WO2022237873A1 - Pharmaceutical composition for preventing and treating osteoporosis - Google Patents
Pharmaceutical composition for preventing and treating osteoporosis Download PDFInfo
- Publication number
- WO2022237873A1 WO2022237873A1 PCT/CN2022/092472 CN2022092472W WO2022237873A1 WO 2022237873 A1 WO2022237873 A1 WO 2022237873A1 CN 2022092472 W CN2022092472 W CN 2022092472W WO 2022237873 A1 WO2022237873 A1 WO 2022237873A1
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- WIPO (PCT)
- Prior art keywords
- extract
- osteoporosis
- spatholobus
- ligustrum lucidum
- eclipta
- Prior art date
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Images
Classifications
-
- 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)
- A61K36/21—Amaranthaceae (Amaranth family), e.g. pigweed, rockwort or globe amaranth
-
- 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)
- A61K36/28—Asteraceae or Compositae (Aster or Sunflower family), e.g. chamomile, feverfew, yarrow or echinacea
-
- 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
- A61K36/486—Millettia
-
- 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
- A61K36/638—Ligustrum, e.g. Chinese privet
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/10—Laxatives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
Definitions
- the invention belongs to the field of traditional Chinese medicine and relates to a pharmaceutical composition, in particular to a pharmaceutical composition for treating and/or preventing osteoporosis.
- Osteoporosis is a systemic bone metabolic disease caused by multiple factors, characterized by decreased bone mass per unit volume and destruction of bone tissue microstructure, resulting in increased bone fragility and susceptibility to fracture.
- the National Institutes of Health defines osteoporosis as a skeletal disease characterized by impaired bone strength, microarchitectural degeneration of bone tissue (trabecular bone of cancellous bone becomes thinner, broken, and reduced in number) and increased risk of fracture. It is a comprehensive reflection of bone density and bone quality.
- Osteoporosis can be divided into two categories: primary OP and secondary OP. Both postmenopausal OP and senile OP belong to primary OP. Patients with osteoporosis generally have no special clinical manifestations, but severe hip, Fractures of the vertebral body or distal radius.
- OP treatment drugs include estrogens, bone resorption inhibitors, bone formation accelerators, and bone mineralizers.
- Perimenopause is a special stage that women must go through. During this period, women's ovarian function declines and estrogen levels drop, causing multi-system dysfunction such as the endocrine system, cardiovascular system, and nervous system, causing a series of symptoms of varying degrees collectively known as perimenopausal syndrome (Perimenopausal Syndrome, PS) .
- perimenopausal Syndrome PS
- the specific manifestations of perimenopausal syndrome vary from person to person, and most symptoms can be improved through self-regulation and psychological counseling [1] .
- perimenopausal osteoporosis as a very serious complication of perimenopausal syndrome, will not only bring great harm to women's psychology and physiology, but even endanger the lives of patients [2] .
- the number of perimenopausal women suffering from osteoporosis accounts for about 25% of the total number of perimenopausal women in my country. Its onset is characterized by a long course of disease, and it is not easy to be detected in the early stage. It will not be paid attention until severe bone pain, vertebral degeneration or even fracture occurs, and the prognosis is poor, which is very likely to cause lifelong disability or even death of the patient [3,4] .
- estrogen replacement therapy is commonly used clinically to treat perimenopausal osteoporosis.
- the curative effect is good but there are many adverse reactions.
- Research results show that long-term use of estrogen therapy will increase the incidence of breast cancer and endometrial cancer, and at the same time increase the risk of stroke, coronary arteriosclerosis, pulmonary embolism and deep vein thrombosis [5-7] .
- other types of drugs for the treatment of osteoporosis will also cause different types of adverse reactions, which may even endanger the lives of patients. Therefore, Chinese medicine has gradually entered people's sight because of its good therapeutic effect, small side effects and good compliance, and the research on Chinese medicine treatment of perimenopausal diseases has attracted increasing attention.
- Erzhi Fang is composed of Ligustrum lucidum and Eclipta chinensis.
- the fruit of Ligustrum lucidum is used as medicine, which is harvested during the winter solstice, while the whole herb of Eclipta edulis is used as medicine, which is harvested during the summer solstice; the pills are called Erzhi pills.
- Ligustrum lucidum often uses wine Ligustrum lucidum, that is, the processed product of Ligustrum lucidum.
