；
(2) 加热胶化： 温度为 70〜130°C， 加热 lmin〜20h;
(3 )冷冻干燥： 将胶化后的海参进行冷冻干燥， 水分小于 10%; (4)粗粉碎： 将冷冻干燥后的海参进行粗粉碎至颗粒细度为 10〜300目；
(5 ) 超微粉碎： 将粗粉碎的海参粉用气流粉碎机进行超微粉碎， 粉碎细度 为 100〜3000目的海参超微粉；
(6 ) 纳米粉碎： 将经过气流粉碎的海参超微粉用高能球磨粉碎机进行纳米 化粉碎， 细度可达到 10〜： LOOOnm, 平均粒径是 100〜200nm;
(7 )纳米海参粉与三七皂甙提取物按照 99~80wt%: l~20wt%的比例进行混 合。
3、 根据权利要求 2所述海参复方制品的制备方法， 其特征在于步骤 （1 ) 原 料处理中用海参体壁或海参体壁连同海参内脏一起绞碎置于密闭容器中。
4、 根据权利要求 2所述海参复方制品的制备方法， 其特征在于步骤 （1 ) 原 料处理中， 原料采用干海参、 半干海参或盐渍海参代替鲜活海参， 将其发制好 清洗干净后代替鲜活海参置于密闭容器中。
5、根据权利要求 1或 4中所述海参复方制品的制备方法，其特征在于步骤（1 ) 原料处理中的原料： 鲜活海参、 干海参、 半干海参或盐渍海参为海刺参、 叶瓜 参品种。
6、 根据权利要求 2所述海参复方制品的制备方法， 其特征在于步骤 （2 ) 加 热胶化的条件： 100〜105°C， lho
7、 根据权利要求 2所述海参复方制品的制备方法， 其特征在于步骤 （3 ) 冷 冻干燥： 将胶化后的海参进行冷冻干燥， 水分小于 3%。
8、 如权利要求 1所述海参复方制品在使用中的剂型， 其特征在于为胶囊剂、 片剂、 冲剂； 其中胶囊为纳米海参粉与三七粉按比例混合后直接装囊； 片剂和 冲剂为纳米海参粉与三七粉按比例混合后与敷料按 2: 1~1: 1的比例混合后制成。
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