WO2016169490A1 - 连翘苷、连翘苷衍生物、连翘苷与连翘脂素组合物在制备预防或/和治疗高血脂症药物中的应用 - Google Patents

连翘苷、连翘苷衍生物、连翘苷与连翘脂素组合物在制备预防或/和治疗高血脂症药物中的应用 Download PDF

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WO2016169490A1
WO2016169490A1 PCT/CN2016/079842 CN2016079842W WO2016169490A1 WO 2016169490 A1 WO2016169490 A1 WO 2016169490A1 CN 2016079842 W CN2016079842 W CN 2016079842W WO 2016169490 A1 WO2016169490 A1 WO 2016169490A1
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forsythin
forsythiaside
extract
glucuronide
derivative
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PCT/CN2016/079842
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English (en)
French (fr)
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富力
盖鑫
王凯乾
樊宏宇
惠敏
刘正贤
王硕
周庆丰
刘国友
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富力
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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)
    • A61K36/63—Oleaceae (Olive family), e.g. jasmine, lilac or ash tree
    • A61K36/634—Forsythia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • A61K31/355—Tocopherols, e.g. vitamin E
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/375—Ascorbic acid, i.e. vitamin C; Salts thereof
    • 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
    • A61K35/63—Arthropods
    • 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)
    • A61K36/23—Apiaceae or Umbelliferae (Carrot family), e.g. dill, chervil, coriander or cumin
    • A61K36/232—Angelica
    • 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
    • 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)
    • A61K36/48—Fabaceae or Leguminosae (Pea or Legume family); Caesalpiniaceae; Mimosaceae; Papilionaceae
    • A61K36/481—Astragalus (milkvetch)
    • 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)
    • A61K36/53—Lamiaceae or Labiatae (Mint family), e.g. thyme, rosemary or lavender
    • A61K36/537—Salvia (sage)
    • 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)
    • A61K36/70—Polygonaceae (Buckwheat family), e.g. spineflower or dock
    • A61K36/708—Rheum (rhubarb)
    • 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)
    • A61K36/73—Rosaceae (Rose family), e.g. strawberry, chokeberry, blackberry, pear or firethorn
    • A61K36/734—Crataegus (hawthorn)
    • 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)
    • A61K36/88—Liliopsida (monocotyledons)
    • A61K36/906—Zingiberaceae (Ginger family)
    • A61K36/9066—Curcuma, e.g. common turmeric, East Indian arrowroot or mango ginger
    • 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)
    • A61K36/88—Liliopsida (monocotyledons)
    • A61K36/906—Zingiberaceae (Ginger family)
    • A61K36/9068—Zingiber, e.g. garden ginger
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/04—Ortho-condensed systems
    • 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

Definitions

  • the invention relates to the field of medicine, relates to a medicine for treating hyperlipemia or health food, in particular to an application of a traditional Chinese medicine forsythia and a forsythia leaf extract component in preventing or/and treating hyperlipemia drugs or health foods.
  • Hyperlipidemia is also called lipid metabolism disorder or dyslipidemia.
  • One or more lipids in plasma are called hyperlipidemia due to abnormalities in fat metabolism or transport.
  • Hyperlipidemia is a risk factor for atherosclerosis. Important risk factors for coronary heart disease, hypertension, stroke, and senile dementia.
  • “Lingshu ⁇ Wuhanjin Liquid” said that “the grain of the liquid and the combination of the liquid and the cream are infiltrated into the bone space, and the brain is indulged in the sinus.” If the physiological function of the five internal organs is dysfunctional, the blood and blood are not running smoothly, and the phlegm and blood stasis will form hyperlipidemia, and the phlegm and blood stasis can cause atherosclerosis. "Certificate of the rule of law and the stroke” cloud "fat people have more disease, with their anger in the outside and apologize in the inside, ... so the hustle and bustle, so the rule must be tempered first.”
  • hyperlipidemia is a syndrome of this virtual standard, and the cause is mostly caused by insufficient endowment, unhealthy diet, internal injuries, long-term illness, and dysfunction caused by old and physical weakness.
  • the main pathological mechanism is spleen loss and health, phlegm and dampness; kidney deficiency and opening are unfavorable, water clotting is phlegm; liver qi stagnation, qi stagnation and blood stasis; phlegm dampness and blood stasis, leaving stagnation; this virtual standard, false and real.
  • liver, spleen and kidney deficiency, especially spleen weakness is the pathological basis of hyperlipidemia.
  • Turbid blood stasis is the basic pathological mechanism of occurrence, development, prognosis and prognosis of hyperlipidemia, which can cause chest sputum, dizziness, palpitations, Wind itch, stroke and other changes occur. Therefore, the treatment is mainly based on traditional Chinese medicine for replenishing spleen and kidney and removing phlegm. Clinically, single-flavor Chinese medicine or compound is used to study its lipid-lowering effect.
  • Atherosclerosis is an subendothelial lipid.
  • Deposition, vascular smooth muscle cells and collagen cell proliferation, foam cell formation are the main pathological changes.
  • the low-density lipoprotein (LDL) and very low-density lipoprotein (VLDL) levels in plasma that transport cholesterol from the liver to the blood continue to increase and the incidence of atherosclerosis Positive correlation, and high triglycerides (TG) are independent risk factors for this disease.
  • LDL low-density lipoprotein
  • VLDL very low-density lipoprotein
  • TG high triglycerides
  • the atherosclerosis index is an important parameter for evaluating lipid metabolism disorders and vascular pathological changes. It can accurately indicate the risk of arteriosclerosis and response to treatment. It has been widely used in hospital evaluation abroad.
  • Forsythia is one of the traditional traditional medicines used in traditional Chinese medicine. It is widely used and has a large dosage. It has the function of clearing away heat and detoxifying and dissipating free radicals. It is often formulated with other Chinese herbal medicines for various types of high-grade drugs. Treatment of dyslipidemia. However, the specific active ingredients are still unclear. The inventors have arduously explored and prepared the active monomer compound forsythin, and chemically synthesized to prepare corresponding derivatives, and carried out a series of pharmacological treatments.
  • the inventors have extracted the forsythiaside and forsythin derivatives which are effective components for treating hyperlipemia from forsythia and forsythia leaves through a large number of modern scientific researches, using advanced separation and purification techniques, and further researched and synthesized A glycoside derivative. It can provide a highly effective and low-toxic drug for patients with hyperlipidemia.
  • the object of the present invention is to provide a combination of forsythin, forsythin derivatives, forsythin and forsythiaside for the technical problems existing in the prior art for the prevention or treatment of hyperlipemia drugs or health care products (ie, even A new application for the prevention or/and treatment of hyperlipidemia, the properties and efficacy of forsythiaside, forsythiaside derivatives, forsythin and forsythiaside compositions for the prevention and treatment of hyperlipidemia It has broad application prospects in the treatment, conditioning and alleviation of hyperlipidemia and lowering blood lipids.
  • an aspect of the present invention provides a use of forsythin, forsythiaside derivative, forsythin/forsylin in the preparation of a medicament for preventing or/and treating hyperlipemia or a health care product.
  • the hyperlipemia includes hypercholesterolemia, hypertriglyceridemia, dietary hyperlipemia, or mixed hyperlipidemia, preferably hypercholesterolemia and hypertriglyceridemia.
  • the medicament or health care product consists of forsythin, forsythin derivative or forsythin/forsyricin and a pharmaceutically acceptable carrier.
  • the forsythiaside derivative is selected from the forsythiaside glucuronic acid derivative.