- Erzhi Fang has the functions of nourishing the liver and kidney, nourishing yin and stopping bleeding.
- Erzhi Fang mainly include immune regulation, anti-oxidation, anti-aging, liver protection, anti-osteoporosis, anti-inflammatory, anti-tumor, hormone-like effects, etc. [8] .
- Ligustrum lucidum in the prescription is the fruit of privet privet of Osmanthus fragrans. It is sweet in taste and cool in nature. It returns to the liver and kidney meridian. The treatment of sore knees, premature graying of beard and hair, and blurred eyesight. Modern studies have shown that Ligustrum lucidum is rich in medicinal substances, mainly including triterpenoids, iridoids, phenethyl alcohols, flavonoids, Ligustrum lucidum polysaccharides, etc., and the 2015 edition of "Chinese Pharmacopoeia" will The iridoid glycoside compound privetin is used as the quality detection component of Ligustrum lucidum [9] .
- Eclipta (commonly known as Eclipta) is the whole herb of the Compositae plant, which is sweet and sour, cool in nature, and returns to the liver and kidney meridians. It has the effects of nourishing liver and kidney, cooling blood and stopping bleeding, and is mainly used for the treatment of diseases such as cooling blood, stopping bleeding, nourishing kidney, and benefiting yin. Modern studies have shown that its medicinal substances mainly include flavonoids, triterpenes and their derivatives, vanillin compounds, thiophenes, steroids, and volatile oils. The 2015 edition of the "Chinese Pharmacopoeia" used the vanillin compound wedelolide as the quality detection component of Eclipta japonica [10] .
- Spatholobus is a commonly used traditional Chinese medicine for promoting blood circulation and removing blood stasis. It belongs to the liver and kidney channels. "Compendium of Materia Medica” points out that "Spathiphyllum japonica, promotes blood circulation and relaxes tendons, treats dry blood labor of men and women, and all fatigue injuries.". Clinically, it is mainly used for irregular menstruation, blood deficiency and chlorosis, numbness and paralysis, and rheumatic arthralgia.
- Spatholobus is complex, containing ten types of flavans (such as catechin), terpenoids (such as lupeol), sterols ( ⁇ -sitosterol), anthraquinones (such as emodin), etc. other types of compounds.
- flavans such as catechin
- terpenoids such as lupeol
- sterols ⁇ -sitosterol
- anthraquinones such as emodin
- Achyranthes bidentata is the root of Achyranthes bidentata plant of Amaranthaceae. Bitter, sour, flat in nature, it returns to the liver and kidney meridian, and has the effects of nourishing the liver and kidney, strengthening muscles and bones, promoting blood circulation and stimulating menstruation, leading qi and blood to descend, diuresis and treating stranguria. It was first recorded in "Shen Nong's Materia Medica”: "It is mainly used for cold-damp impotence, spasms of limbs, knee pain that cannot be flexed and stretched, expels blood, hurts heat and burns, and long-term use makes light of body and endures old age.”
- the present inventor has obtained a pharmaceutical composition for preventing and treating diseases such as osteoporosis and an extract thereof.
- the inventors surprisingly found that the drug combination or its extract can effectively prevent and treat osteoporosis, especially perimenopausal osteoporosis, prevent and treat constipation and/or lower blood lipid.
- the effect of the pharmaceutical composition or extract of the invention is better than that of Erzhi Fang (Erzhi Pill), and the safety of long-term use is good.
- One aspect of the present invention relates to a pharmaceutical composition
- a pharmaceutical composition comprising:
- the pharmaceutical composition includes:
- the unit dose of the pharmaceutical composition is 10-60g, preferably 15-40g, 20-30g, 22-28g or 24-26g, more preferably 25g.
- various medicinal materials for example, 2, 3 or 4 of them
- the pharmaceutical composition is composed of the above four herbs.
- the pharmaceutical composition is composed of the above four herbs and pharmaceutically acceptable excipients.
- Another aspect of the present invention relates to an extract prepared from any one of the pharmaceutical compositions of the present invention.