  • the forsythin derivative comprises 33-hydroxy-philoxyphilin-8-O- ⁇ -D-glucuronide, 9-hydroxy-Forsylin glucagon Acid glucoside (9-Hydroxy phillygenin-8-O- ⁇ -D-glucuronide), 33,34-methylenedioxy-Forsythine glucuronide (33,34-Methylenedioxy phillygenin-8-O- ⁇ -D-glucuronide), forsythiaside methyl glucuronide ((2R,3R,4R,5S)-methyl6-(5-((1R,4S)-4-(3,4-dimethoxyphenyl)hexahydrofuro[3 , 4-c]furan-1-yl)-2-methoxyphenoxy)-3,4,5-trihydroxytetra hydro-2H-pyran-2-carboxylate), forsythiaside sodium glucuronate (sodium(2R,3R, 4R
  • the weight ratio of forsythin to forsythiaside in the forsythiaside and forsythiaside composition is from 2 to 98:2 to 98; preferably from 2 to 10:90 to 98; further preferably It is 80:20 or 20:80, further preferably 90:10 or 10:90, still more preferably 98:2 or 2:98; still more preferably 98:2.
  • the content of the forsythin, forsythiaside derivative is ⁇ 1%, preferably ⁇ 30%, further preferably ⁇ 60%, still more preferably ⁇ 80%, still more preferably ⁇ 98%;
  • the content of the combination of forsythin and forsythin is ⁇ 1%, preferably ⁇ 30%, further preferably ⁇ 60%, still more preferably ⁇ 80%, still more preferably ⁇ 98%.
  • the content of the forsythin and forsythin derivatives is from 1% to 98%; preferably from 30 to 80%; the content of the combination of forsythin and forsythin is from 1% to 98%; It is 30 to 80%.
  • pharmaceutically acceptable carriers are generally approved by health care professionals for this purpose and as inactive ingredients of the agent.
  • a compilation of pharmaceutically acceptable carriers can be found in the Handbook of Pharmaceutical excipients, 2nd edition, edited by A. Wade and PJ Weller; published by the American Pharmaceutical Association, Washington and The Pharmaceutical Press, London, 1994) found in the reference book.
  • the carrier comprises an excipient such as starch, water or the like; a lubricant such as magnesium stearate or the like; a disintegrating agent such as microcrystalline cellulose; a filler such as lactose; and a binder, Such as pregelatinized starch, dextrin, etc.; sweeteners; antioxidants; preservatives, flavors, spices, etc.
  • the medicament is in the form of a tablet, a capsule, a pill, a powder, a granule, or a syrup.
  • the forsythin, forsythiaside derivative content is ⁇ 1%, preferably ⁇ 30%, further preferably ⁇ 60%, still more preferably ⁇ 80%, still more preferably ⁇ 98%;
  • the content of the combination of scutellarin and forsythiaside is ⁇ 1%, preferably ⁇ 30%, further preferably ⁇ 60%, still more preferably ⁇ 80%, still more preferably ⁇ 98%.
  • Another aspect of the present invention provides a medicament or health care product comprising forsythiaside, forsythiaside derivative or forsythiaside and forsythiaside composition for preventing or/and treating hyperlipemia.
  • the forsythin derivative comprises 33-hydroxy-Forsylin glucuronide, 9-hydroxy-Forsylin glucuronide, 33,34-methylenedioxy-linked sulfonate Glucuronide, forsythiaside methyl glucuronate, forsythiaside sodium glucuronate, forsythias glucuronide, forsythiaglycine glucuronic acid; preferably 33-hydroxy-forsythia Lipid glucuronide, 9-hydroxy-Forsyric acid glucuronide, 33,34-methylenedioxy-Forsythine glucuronide, forsythias glucuronide methyl ester, even Sodium lipoate or sodium forsylate. Glucuronide.
  • the weight ratio of forsythin to forsythin in the forsythiaside and forsythiaside composition is from 2 to 98:2 to 98; preferably from 2 to 10:90 to 98; further preferably 80:20 or 20:80, further preferably 90:10 or 10:90, still more preferably 98:2 or 2:98; still more preferably 98:2.
  • the content of the forsythin or forsythin derivative is ⁇ 1%, preferably ⁇ 30%, further preferably ⁇ 60%, still more preferably ⁇ 80%, still more preferably ⁇ 98%
  • the composition of forsythin and forsythiaside is ⁇ 1%, preferably ⁇ 30%, further preferably ⁇ 60%, still more preferably ⁇ 80%, still more preferably ⁇ 98%.
  • the content of the forsythin or forsythin derivative is ⁇ 1%, preferably from 1% to 98%; preferably from 30% to 80%, still more preferably 60%; forsythin and forsythiaside
  • the composition of the composition is ⁇ 1%, preferably from 1% to 98%; preferably from 30 to 80%, still more preferably 60%.
  • the ratio of the weight of the forsythin, the forsythin derivative or the forsythin to the forsythiaside composition to the total weight of the drug or nutraceutical is from 0.01 to 10:100, preferably from 0.1 to 10:100, further preferably 1 to 10:100.
  • the forsythin/forsylin composition is composed of forsythin, forsythiaside monomer, or a solvent-heat extraction method, or a forsythia-penicillin extraction composition, or Forsythin and forsythin are combined with cyclodextrin or a cyclodextrin derivative to form a forsythiaside-forsylin-cyclodextrin composition.
  • the forsythiaside-forsylin-cyclodextrin composition is a mixture of forsythiaside and forsythin mixed with ⁇ -, ⁇ - or ⁇ -cyclodextrin or a derivative thereof. , or forsythiaside and forsythin with ⁇ -, ⁇ - or ⁇ -cyclodextrin or its derivatives
  • the formed complex is treated chemically and chemically.
  • ratio of the weight of forsythin and forsythin in the forsythiaside-forsylin-cyclodextrin composition to the weight of the cyclodextrin or cyclodextrin derivative is 1:1-50.
  • the cyclodextrin is ⁇ - or ⁇ -, ⁇ -cyclodextrin;
  • the cyclodextrin derivative is hydroxyethyl-cyclodextrin, 2,6-dimethyl-cyclodextrin, 2 ,3,6-trimethyl-cyclodextrin, 2,6-diethyl-cyclodextrin, 2,3,6-triethyl-cyclodextrin, maltosyl-cyclodextrin or sulfobutylether ⁇ - cyclodextrin, p-TsCl substituted ⁇ -cyclodextrin, 6-substituted ⁇ -CD p-toluenesulfonate ( ⁇ -cyclodextrin-6-OTs) , 2-oxohydroxypropyl- ⁇ -cyclodextrin, 2-position monosubstituted p-toluenesulfonate ( ⁇ -cyclodextr
  • the medicine or health care product further comprises salvia miltiorrhiza extract, hawthorn extract, astragalus extract, angelica extract, mountain seven extract, curcumin extract, ginger extract, raw rhubarb extract, white silkworm extract
  • salvia miltiorrhiza extract, hawthorn extract, astragalus extract, angelica extract, mountain seven extract, curcumin extract, ginger extract, raw rhubarb extract, white silkworm extract One or more of vitamin C, its derivatives or vitamin E and its derivatives.
  • the present invention has the following distinct advantages:
  • the present invention excavates new medicinal value for the known compound forsythin, which is used for relieving, treating hyperlipemia, lowering blood fat, and preparing a medicine or health food for preventing or/and treating hyperlipemia. This has opened up a new field for the application of Forsythia and Forsythia sinensis.
  • the forsythin and forsythin derivatives of the invention have strong pharmacological action, are used for relieving, regulating and treating hyperlipemia, and have the effects of reducing blood fat, have quick effect, small side effects, good safety, and can be taken for a long time. Has a good medicinal prospects.
  • the raw materials of the invention have rich sources, low cost, safe clinical use, simple preparation process, can be made into various dosage forms, and have small dosage and convenient use, so it is easy to promote.
  • a combination of a single component of forsythin, a forsythin derivative as an active ingredient, or a combination of forsythin and forsygin, a drug for relieving and treating hyperlipidemia, and forsythiaside may be used.
  • Forsythin derivatives and other active ingredients for example, with Salvia miltiorrhiza extract, Hawthorn extract, Astragalus extract, Angelica extract, Mountain seven extract, Rhizoma extract, Ginger extract, Rhubarb extract, White silkworm Extract, vitamin C and its derivatives or vitamin E and its derivatives.
  • a combination of prescriptions to prepare a compound for the treatment of hypolipidemic drugs A combination of prescriptions to prepare a compound for the treatment of hypolipidemic drugs.
  • Glucuronide is the same as the forsythiaside derivative described in the patent application (Application No.: 201510319303.4, Priority No.: 201510164294.6); forsythiaside methyl glucuronide, forsythiaside sodium glucuronate, forsythia
  • the fatty acid potassium gluconate, forsythiaside glucuronic acid is the same as in the patent application (Application No.: 201510320579.4, priority number: 201410825547.5).
  • the forsythin and the starch are uniformly mixed and then filled into capsules to make 10,000 tablets.
  • the forsythin and the starch are uniformly mixed and then filled into capsules to make 10,000 tablets.
  • the forsythin, the astragalus extract, the vitamin C and the starch are uniformly mixed and granulated, and the talc powder and the magnesium stearate are added and mixed, and then pressed into 10,000 tablets.
  • the 33-hydroxy-Forsythine glucuronide, the Astragalus membranaceus extract, the vitamin C and the starch are uniformly mixed and granulated, and the talc powder and magnesium stearate are added and mixed, and then pressed into 10,000 tablets.
  • the forsythin/forsylin composition was uniformly mixed with starch in the weight ratio of the following table, and then filled into capsules, each of which was made into 10,000 capsules.
  • the forsythin/forsylin composition was uniformly mixed with the microcrystalline cellulose in the weight ratio of the following table, and then granulated and bagged to prepare 10,000 bags.
  • Test Example 1 Effect of forsythin, forsythin derivative, forsythin/forsylin composition on hyperlipidemic rats
  • Triglyceride Detection Kit (Beijing Jiuqiang Biotechnology Co., Ltd.); Total Cholesterol Detection Kit (Beijing Jiuqiang Biotechnology Co., Ltd.); High Density Lipoprotein Cholesterol Detection Kit (Shanghai Kehua Bioengineering Co., Ltd.); Low Density Grease Protein Cholesterol Detection Kit (Shanghai Kehua Bio-engineering Co., Ltd.); Cholesterol [China Pharmaceutical (Group) Shanghai Chemical Reagent Company]; propylthiouracil (Shenyang Northeast Pharmacy); lard (Shenyang City May 1 market selling plate oil refining) System); 95% medicinal alcohol (Shenyang Weilong Trading Co., Ltd.); 20% urethane solution (provided by the Department of Pharmacology, Liaoning University of Traditional Chinese Medicine).
  • Forsythin (content >98%), white powder, produced by Dalian Fusheng Natural Medicine Development Co., Ltd., batch number: 20130303. It was determined by the high-performance liquid chromatography two detector UV detector and the evaporative light scattering detector area normalization method, the purity of which was 99.5%, and the content of the forsythiaside reference substance was determined and confirmed by the Chinese pharmaceutical biological product content determination. 99.5%.
  • Forsythin/Forsythiamin composition A forsythin (content > 98%), white powder, produced by Dalian Fusheng Natural Medicine Development Co., Ltd., batch number: 20130303; forsythiaside (content > 98%), white Powder, produced by Dalian Fusheng Natural Medicine Development Co., Ltd., batch number: 20130301; the ratio of forsythin to forsythin is 98:2.
  • Forsythin/Forsythiamin B forsythin (>98%), white powder, Dalian Fusheng Natural Medicine Development Co., Ltd., batch number: 20130303; forsythias (content > 98%), white Powder, produced by Dalian Fusheng Natural Medicine Development Co., Ltd., batch number: 20130301; the ratio of forsythin to forsythin is 89:11.
  • Forsythiaside derivatives A, B, and C were set in three experimental groups of forsythin derivatives, namely, low, medium, and high doses of forsythin derivatives A, the doses were 480, 960, and 1980 mg/kg, respectively.
  • the low, medium and high doses of glycoside derivative B were 480, 960, and 1980 mg/kg, respectively;
  • the low, medium, and high doses of forsythin derivative C were 480, 960, and 1980 mg/kg, respectively;
  • Forsythin/Forsythiaside compositions A and B were set up with three forsythin/Forsythialipid experimental groups, respectively, for the forsythiaside/Forsythiaside A low, medium and high dose groups, the dose was 480 960, 960, 1980mg/kg; forsythiaside/Forsythiaside B low, medium and high dose groups, the dose was 480, 960, 1980mg / kg.
  • model control group the forsythiaside group (dose was 1980 mg/kg), the blank control group and the obese model control group (hereinafter referred to as "model control group").
  • Male Wistar rats were routinely reared for 1 week and divided into 21 groups, 8 rats in each group, which were blank control group, model control group, administration group, for example, forsythiaside group and forsythin group (low, medium and high).
  • One dose group forsythiaside derivatives A, B, C (low, medium, high three dose groups), forsythin / forsythiaside compositions A, B (low, medium, high three dose groups).
  • the rats in the blank control group were fed with normal diet and fed with normal basal diet.
  • the rats in the model control group were given normal basal diet from the first day of the experiment, and 2% cholesterol and 2% propylthiouracil were intragastrically administered daily.
  • Lard; the other drug groups were given normal basal feed from the first day of the experiment, and the lard containing 2% cholesterol and 2% propylthiouracil was intragastrically administered daily.
  • the drug group was administered with lard 4 After -5h, the corresponding doses of the drug were administered by weight, and fed continuously for 16 days. All rats were fasted for 12 hours after weighing the night, and all animals were anesthetized with 20% urethane solution the next day. After the blood was taken from the carotid artery, serum cholesterol (TC), triglyceride (TG), low-density lipoprotein (LDL), and high-density lipoprotein (HDL) content were measured.
  • TC serum cholesterol
  • Forsythiaside has no effect on hyperlipidemia, and forsythin/forsylin composition has a synergistic effect in the treatment of hyperlipidemia, which can significantly inhibit dietary hyperlipidemia and significantly inhibit serum.
  • the increase of TC, TG, LDL and HDL significantly reduced the contents of TC, TG, LDL and HDL, and had obvious preventive and therapeutic effects on dietary hyperlipidemia.