- the extract is prepared by a preparation method comprising the following steps:
- the extract is characterized by any one or more of the following items 1-8:
- step (1) the extraction is one or more times, and when it is multiple times, the extracts of each time are combined;
- step (1) extract the mixture of Ligustrum lucidum, Eclipta chinensis, Caulis Spatholobus and Achyranthes bidentata; or extract any 1 flavor and the mixture of the remaining 3 flavors to obtain the respective extracts, combined or not Each extract; or extract the mixture of any 2 flavors and the mixture of the remaining 2 flavors separately to obtain the extracts, combine or not combine the extracts; or extract any 1 flavor, the other 1 flavor and the mixture of the remaining 2 flavors extracting separately to obtain each extract, merging or not merging each extract; or extracting 4 medicinal materials separately to obtain each extract, merging or not merging each extract;
- the concentration of the ethanol is 10%-99%, 20%-90%, 30%-80%, 40%-80%, 50%-80%, 50%-70% or 60% %-80%;
- step (1) the extraction is reflux extraction or decoction
- step (1) the extraction time is at least 0.5 hour, at least 1 hour, at least 2 hours or 1-5 hours;
- step (1) the consumption of water or ethanol solution is 5-20 times the amount (ml/g), preferably 8-16 times the amount;
- step (2) the concentration is concentration under reduced pressure
- the concentrate is an extract.
- the extract wherein, in step (2), the concentrate is one or more (eg 2, 3 or 4).
- the concentrate is one or more (eg 2, 3 or 4).
- the extract wherein Ligustrum lucidum and Eclipta chinensis are respectively extracted to obtain Ligustrum lucidum concentrate and Eclipta edulis extract; Extract with the mixture of Spatholobus Spatholobus and Achyranthes bidentata to obtain the concentrate of Ligustrum lucidum Spatholobus Spatholobus and Achyranthes bidentata; the three obtained concentrates are the extracts of the present invention.
- the extract wherein,
- Step (1) comprises the following steps:
- step (2) comprises the steps of:
- Ligustrum lucidum extract Concentrate the Ligustrum lucidum extract, the Eclipta chinensis extract and the Ligustrum lucidum Caulis Spatholobus Achyranthes extract respectively and then mix or combine the extracts and then concentrate to obtain the extract.
- Another aspect of the present invention relates to a pharmaceutical preparation, which comprises the extract described in any one of the present invention, and one or more pharmaceutically acceptable excipients;
- the unit dose of the pharmaceutical preparation is 10-60 g, preferably 15-40 g or 20-30 g, more preferably 25 g, calculated according to the mass of the crude drug.
- the pharmaceutical preparation wherein the extract is the only active ingredient.
- the pharmaceutical preparation consists of the extract and one or more pharmaceutically acceptable excipients.
- the pharmaceutical preparation is a pill, tablet, granule, capsule, tincture or suspension.
- the pharmaceutical preparation further comprises one or more selected from the following drugs:
- Calcium calcium, vitamin D, bisphosphonates, estrogens such as estradiol, estrogen receptor modulators, calcitonin, parathyroid hormone, and osteoprotegerin.
- the extract according to any one of the present invention or the pharmaceutical preparation according to any one of the present invention is used for treating and/or preventing osteoporosis , perimenopausal syndrome, constipation or obesity or hypolipidemia;
- the osteoporosis is primary osteoporosis or secondary osteoporosis;
- the osteoporosis is postmenopausal osteoporosis or senile osteoporosis;
- the osteoporosis is perimenopausal osteoporosis
- the obesity is climacteric obesity.
- Yet another aspect of the present invention relates to a combination pharmaceutical product comprising a first product and a second product in separate packages,
- the first product comprises the pharmaceutical composition according to any one of the present invention, the extract according to any one of the present invention or the pharmaceutical preparation according to any one of the present invention;
- the second product contains one or more selected from the following drugs:
- the second product further comprises one or more pharmaceutically acceptable excipients
- the unit dose of the first product is 10-60g, preferably 15-40g or 20-30g, more preferably 25g, calculated according to the mass of the crude drug.
- Another aspect of the present invention relates to the pharmaceutical composition described in any one of the present invention, the extract described in any one of the present invention or the pharmaceutical preparation described in any one of the present invention in preparation treatment and/or prophylaxis Osteoporosis, perimenopausal syndrome, constipation or obesity drugs, or the use of blood lipid-lowering drugs;
- the osteoporosis is primary osteoporosis or secondary osteoporosis;
- the osteoporosis is postmenopausal osteoporosis or senile osteoporosis;
- the osteoporosis is perimenopausal osteoporosis
- the obesity is climacteric obesity.