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Abstract

一种连翘苷、连翘苷衍生物、连翘苷与连翘脂素组合物在制备预防或/和治疗高血脂症药物中的新应用。试验证明，连翘苷、连翘苷衍生物、连翘苷与连翘脂素组合物治疗高血脂的疗效显著，见效快，毒副作用小、是一种安全、高效、稳定、制备工艺简单的治疗高血脂药物，适于工业化生产，易于推广，为预防和治疗高血脂及其并发症提供了一种新的药物来源。

Description

连翘苷、连翘苷衍生物、连翘苷与连翘脂素组合物在制备预防或/和治疗高血脂症药物中的应用 技术领域
本发明涉及医药领域，涉及一种治疗高血脂的药物或保健食品，特别涉及一种中药连翘及连翘叶提取成分在预防或/和治疗高血脂药物或保健食品中的应用。
背景技术
高血脂又称脂代谢紊乱或血脂异常。由于脂肪代谢或转运异常使血浆一种或几种脂质高于正常称为高脂血症。可表现为高胆固醇血症、高甘油三脂血症或混合型高脂血症。与年龄、饮食有一定的依赖关系，但是近年来呈低龄发病的趋势。随着人口老龄化加重、生活方式的改变，脂代谢异常的危害越来越严重，关于血脂异常的研究已在国内外引起高度重视，高脂血症是致动脉粥样硬化的危险因子，是冠心病、高血压、脑卒中、老年痴呆的重要危险因素，流行病学调查显示我国人群的血脂平均水平和血脂异常的患病率无论城乡、南北正在迅速上升，其中在经济发达地区已达到较高水平，并已把对血脂异常潜在危险的研究从对冠心病单一疾病的评价发展到对冠心病、脑卒中、恶性肿瘤、总死亡等多种健康结局的评价。
祖国医学虽无高脂血症的概念，历代中医文献中也无高血脂的独立病名，但对人体膏脂己有所认识，认为血中膏脂在正常情况下是生理性的，是人体组成成分之一，属“液”“营阴”范畴，《灵枢·五癃津液别》说“五谷之津液和合而为膏者，内渗入于骨空，补益脑髓，而下流于阴股。”若五脏生理功能失调，气血运行不畅，痰浊血瘀，则形成高脂血症，痰瘀互结又可致动脉粥样硬化形成。《证治要诀·中风》云“肥人多有中病，以其气盛于外而歉于内也，……故痰涎壅盛，所以治之必先理气为急。”
中医学认为高脂血症属本虚标实之证，病因多由禀赋不足、饮食不节、七情内伤、久病失治、年老体虚引起脏腑功能失调所致。其主要病理机制为脾失健运，痰湿内生；肾虚开合不利，水凝为痰；肝气郁结，气滞血痪；痰湿血癖，留滞脉络；本虚标实，虚实夹杂。总之肝脾肾不足尤其是脾气虚弱是高脂血症发生的病理基础，痰浊血瘀是高脂血症发生、发展、转归和预后的基本病理机制，可致胸痹、眩晕、心悸、风痒、中风等变端发生。故治疗以补益脾肾，化痰祛瘀的中药为主。临床多采用单味中药或复方等研究其降脂作用。
现代医学认为高脂血症是动脉粥样硬化的重要危险因子，动脉粥样硬化是以内膜下脂质 沉积、血管平滑肌细胞和胶原细胞增殖、泡沫细胞形成为主要病理变化特征。血浆中负责将胆固醇从肝脏运送到血液的低密度脂蛋白(low-density lipoprotein,LDL)和极低密度脂蛋白(very low-density lipoprotein,VLDL)水平持续升高与动脉粥样硬化的发病率呈正相关，而高甘油三脂(triglycerides,TG)是本病的独立危险因素。动脉粥样硬化指数是评价脂代谢紊乱、血管病理改变的重要参数，能准确地表明动脉硬化的危险性和对治疗的反应，在国外己广泛用于医院评估。高血脂与冠心病关系的研究资料非常丰富。血脂异常是冠心病的重要危险因素。血清脂蛋白(a)、血浆纤维蛋白原水平与冠状动脉粥样硬化及其程度呈显著相关。国内外对于血脂异常与脑卒中的关系研究相对较少。流行病学调查表明血脂水平与缺血性卒中密切相关，降低血脂的治疗是安全可靠的。缺血性脑卒中作为全身动脉粥样硬化的一部分，其发生发展也与动脉粥样硬化发生发展的病理过程相符，尤其体现在血管紧张素II促进体内LDL的氧化和瘦素样氧化低密度脂蛋白受体I(Leptin-Like Oxidized Low-Density Lipoprotein Receptor 1,Lox-1)的表达中，这些机制造成了脑动脉内皮损伤，进而导致动脉粥样硬化和血栓形成。
西医学认为高脂血症病因复杂，治疗较为困难，部分可通过调整饮食和改善生活方式得到改善；有些需要药物治疗，现今研究最为广泛的是他汀类药物:对于难治性高脂血症可以采用血液净化或外科手术法；基因缺陷所致的高脂血症还需要基因治疗。目前药物和治疗方法疗效并不理想，即使有效，停药后血脂水平即回到用药前，并且有效的降脂药物存在一定的副作用，因此高脂血症的现代医学治疗是一个长期的、相当费钱的、并有一定安全风险的任务。中药对高血脂的治疗和预防均有良好的效果，且副作用小，开发具有独立知识产权、治疗血脂异常的药物已迫在眉睫。寻找有效的药物防止、延缓和逆转动脉粥样硬化是一个重要医学课题，是防治心脑血管疾病的重要基础。
连翘是中药临床常用传统药物之一，应用广泛，用量巨大，它具有清热"解毒"消肿散结"清除自由基的功能，临床上常与其他的中草药制成配方，用于各类高血脂症治疗。但是，其中具体活性成分尚不清楚，发明者经过艰苦探索，制备提取了其中活性单体化合物连翘苷，并经化学合成，制备了相应的衍生物，进行了一系列的药理活性研究，发现连翘苷、连翘苷衍生物、连翘苷与连翘脂素组合物具有抑制高血脂，增强人体免疫功能活性，为高血脂患者开辟了新的治疗途经。
Figure PCTCN2016079842-appb-000001
本发明人通过大量的现代科学研究，采用先进的分离纯化技术从连翘及连翘叶中提取其治疗高血脂的有效成分连翘苷、连翘苷衍生物，并经进一步研究合成制备了连翘苷衍生物。可以为高血脂患者提供一种高效低毒的药物。
发明内容
本发明的目的时针对现有预防、治疗高血脂症的药物或保健品的应用中存在的技术问题提供连翘苷、连翘苷衍生物、连翘苷与连翘脂素组合物(即连翘苷/连翘脂素)预防或/和治疗高血脂疾病的新应用，连翘苷、连翘苷衍生物、连翘苷与连翘脂素组合物预防和治疗高血脂的性能和功效显著，在治疗、调理和缓解高血脂症，降低血脂方面具有广阔的应用前景。
为实现本发明的目的，本发明一方面提供一种连翘苷、连翘苷衍生物、连翘苷/连翘脂素在制备预防或/和治疗高血脂症药物或保健品中的应用。
在筛选具有降血脂作用的天然活性成分的过程中，发明人发现连翘的化学成分中连翘苷、连翘苷衍生物具有强烈的抑制高血脂、降低血脂的作用。
其中，所述的高血脂症选择高胆固醇血症、高甘油三脂血症、饮食性高血脂症或混合型高脂血症，优选为高胆固醇血症、高甘油三脂血症。
其中，所述药物或保健品由连翘苷、连翘苷衍生物或连翘苷/连翘脂素和药学上可接受的载体组成。
特别是，所述连翘苷衍生物选择连翘脂素葡萄糖醛酸衍生物。