- the use, wherein the dosage per kilogram of body weight per day is 0.1g-2g, 0.2g-1g or 0.4g-0.8g, preferably 0.5g.
- Another aspect of the present invention relates to a method for preparing an extract, comprising the steps of:
- the preparation method is characterized in that any one or more of the following items 1-8:
- step (1) the extraction is one or more times, and when it is multiple times, the extracts of each time are combined;
- step (1) extract the mixture of Ligustrum lucidum, Eclipta chinensis, Caulis Spatholobus and Achyranthes bidentata; or extract any 1 flavor and the mixture of the remaining 3 flavors to obtain the respective extracts, combined or not Each extract; or extract the mixture of any 2 flavors and the mixture of the remaining 2 flavors separately to obtain the extracts, combine or not combine the extracts; or extract any 1 flavor, the other 1 flavor and the mixture of the remaining 2 flavors extracting separately to obtain each extract, merging or not merging each extract; or extracting 4 medicinal materials separately to obtain each extract, merging or not merging each extract;
- the concentration of the ethanol is 10%-99%, 20%-90%, 30%-80%, 40%-80%, 50%-80%, 50%-70% or 60% %-80%;
- step (1) the extraction is reflux extraction or decoction
- the extraction time is at least 0.5 hour, at least 1 hour, at least 2 hours or 1-5 hours;
- step (1) the consumption of water or ethanol solution is 5-20 times the amount (ml/g), preferably 8-16 times the amount;
- step (2) the concentration is concentration under reduced pressure
- the concentrate is an extract.
- Step (1) comprises the following steps:
- step (2) comprises the steps of:
- Ligustrum lucidum extract Concentrate the Ligustrum lucidum extract, the Eclipta chinensis extract and the Ligustrum lucidum Caulis Spatholobus Achyranthes extract respectively and then mix or combine the extracts and then concentrate to obtain the extract.
- the ethanol solution involved in the present invention refers to the aqueous solution of ethanol unless otherwise specified.
- the concentration of the ethanol or the concentration of the ethanol solution is the volume percent concentration (v/v)%.
- Erzhi Fang refers to a prescription composed of Ligustrum lucidum and Eclipta chinensis (commonly known as Eclipta), and the term “Erzhi Wan” refers to a preparation obtained through industrial production.
- the pharmaceutical composition or extract of the present invention is also sometimes referred to as Jiawei Erzhifang.
- the pharmaceutical preparation of the present invention contains 0.1% by weight to 90% by weight of the extract of the present invention as the main ingredient.
- Pharmaceutical formulations can be prepared according to methods known in the art.
- the main drug can be combined with one or more solid or liquid pharmaceutical excipients and/or adjuvants to prepare an appropriate administration form or dosage form for human use.
- adjuvant in this application refers to the excipient or vehicle used to administer the main drug, which includes but not limited to diluents, disintegrating agents, precipitation inhibitors, surfactants, glidants, viscose Mixtures, lubricants, coating materials, etc. Excipients are generally described in “Remington's Pharmaceutical Sciences” by E.W. Martin.
- excipients include, but are not limited to, aluminum monostearate, aluminum stearate, carboxymethylcellulose, sodium carboxymethylcellulose, crospovidone, glyceryl isostearate, glyceryl monostearate, Hydroxyethyl Cellulose, Hydroxy Methyl Cellulose, Hydroxy Octacyl Hydroxystearate, Hydroxy Propyl Cellulose, Hydroxy Propyl Methyl Cellulose, Lactose, Lactose Monohydrate, Magnesium Stearate, Mannitol , microcrystalline cellulose, etc.
- the extracts of the present invention can be formulated into pharmaceutical preparations, including dosage forms suitable for oral administration, dosage forms suitable for parenteral injection (such as intravenous injection, subcutaneous injection) (such as as a solution), dosage forms suitable for topical administration (for example as an ointment, patch or cream), and formulations suitable for rectal administration (for example as a suppository) and the like.
- dosage forms suitable for oral administration dosage forms suitable for parenteral injection (such as intravenous injection, subcutaneous injection) (such as as a solution), dosage forms suitable for topical administration (for example as an ointment, patch or cream), and formulations suitable for rectal administration (for example as a suppository) and the like.
- Another aspect of the present invention relates to a method for treating and/or preventing osteoporosis, perimenopausal syndrome, constipation or obesity or lowering blood lipids, comprising administering an effective amount of any of the present invention to a subject in need Steps of one of the pharmaceutical compositions described in the present invention, the extracts described in any one of the present invention or the pharmaceutical preparations described in any one of the present invention;
- the osteoporosis is primary osteoporosis or secondary osteoporosis;
- the osteoporosis is postmenopausal osteoporosis or senile osteoporosis;
- the osteoporosis is perimenopausal osteoporosis
- the obesity is climacteric obesity.
- the method wherein the dosage per kilogram of body weight per day is 0.1g-2g, 0.2g-1g or 0.4g-0.8g, preferably 0.5g.
- the pharmaceutical preparations according to the invention can be administered once or several times a day in different doses.
- the dosage depends on many factors, such as the severity of the osteoporosis to be treated or prevented, the sex, age, body weight and individual response of the patient, the route of administration and the frequency of administration, etc.
- the above dose can be administered as a single dose or divided into several, eg two, three or four doses.
- the actual dosage level of the principal ingredient (extract) in the pharmaceutical formulations of the present invention can be varied to effectively achieve the desired therapeutic response for a particular patient, composition and mode of administration. Dosage levels will be selected based on the route of administration, the severity of the condition being treated and the condition and previous medical history of the patient being treated. However, it is the practice in the art to start doses below that required to obtain the desired therapeutic effect and to gradually increase the dosage until the desired effect is obtained.
- the term "effective amount” refers to a dose that can achieve treatment, prevention, alleviation and/or alleviation of the diseases or conditions described in the present invention in a subject.
- the present invention achieves any one or more of the following technical effects (1)-(6):
- the pharmaceutical composition or extract of the present invention can effectively treat or prevent osteoporosis.
- composition or extract of the present invention can effectively treat or prevent constipation.
- composition or extract of the present invention can effectively lower blood fat, treat or prevent hyperlipidemia.
- the preparation method of the present invention is superior to the traditional Erzhifang (Erzhiwan) preparation process, for example, under the same prescription, the extract prepared by the preparation method of the present invention has better anti-osteogeny Porous effects, such as better bone density.
- Figure 1 Curves of body weight of animals in each group over time.
- Figure 2 Histogram of body weight of animals in each group before sampling (before sacrifice).
- Figure 3 Histogram of liver mass index of animals in each group.
- Figure 4 Histogram of spleen index of animals in each group.
- Figure 5 Histogram of kidney indices of animals in each group.
- Figure 6 Histogram of uterine index of animals in each group.
- Figure 7 Representative hysterograms of animals in each group.
- Figure 8 Histogram of animal fat index for each group.
- Figure 9 Histogram of white fat index of animals in each group.
- Figure 10 Histogram of serum LDL-C levels of animals in each group.
- Figure 11 Histogram of bone density of animals in each group.
- Ligustrum lucidum medicinal material Take 300g of Ligustrum lucidum medicinal material, put it into a 20L round-bottomed flask, add 10L of 80% (v/v) ethanol, put it on a heating mantle for heating and reflux extraction, count from the slight boiling of the liquid, and turn off the heating mantle to cool after 2 hours , filter out the liquid in the flask with gauze, add 10L 80% ethanol again for extraction, combine the two extracts, concentrate under reduced pressure at 50°C to a thick extract, put it in a vacuum oven at 45°C for drying, and weigh.
- Preparation of the reference substance solution Accurately weigh the privetin reference substance, and dissolve it in methanol to make a reference substance solution.
- Ligustrum lucidum extract contains privetin 19.82mg/g.
- Preparation of the reference substance solution Accurately weigh the wedelia lactone reference substance, dissolve it in methanol to prepare the reference substance solution.
- the content of wedelolide in the extract of Eclipta chinensis is 0.8mg/g.
- Achyranthes bidentata decoction pieces 250g add 8 times the amount of 60% ethanol 2000ml to reflux for extraction for 2 hours, pour out the extract, then add 2000ml of 60% ethanol to reflux and extract for 2 hours, combine the two extracts, concentrate and dry to obtain 126.4g of Achyranthes bidentata extract , The cream yield is 50.6%.