特别是，所述连翘苷衍生物包括33-羟基-连翘脂素葡萄糖醛酸苷(33-Hydroxy phillygenin-8-O-β-D-glucuronide)、9-羟基-连翘脂素葡萄糖醛酸苷(9-Hydroxy phillygenin-8-O-β-D-glucuronide)、33，34-亚甲基二氧-连翘脂素葡萄糖醛酸苷(33,34-Methylenedioxy phillygenin-8-O-β-D-glucuronide)、连翘脂素葡萄糖醛酸甲酯((2R,3R,4R,5S)-methyl6-(5-((1R,4S)-4-(3,4-dimethoxyphenyl)hexahydrofuro[3,4-c]furan-1-yl)-2-methoxyphenoxy)-3,4,5-trihydroxytetra hydro-2H-pyran-2-carboxylate)、连翘脂素葡萄糖醛酸钠(sodium(2R,3R,4R,5S)-6-(5-((1R,4S)-4-(3,4-dimethoxyphenyl)hexahydrofuro[3,4-c]furan-1-yl)-2-methoxyphenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate)、连翘脂素葡萄糖醛酸钾(potassium(2R,3R,4R,5S)-6-(5-((1R,4S)-4-(3,4-dimethoxyphenyl)hexahydrofuro[3,4-c]furan-1-yl)-2-methoxyphenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate)、连翘脂素葡萄糖醛酸((2R,3R,4R,5S)-6-(5-((1R,4S)-4-(3,4-dimethoxyphenyl)hexahydrofuro[3,4-c]furan-1-yl)-2-methoxyphenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid)；优选为33-羟基-连翘脂素葡萄糖醛酸苷、9-羟基-连翘脂素葡萄糖醛酸苷、33，34-亚甲基二氧-连翘脂素葡萄糖醛酸苷、连翘脂素葡萄糖醛酸甲酯、连翘脂素葡萄糖醛酸钠或连翘脂素葡萄糖醛酸钾。
特别是，所述连翘苷与连翘脂素组合物中连翘苷与连翘脂素的重量份配比为2～98：2～98；优选为2-10:90-98；进一步优选为80:20或20:80，进一步优选为90:10或10:90，更进一步优选为98:2或2:98；再进一步优选为98:2。
其中，所述的连翘苷、连翘苷衍生物的含量≥1％，优选为≥30％，进一步优选为≥60％，更进一步优选为≥80％，再更进一步优选为≥98％；连翘苷与连翘脂素的组合物含量≥1％，优选为≥30％，进一步优选为≥60％，更进一步优选为≥80％，再更进一步优选为≥98％。
特别是，所述的连翘苷、连翘苷衍生物含量为1％～98％；优选为30～80％；连翘苷与连翘脂素的组合物含量为1％～98％；优选为30～80％。
特别是，药学上可接受的载体通常被保健专家认可用于这一目的且作为药剂的非活性成分。有关药学上可接受的载体的汇编可以在《药物赋形剂手册》(Handbook of Pharmaceutical excipients，第2版，由A.Wade和P.J.Weller编辑；American Pharmaceutical Association出版，Washington and The Pharmaceutical Press,London,1994)等工具书中找到。
尤其是，所述的载体包括赋形剂，如淀粉、水等；润滑剂，如硬脂酸镁等；崩解剂，如微晶纤维素等；填充剂，如乳糖等；粘结剂，如预胶化淀粉、糊精等；甜味剂；抗氧化剂；防腐剂、矫味剂、香料等。
其中，所述药物以片剂、胶囊剂、丸剂、散剂、颗粒剂、糖浆剂形式存在。
特别是，所述连翘苷、连翘苷衍生物含量≥1％，优选为≥30％，进一步优选为≥60％，更进一步优选为≥80％，再更进一步优选为≥98％；连翘苷与连翘脂素的组合物含量≥1％，优选为≥30％，进一步优选为≥60％，更进一步优选为≥80％，再更进一步优选为≥98％。
本发明另一方面提供一种含有连翘苷、连翘苷衍生物或连翘苷与连翘脂素组合物的预防或/和治疗高血脂疾病的药物或保健品。
特别是，所述连翘苷衍生物包括33-羟基-连翘脂素葡萄糖醛酸苷、9-羟基-连翘脂素葡萄糖醛酸苷、33，34-亚甲基二氧-连翘脂素葡萄糖醛酸苷、连翘脂素葡萄糖醛酸甲酯、连翘脂素葡萄糖醛酸钠、连翘脂素葡萄糖醛酸钾、连翘脂素葡萄糖醛酸；优选为33-羟基-连翘脂素葡萄糖醛酸苷、9-羟基-连翘脂素葡萄糖醛酸苷、33，34-亚甲基二氧-连翘脂素葡萄糖醛酸苷、连翘脂素葡萄糖醛酸甲酯、连翘脂素葡萄糖醛酸钠或连翘脂素葡萄糖醛酸钾。
其中，所述连翘苷与连翘脂素组合物中连翘苷与连翘脂素的重量份配比为2～98：2～98；优选为2-10:90-98；进一步优选为80:20或20:80，进一步优选为90:10或10:90，更进一步优选为98:2或2:98；再进一步优选为98:2。
特别是，所述的连翘苷、连翘苷衍生物的含量≥1％，优选为≥30％，进一步优选为≥60％，更进一步优选为≥80％，再更进一步优选为≥98％；连翘苷与连翘脂素的组合物含量≥1％，优选为≥30％，进一步优选为≥60％，更进一步优选为≥80％，再更进一步优选为≥98％。
尤其是，所述的连翘苷、连翘苷衍生物的含量≥1％，优选为1％～98％；优选为30～80％，更进一步优选为60％；连翘苷与连翘脂素的组合物含量≥1％，优选为1％～98％；优选为30～80％，更进一步优选为60％。
特别是，所述连翘苷、连翘苷衍生物或连翘苷与连翘脂素组合物的重量与所述药物或保健品的总重量之比为0.01-10：100，优选为0.1～10：100，进一步优选为1～10：100。
其中，所述连翘苷/连翘脂素组合物以连翘苷、连翘脂素单体组成、或采用溶剂加热提取方法制备而成的连翘脂素-连翘苷提取组合物，或连翘脂素和连翘苷与环糊精或环糊精的衍生物组合而成连翘脂素-连翘苷-环糊精组合物。
特别是，所述连翘脂素-连翘苷-环糊精组合物选择连翘脂素和连翘苷与α-、β-或γ-环糊精或其衍生物相混合而成的混合物，或连翘脂素和连翘苷与α-、β-或γ-环糊精或其衍生物经物 理、化学方法处理形成的复合物。
其中，所述连翘脂素-连翘苷-环糊精组合物中连翘苷和连翘脂素重量与环糊精或环糊精的衍生物的重量之比为1：1-50。
特别是，所述环糊精为α-或β-、γ-环糊精；所述环糊精衍生物为羟乙基-环糊精、2,6-二甲基-环糊精、2,3,6-三甲基-环糊精、2,6-二乙基-环糊精、2,3,6-三乙基-环糊精、麦芽糖基-环糊精或磺丁醚β-环糊精、对甲基苯磺酰氯(p-TsCl)取代的β-环糊精、6-位取代的β-CD对甲基苯磺酸酯(β-环糊精-6-OTs)、2-氧羟丙基-β-环糊精、2-位单取代的对甲基苯磺酸酯(β-环糊精-2-OTs)、β-环糊精对甲基苯磺酸酯(Tosyl-β-CD)、β-环糊精的星形大分子PCL-(Tos)7-β-CD。
特别是，所述药物或保健品中还包括丹参提取物、山楂提取物、黄芪提取物、当归提取物、山七提取物、莪术提取物、生姜提取物、生大黄提取物、白僵蚕提取物、维生素C及其衍生物或维生素E及其衍生物中的一种或多种。
与现有技术相比，本发明具有如下的明显优点：
1、本发明对已知化合物连翘苷发掘了新的药用价值，将其用于缓解、治疗高血脂症，降低血脂，并可制备成预防或/和治疗高血脂的药物或保健食品，从而为连翘及连翘叶药材的应用开拓了一个新的领域。
2、本发明的系列试验研究证明连翘苷、连翘苷衍生物具有显著的缓解、治疗高血脂的功效。
3、本发明的连翘苷、连翘苷衍生物药理作用强，用于缓解、调理和治疗高血脂症，降血脂的功效显著，见效快、毒副作用小、安全性好，能够长期服用，具有良好的药用前景。
4、本发明的产品原料来源丰富、价廉、临床使用安全，制备工艺简单，可制成各种剂型，且服量小，使用方便，因此易于推广。
5、本发明既可采用单一成分的连翘苷、连翘苷衍生物作为活性成分、或连翘苷与连翘脂素的组合物制备缓解和治疗高血脂的药物，又可采用连翘苷、连翘苷衍生物与其它活性成分(例如与丹参提取物、山楂提取物、黄芪提取物、当归提取物、山七提取物、莪术提取物、生姜提取物、生大黄提取物、白僵蚕提取物、维生素C及其衍生物或维生素E及其衍生物。)共同组方，制备治疗降血脂的复方药物。