- Ligustrum lucidum medicinal material Take 200g of Ligustrum lucidum medicinal material, put it in a round bottom flask, add 2400ml of 60% ethanol, heat and reflux for extraction for 2 hours, pour out the filtrate to obtain the first extract of Ligustrum lucidum, then add 2400ml of 60% ethanol, heat Reflux extraction for 2 hours, pour out the filtrate to obtain the second extract of Ligustrum lucidum, and the medicinal residue of Ligustrum lucidum for later use, combine the two extracts, concentrate and dry to obtain 48.78 g of Ligustrum lucidum extract.
- Eclipta medicinal material put in a round bottom flask, add 2000 milliliters of 70% ethanol, heat and reflux the extract for 3 hours, pour out the filtrate to obtain the first extract of Eclipta, then add 2000 milliliters of 70% ethanol, Heated and refluxed for 3 hours, poured out the filtrate to obtain the second extract of Eclipta chinensis, combined the two extracts, concentrated and dried to obtain 28.52 g of Eclipta eclipta extract.
- Ligustrum lucidum extract Mix 48.78g of Ligustrum lucidum extract, 28.52g of Eclipta chinensis extract and 67.56g of Ligustrum lucidum Caulis Spatholobus Achyranthes extract to obtain the extract of the present invention, code-named XGY.
- the inventors found that the sample prepared by the preparation method of Preparation Example 2 is conducive to the formation of the preparation and the extraction of possible active ingredients with higher content (Ligustrum lucidum polysaccharide, verbascoside and/or ecclidene glycoside A, etc.) , Better efficacy.
- any two or any three of the four medicinal materials may be mixed for extraction.
- Flavored Erzhi Prescription Group Ligustrum lucidum extract, Eclipta chinensis extract, Caulis Spatholobus extract, and Achyranthes bidentata extract were all prepared according to the method of Preparation Example 1.
- Preparation method Weigh 14.4g of Ligustrum lucidum extract, 10.65g of Eclipta officinalis extract, 7.23g of Caulis Spatholobus extract, and 12.14g of Achyranthes bidentata extract, dissolve in 0.2% CMCNa, and dilute to 100mL, as the flavored two to Prescription group administration solution. Store at 4°C.
- mice were randomly divided into a sham operation group (sham) and an operation group (OVX) according to body weight.
- sham sham
- OVX operation group
- the animals were anesthetized with tribromoethanol, the mice were fixed on the operating board, the middle and lower 1/3 of the back of the mice were depilated and skinned, disinfected with povidone iodine, and about 2 cm was cut longitudinally in the center of the bilateral backs.
- mice were given 0.1mL/10g/d orally for 8 weeks. During the period of administration, the growth of the mice was observed, and the weight was recorded every week. The whole process was fed with standard feed, and they had free access to food and water.
- Gastrointestinal administration was carried out once a day for 8 consecutive weeks, and the changes in the body weight and organs of the mice in each group were observed.
- the results showed that the weight of the mice in the Model group increased significantly, and the modified Erzhifang group could significantly reduce the castration rate.
- the body weight of the mice increased (P ⁇ 0.05). There were no significant changes in internal organs of mice in each group.
- the bone mineral density (BMD) of the mouse tibia was detected by dual-energy X-ray absorptiometry, and the results showed that, compared with the sham operation group, the bone mineral density (BMD) of the mouse tibia in the model group decreased significantly (P ⁇ 0.01).
- the administration of the modified Erzhi Fang can increase the bone density of the tibia.
- Modified Erzhi Formula Group (XGY) Ligustrum lucidum extract, Eclipta chinensis extract, and Ligustrum lucidum, Caulis Spatholobus and Achyranthes bidentata mixed extracts were all prepared according to the method of Preparation Example 2.
- Preparation method weigh 14.63g of Ligustrum lucidum extract, 8.56g of Eclipta officinalis extract, and 20.27g of mixed extract of Ligustrum lucidum and Caulis Spatholobus Achyranthes bidentata, dissolve in 0.2% CMCNa, dilute to 100mL, and use it as flavored Erzhi recipe Group (XGY) was administered the solution. Store at 4°C.
- Added flavored Erzhi formula group (XF) take the mixed medicinal materials of Ligustrum lucidum, Eclipta chinensis, Caulis Spatholobus and Achyranthes bidentata, and prepare according to the method of Preparation Example 3.