具体实施方式
下面通过具体实施方式来进一步描述本发明所述配方的有益效果，这些实施例包括了本 发明的连翘苷、连翘苷衍生物的胶囊、片剂、软胶囊剂的药效学试验。这些实施例仅是范例性的，并不对本发明的范围构成任何限制。本领域技术人员应该理解的是，在不偏离本发明的配方思路、用途范围下可以对本发明技术方案的细节和形式进行修改或替换，但这些修改和替换均落入本发明的保护范围内。
本发明中所述连翘苷衍生物33-羟基-连翘脂素葡萄糖醛酸苷、9-羟基-连翘脂素葡萄糖醛酸苷、33，34-亚甲基二氧-连翘脂素葡萄糖醛酸苷与专利申请(申请号：201510319303.4，优先权号：201510164294.6)中所述连翘苷衍生物相同；连翘脂素葡萄糖醛酸甲酯、连翘脂素葡萄糖醛酸钠、连翘脂素葡萄糖醛酸钾、连翘脂素葡萄糖醛酸与专利申请(申请号：201510320579.4，优先权号：201410825547.5)中的相同。
实施例1 连翘苷片剂
1、按照如下配比准备原料
Figure PCTCN2016079842-appb-000002
2、将连翘苷和淀粉混合均匀后，制成颗粒，加入滑石粉和硬脂酸镁混合均匀后压制成10000片。
实施例2 连翘苷胶囊剂
1、按照如下配比准备原料
连翘苷(纯度60％)             200g
淀粉                         1000g
2、将连翘苷和淀粉混合均匀后装胶囊，制成10000粒。
实施例3 连翘苷胶囊剂
1、按照如下配比准备原料
连翘苷(纯度98％)             500g
淀粉                         1000g
2、将连翘苷和淀粉混合均匀后装胶囊，制成10000粒。
实施例4 连翘苷片剂
1、按照如下配比准备原料
Figure PCTCN2016079842-appb-000003
2、将连翘苷、黄芪提取物、维生素C和淀粉混合均匀后制粒，加入滑石粉和硬脂酸镁混匀后压制成10000片。
实施例5 连翘苷胶囊剂
1、按照如下配比准备原料
Figure PCTCN2016079842-appb-000004
2、将连翘苷、丹参提取物、维生素C和淀粉混合均匀后装胶囊，制成10000粒。
实施例6 连翘苷颗粒剂
1、按照如下配比准备原料
Figure PCTCN2016079842-appb-000005
2、将连翘苷、当归提取物、维生素C和蔗糖粉混合均匀制成颗粒后装袋，制成10000袋。
实施例7 连翘苷口服液
1、按照如下配比准备原料
Figure PCTCN2016079842-appb-000006
2、取连翘苷、生姜提取物、三七提取物，用乙醇溶解后加入葡萄糖糖浆，最终加去离子水至1000ml，即得。
实施例8 33-羟基-连翘脂素葡萄糖醛酸苷片剂
1、按照如下配比准备原料
Figure PCTCN2016079842-appb-000007
2、将33-羟基-连翘脂素葡萄糖醛酸苷和淀粉混合均匀后，制成颗粒，加入滑石粉和硬脂酸镁混合均匀后压制成10000片。
实施例9 33-羟基-连翘脂素葡萄糖醛酸苷胶囊剂
1、按照如下配比准备原料
33-羟基-连翘脂素葡萄糖醛酸苷(纯度97％)   200g
淀粉                                     1000g
2、将33-羟基-连翘脂素葡萄糖醛酸苷和淀粉混合均匀后装胶囊，制成10000粒。
实施例10 33-羟基-连翘脂素葡萄糖醛酸苷胶囊剂
1、按照如下配比准备原料
33-羟基-连翘脂素葡萄糖醛酸苷(纯度98％)   500g
淀粉                                     1000g
2、将33-羟基-连翘脂素葡萄糖醛酸苷和淀粉混合均匀后装胶囊，制成10000粒。
实施例11 33-羟基-连翘脂素葡萄糖醛酸苷片剂
1、按照如下配比准备原料
Figure PCTCN2016079842-appb-000008
2、将33-羟基-连翘脂素葡萄糖醛酸苷、黄芪提取物、维生素C和淀粉混合均匀后制粒，加入滑石粉和硬脂酸镁混匀后压制成10000片。
实施例12 33-羟基-连翘脂素葡萄糖醛酸苷胶囊剂
1、按照如下配比准备原料
Figure PCTCN2016079842-appb-000009
2、将33-羟基-连翘脂素葡萄糖醛酸苷、生大黄提取物、维生素C和淀粉混合均匀后装胶囊，制成10000粒。
实施例13 33-羟基-连翘脂素葡萄糖醛酸苷颗粒剂
1、按照如下配比准备原料
Figure PCTCN2016079842-appb-000010
2、将33-羟基-连翘脂素葡萄糖醛酸苷、莪术提取物、维生素C和蔗糖粉混合均匀制成颗粒后装袋，制成10000袋。
实施例14 33-羟基-连翘脂素葡萄糖醛酸苷口服液
1、按照如下配比准备原料
Figure PCTCN2016079842-appb-000011
2、取33-羟基-连翘脂素葡萄糖醛酸苷、山楂提取物、当归提取物，用乙醇溶解后加入葡萄糖糖浆，最终加去离子水至100ml，即得。
实施例15 9-羟基-连翘脂素葡萄糖醛酸苷片剂
1、按照如下配比准备原料
Figure PCTCN2016079842-appb-000012
2、将9-羟基-连翘脂素葡萄糖醛酸苷和淀粉混合均匀后，制成颗粒，加入滑石粉和硬脂酸镁混合均匀后压制成10000片。
实施例16 9-羟基-连翘脂素葡萄糖醛酸苷胶囊剂
1、按照如下配比准备原料
9-羟基-连翘脂素葡萄糖醛酸苷(纯度97％)   200g
淀粉                                    1000g
2、将9-羟基-连翘脂素葡萄糖醛酸苷和淀粉混合均匀后装胶囊，制成10000粒。
实施例17 9-羟基-连翘脂素葡萄糖醛酸苷胶囊剂
1、按照如下配比准备原料
9-羟基-连翘脂素葡萄糖醛酸苷(纯度98％)   500g
淀粉                                    1000g
2、将9-羟基-连翘脂素葡萄糖醛酸苷和淀粉混合均匀后装胶囊，制成10000粒。
实施例18 9-羟基-连翘脂素葡萄糖醛酸苷片剂
1、按照如下配比准备原料
Figure PCTCN2016079842-appb-000013
2、将9-羟基-连翘脂素葡萄糖醛酸苷、黄芪提取物、维生素C和淀粉混合均匀后制粒，加入滑石粉和硬脂酸镁混匀后压制成10000片。
实施例19 9-羟基-连翘脂素葡萄糖醛酸苷胶囊剂
1、按照如下配比准备原料
Figure PCTCN2016079842-appb-000014
2、将9-羟基-连翘脂素葡萄糖醛酸苷、生大黄提取物、维生素C和淀粉混合均匀后装胶囊，制成10000粒。
实施例20 9-羟基-连翘脂素葡萄糖醛酸苷颗粒剂
1、按照如下配比准备原料
Figure PCTCN2016079842-appb-000015
2、将9-羟基-连翘脂素葡萄糖醛酸苷、莪术提取物、维生素C和蔗糖粉混合均匀制成颗粒后装袋，制成10000袋。
实施例21 9-羟基-连翘脂素葡萄糖醛酸苷口服液
1、按照如下配比准备原料
Figure PCTCN2016079842-appb-000016
2、取9-羟基-连翘脂素葡萄糖醛酸苷、山楂提取物、当归提取物，用乙醇溶解后加入葡萄糖糖浆，最终加去离子水至100ml，即得。
实施例22 33，34-亚甲基二氧-连翘脂素葡萄糖醛酸苷片剂
1、按照如下配比准备原料
Figure PCTCN2016079842-appb-000017
2、将33，34-亚甲基二氧-连翘脂素葡萄糖醛酸苷和淀粉混合均匀后，制成颗粒，加入滑石粉和硬脂酸镁混合均匀后压制成10000片。
实施例23 33，34-亚甲基二氧-连翘脂素葡萄糖醛酸苷胶囊剂
1、按照如下配比准备原料
33，34-亚甲基二氧-连翘脂素葡萄糖醛酸苷(纯度97％)   200g
淀粉                                       1000g
2、将33，34-亚甲基二氧-连翘脂素葡萄糖醛酸苷和淀粉混合均匀后装胶囊，制成10000粒。
实施例24 33，34-亚甲基二氧-连翘脂素葡萄糖醛酸苷胶囊剂
1、按照如下配比准备原料
33，34-亚甲基二氧-连翘脂素葡萄糖醛酸苷(纯度98％)   500g
淀粉                                       1000g
2、将33，34-亚甲基二氧-连翘脂素葡萄糖醛酸苷和淀粉混合均匀后装胶囊，制成10000粒。
实施例25 33，34-亚甲基二氧-连翘脂素葡萄糖醛酸苷片剂
1、按照如下配比准备原料
Figure PCTCN2016079842-appb-000018
2、将33，34-亚甲基二氧-连翘脂素葡萄糖醛酸苷、黄芪提取物、维生素C和淀粉混合均匀后制粒，加入滑石粉和硬脂酸镁混匀后压制成10000片。
实施例26 33，34-亚甲基二氧-连翘脂素葡萄糖醛酸苷胶囊剂
1、按照如下配比准备原料
Figure PCTCN2016079842-appb-000019
2、将33，34-亚甲基二氧-连翘脂素葡萄糖醛酸苷、生大黄提取物、维生素C和淀粉混合均匀后装胶囊，制成10000粒。
实施例27 33，34-亚甲基二氧-连翘脂素葡萄糖醛酸苷颗粒剂
1、按照如下配比准备原料
Figure PCTCN2016079842-appb-000020
2、将33，34-亚甲基二氧-连翘脂素葡萄糖醛酸苷、莪术提取物、维生素C和蔗糖粉混合均匀制成颗粒后装袋，制成10000袋。
实施例28 33，34-亚甲基二氧-连翘脂素葡萄糖醛酸苷颗粒剂
1、按照如下配比准备原料
Figure PCTCN2016079842-appb-000021
2、将33，34-亚甲基二氧-连翘脂素葡萄糖醛酸苷、莪术提取物、维生素C和蔗糖粉混合均匀制成颗粒后装袋，制成10000袋。
实施例29 33，34-亚甲基二氧-连翘脂素葡萄糖醛酸苷口服液
1、按照如下配比准备原料
Figure PCTCN2016079842-appb-000022
2、取33，34-亚甲基二氧-连翘脂素葡萄糖醛酸苷、山楂提取物、当归提取物，用乙醇溶解后加入葡萄糖糖浆，最终加去离子水至100ml，即得。
实施例30 连翘苷和连翘脂素组合物片剂制备
1、按照如下配比制备连翘苷/连翘脂素组合物的片剂：
Figure PCTCN2016079842-appb-000023
2、取连翘苷490g、连翘脂素10g与淀粉混合均匀后，制成颗粒，加入滑石粉和硬脂酸镁混合均匀后压制成10000片。
实施例31 连翘苷/连翘脂素组合物颗粒剂制备
1、按照如下配比制备连翘苷/连翘脂素组合物的颗粒剂：
连翘苷/连翘脂素组合物(两者重量比为98:2)           100g
微晶纤维素                                        10000g
2、取连翘苷98g、连翘脂素2g与微晶纤维素混合均匀后，制成颗粒装袋，制成10000袋。
实施例32 连翘苷/连翘脂素组合物胶囊剂制备
1、按照如下配比制备连翘苷/连翘脂素组合物的胶囊剂：
连翘苷/连翘脂素组合物(两者重量比为98:2)        250g
淀粉                                           2500g
2、取连翘苷245g、连翘脂素5g与淀粉混合均匀后装胶囊，制成10000粒。
实施例33-36 连翘苷/连翘脂素组合物胶囊剂制备
实施例33-36中，连翘苷/连翘脂素组合物分别按下表的重量比与淀粉混合均匀后装胶囊，各制成10000粒胶囊。
Figure PCTCN2016079842-appb-000024
实施例:37-40 连翘苷/连翘脂素组合物颗粒剂制备
实施例37-30中，连翘苷/连翘脂素组合物分别按下表的重量比与微晶纤维素混合均匀后，制成颗粒装袋，制成10000袋。
Figure PCTCN2016079842-appb-000025
实施例41 连翘苷/连翘脂素组合物片剂制备
1、按照如下配比制备连翘苷/连翘脂素组合物的片剂：
Figure PCTCN2016079842-appb-000026
2、称取连翘苷490g、连翘脂素10g与生姜提取物粉末混合均匀，再与淀粉混合均匀后 制成颗粒，加入滑石粉和硬脂酸镁混合均匀后压制成10000片。
实施例42 连翘苷/连翘脂素组合物颗粒剂制备
1、按照如下配比制备连翘苷/连翘脂素组合物的颗粒剂：
Figure PCTCN2016079842-appb-000027
2、取连翘苷245g、连翘脂素5与上丹参提取物、当归提取物粉末混合均匀，再与微晶纤维素混合均匀后制成颗粒装袋，制成10000袋。
实施例43 连翘苷/连翘脂素组合物胶囊剂制备
1、按照如下配比制备连翘苷/连翘脂素组合物的胶囊剂：
Figure PCTCN2016079842-appb-000028
2、连翘苷245g、连翘脂素5g与黄芪提取物、丹参提取物粉末混合均匀，再与淀粉混合均匀后装胶囊，制成10000粒。
实施例44 连翘苷/连翘脂素组合物片剂制备
1、按照如下配比制备连翘苷/连翘脂素组合物的片剂：
Figure PCTCN2016079842-appb-000029
2、取连翘苷490g、连翘脂素10g与当归提取物粉末混合均匀，再与淀粉混合均匀后制成颗粒，然后加入滑石粉和硬脂酸镁混合均匀后压，制成10000片。
实施例45 连翘苷/连翘脂素组合物颗粒剂制备
1、按照如下配比制备连翘苷/连翘脂素组合物的颗粒剂：
Figure PCTCN2016079842-appb-000030
Figure PCTCN2016079842-appb-000031
2、取连翘苷900g、连翘脂素100g与上述提取物(莪术、三七提取物)粉末混合均匀，再与微晶纤维素混合均匀后制成颗粒装袋，制成10000袋。
实施例46 连翘苷/连翘脂素组合物胶囊剂制备
1、按照如下配比制备连翘苷/连翘脂素组合物的胶囊剂：
Figure PCTCN2016079842-appb-000032
2、连翘苷1880g、连翘脂素120g与上述提取物(白僵蚕、生大黄、生姜提取物)粉末混合均匀，再与淀粉混合均匀后装胶囊，制成10000粒。
试验例1 连翘苷、连翘苷衍生物、连翘苷/连翘脂素组合物对高血脂大鼠的影响
1 材料与方法
1.1 实验动物
雄性Wistar大鼠，清洁级，体重180-220g，由辽宁中医药大学实验动物中心提供。合格证号：辽实动字第(2000)042号。
1.2 仪器与设备
7600型全自动生化分析仪(日本日立公司)；AR2140电子分析天平(上海奥豪斯公司)；LD4-2型离心机(常州国华电器有限公司)；HH-4数显恒温水浴锅(常州国华电器有限公司)；DW-2型恒温调热器(江苏南通县教学仪器二厂)；ZDHW调温电热套(北京中兴伟业仪器有限公司)。
1.3 试剂
甘油三酯检测试剂盒(北京九强生物有限公司)；总胆固醇检测试剂盒(北京九强生物有限公司)；高密度脂蛋白胆固醇检测试剂盒(上海科华生物工程有限公司)；低密度脂蛋白胆固醇检测试剂盒(上海科华生物工程有限公司)；胆固醇[中国医药(集团)上海化学试剂公司]；丙硫氧嘧啶(沈阳东北大药房)；猪油(沈阳市五一市场售板油炼制)；95％药用酒精(沈阳卫龙商贸有限公司)；20％乌拉坦溶液(辽宁中医药大学药理教研室提供)。
1.4 动物饲料
基础饲料(辽宁中医药大学实验动物中心提供)；普通饲料的配比如下：面粉19％；玉米面23％；高粱粉6％；麸皮10％；大豆粕15％；植物油2％；鱼肝油1％；鱼粉10％；骨粉1％；啤酒酵母1％；食盐1％；淀粉6.6％；甘氨酸3.4％；蛋氨酸0.5％；碳酸钙0.5％。
1.5 实验药物
连翘苷(含量＞98％)，白色粉末，大连富生天然药物开发有限公司生产，批号：20130303。经高效液相色谱两种检测器紫外检测器和蒸发光散射检测器面积归一化法测定，其纯度为99.5％，并用中国药品生物制品含量测定用连翘苷对照品标定和确认其含量为99.5％。
33-羟基-连翘脂素葡萄糖醛酸苷(连翘苷衍生物A，含量＞98％)，白色粉末，大连富生天然药物开发有限公司生产，批号：20130301。经高效液相色谱两种检测器紫外检测器和蒸发光散射检测器面积归一化法测定，其纯度为98.5％。
9-羟基-连翘脂素葡萄糖醛酸苷(连翘苷衍生物B，含量＞98％)，白色粉末，大连富生天然药物开发有限公司生产，批号：20130302。经高效液相色谱两种检测器紫外检测器和蒸发光散射检测器面积归一化法测定，其纯度为99.2％。
33，34-亚甲基二氧-连翘脂素葡萄糖醛酸苷(连翘苷衍生物C，含量＞98％)，白色粉末，大连富生天然药物开发有限公司生产，批号：20130301。经高效液相色谱两种检测器紫外检测器和蒸发光散射检测器面积归一化法测定，其纯度为98.7％。
连翘苷/连翘脂素组合物A，连翘苷(含量＞98％)，白色粉末，大连富生天然药物开发有限公司生产，批号：20130303；连翘脂素(含量＞98％)，白色粉末，大连富生天然药物开发有限公司生产，批号：20130301；连翘苷与连翘脂素的重量之比为98：2。
连翘苷/连翘脂素组合物B，连翘苷(含量＞98％)，白色粉末，大连富生天然药物开发有限公司生产，批号：20130303；连翘脂素(含量＞98％)，白色粉末，大连富生天然药物开发有限公司生产，批号：20130301；连翘苷与连翘脂素的重量之比为89：11。
2 实验方法
2.1 剂量选择
根据受试物的人体推荐用量及样品的最大可能灌胃剂量设置3个连翘苷实验组，即连翘苷低、中、高剂量组，剂量分别为480、960、1980mg/kg；
连翘苷衍生物A、B、C分别设置3个连翘苷衍生物实验组，即连翘苷衍生物A低、中、高剂量组，剂量分别为480、960、1980mg/kg；连翘苷衍生物B低、中、高剂量组，剂量分别为480、960、1980mg/kg；连翘苷衍生物C低、中、高剂量组，剂量分别为480、960、1980mg/kg；
连翘苷/连翘脂素组合物A、B分别设置3个连翘苷/连翘脂素实验组，即连翘苷/连翘脂素A低、中、高剂量组，剂量分别为480、960、1980mg/kg；连翘苷/连翘脂素B低、中、高剂量组，剂量分别为480、960、1980mg/kg。
另设连翘脂素组(剂量为1980mg/kg)，空白对照组和肥胖模型对照组(以下称“模型对照组”)。
2.2 动物分组
将雄性Wistar大鼠常规饲养1周后分为21组，每组8只，分别为空白对照组、模型对照组、给药组即连翘脂素组、连翘苷组(低，中，高三个剂量组)、连翘苷衍生物A、B、C(低，中，高三个剂量组)、连翘苷/连翘脂素组合物A、B(低，中，高三个剂量组)。
空白对照组大鼠给以常规饲料，喂食普通基础饲料；模型对照组大鼠从实验第1天起给予普通基础饲料外，每日按体重灌胃给予含2％胆固醇、2％丙硫氧嘧啶的猪油；其余各药物组从实验第1天起给予普通基础饲料外，每日按体重灌胃给予含2％胆固醇、2％丙硫氧嘧啶的猪油，给药组灌胃猪油4-5h后，按体重分别灌服相应剂量的药物，连续喂饲16天，于当晚先称体重后将所有大鼠禁食12h，并于次日用20％的乌拉坦溶液将所有的动物麻醉后于颈动脉取血，测血清中胆固醇(TC)、甘油三酯(TG)、低密度脂蛋白(LDL)、高密度脂蛋白(HDL)含量等指标。
3 实验结果
大鼠颈动脉血液生化检测结果见表1。统计学处理用Sigma Plot l0.0完成。
表1 连翘苷、连翘苷衍生物、连翘苷/连翘脂素对高血脂大鼠血清的影响
Figure PCTCN2016079842-appb-000033
Figure PCTCN2016079842-appb-000034
Figure PCTCN2016079842-appb-000035
以上实验结果表明，连翘苷、连翘苷衍生物、连翘苷与连翘脂素组合物能明显降低饮食性高血脂大鼠的TC水平，本发明实验药物组血清TC明显低于模型组。连翘苷、连翘苷衍生物、连翘苷与连翘脂素组合物对大鼠血清中TC、LDL等含量的上升均有很明显的抑制作用，同时实验药物组与造模组相比，其HDL含量大部分有所提高，证明连翘苷、连翘苷衍生物、连翘苷与连翘脂素组合物有显著降低大鼠高血酯作用。
连翘脂素无治疗高血脂症的作用，连翘苷/连翘脂素组合物在治疗高血脂症中二者具有协同增效作用，能显著抑制饮食性高血脂症，明显抑制血清中的TC、TG、LDL、HDL含量的上升，显著降低TC、TG、LDL、HDL含量，对于饮食性高血脂症具有明显预防和治疗效果。

Claims (10)

  1. 连翘苷、连翘苷衍生物、连翘苷与连翘脂素组合物在制备用于预防或/和治疗高血脂症的药物或保健品中的应用。
  2. 根据权利要求1所述的应用，其特征是所述药物由连翘苷、连翘苷衍生物、连翘苷与连翘脂素组合物和药学上可接受的载体组成。
  3. 根据权利要求1或2所述的应用，其特征是所述药物以片剂、胶囊剂、丸剂、散剂、颗粒剂、糖浆剂、溶液剂形式存在。
  4. 根据权利要求1或2所述的应用，其特征是所述连翘苷、连翘苷衍生物的纯度为≥1％；连翘苷与连翘脂素的组合物的含量≥1％。
  5. 根据权利要求4所述的应用，其特征是所述的连翘苷、连翘苷衍生物的纯度为1％～98％；连翘苷与连翘脂素的组合物的含量为1％～98％。
  6. 一种防或/和治疗高血脂症的药物或保健品，其特征是含有连翘苷、连翘苷衍生物或连翘苷与连翘脂素的组合物。
  7. 根据权利要求6所述的药物或保健品，其特征是所述的连翘苷、连翘苷衍生物的纯度为≥1％；连翘苷与连翘脂素的组合物的含量≥1％。
  8. 根据权利要求6所述的药物或保健品，其特征是所述连翘苷、连翘苷衍生物、连翘苷与连翘脂素组合物的重量与所述药物或保健品的总重量之比为0.01-10：100。
  9. 根据权利要求6所述的药物或保健品，其特征是所述连翘苷与连翘脂素组合物选择连翘脂素和连翘苷与α-、β-或γ-环糊精或其衍生物相混合而成的混合物，或连翘脂素和连翘苷与α-、β-或γ-环糊精或其衍生物经物理、化学方法处理形成的复合物。
  10. 根据权利要求6所述的药物或保健品，其特征是还包括丹参提取物、山楂提取物、黄芪提取物、当归提取物、山七提取物、莪术提取物、生姜提取物、生大黄提取物、白僵蚕提取物、维生素C及其衍生物或维生素E及其衍生物中的一种或多种。
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