- Preparation method Weigh 42.2 g of the above-mentioned XF extract, dissolve it with 0.2% CMCNa, and dilute to 100 mL, and use it as the dosing solution of the flavored Erzhifang group (XF). Store at 4°C.
- Erzhifang Group Ligustrum lucidum extract and Eclipta chinensis extract were both prepared according to the method of Preparation Example 1.
- Preparation method Weigh 14.4 g of the above-mentioned Ligustrum lucidum extract and 10.65 g of the Eclipta chinensis extract, dissolve them in 0.2% CMCNa, and dilute to 100 mL, as the administration solution for the Erzhifang group (EZF). Store at 4°C.
- mice were randomly divided into a sham operation group (sham) and an operation group (OVX) according to body weight.
- sham sham
- OVX operation group
- the animals were anesthetized with tribromoethanol, the mice were fixed on the operating board, the middle and lower 1/3 of the back of the mice were depilated and skinned, disinfected with povidone iodine, and about 2 cm was cut longitudinally in the center of the bilateral backs.
- mice were given 0.1mL/10g/d orally for 8 weeks. During the period of administration, the growth of the mice was observed, and the weight was recorded every week. The whole process was fed with standard feed, and they had free access to food and water.
- mice serum samples were taken out from the -80°C refrigerator and equilibrated to room temperature, and the low-density lipoprotein cholesterol (LDL-C ) assay kit (batch number: 142020006) to detect LDL-C content in mouse serum.
- LDL-C low-density lipoprotein cholesterol
- the intragastric administration was carried out once a day for 8 consecutive weeks, and the changes in the body weight and organs of the mice in each group were observed. The results are shown in Figures 1 to 5.
- mice in the Model group increased significantly, and the Erzhifang group, the flavored Erzhifang group (XGY) and the flavored Erzhifang group (XF) could all significantly reduce the weight gain of castrated mice ( Figure 1 and Figure 2, P ⁇ 0.05). There were no significant changes in internal organs of the mice in each group (Fig. 3 to Fig. 5).
- the bone mineral density of the mouse femur was detected by dual-energy X-ray absorptiometry, and the results are shown in FIG. 11 .
- Bai Junli Clinical observation of hormone replacement therapy combined with alendronate sodium in the treatment of perimenopausal women with osteoporosis [J]. Clinical Medicine Practice, 2017,26(2):107-109.
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Abstract
A pharmaceutical composition for treating and/or preventing osteoporosis, the pharmaceutical composition comprising 2-8 parts by weight of Ligustri lucidi fructus, 2-8 parts by weight of Ecliptae herba, 1-5 parts by weight of Spatholobi caulis, and 1-5 parts by weight of Achyranthis bidentatae radix. The pharmaceutical composition can effectively prevent and treat osteoporosis, perimenopausal syndrome, constipation or obesity and reduce blood fat, and has a better effect than that of the Erzhi formula.
Description
本发明属于中医药领域,涉及一种药物组合物,具体地,涉及一种治疗和/或预防骨质疏松症的药物组合物。The invention belongs to the field of traditional Chinese medicine and relates to a pharmaceutical composition, in particular to a pharmaceutical composition for treating and/or preventing osteoporosis.
骨质疏松(osteoporosis,OP)是由多因素引起的一种以单位体积内骨量减少和骨组织微结构破坏为特征,从而导致骨脆性增加和易于骨折的全身性骨代谢性疾病。美国国立卫生研究院定义骨质疏松是一种以骨强度受损,骨组织微结构退化(松质骨的骨小梁变细、断裂、数目减少)和骨折危险性增加的骨骼疾病,骨强度是骨密度和骨质量的综合反映。骨质疏松可分为原发性OP和继发性OP两大类,绝经后OP和老年性OP均属于原发性OP,骨质疏松患者一般无特殊临床表现,但严重时常发生髋部、椎体或桡骨远端等处骨折。目前常用的OP治疗药物包括雌激素、骨吸收抑制剂、骨形成促进剂和骨矿化物等。Osteoporosis (Osteoporosis, OP) is a systemic bone metabolic disease caused by multiple factors, characterized by decreased bone mass per unit volume and destruction of bone tissue microstructure, resulting in increased bone fragility and susceptibility to fracture. The National Institutes of Health defines osteoporosis as a skeletal disease characterized by impaired bone strength, microarchitectural degeneration of bone tissue (trabecular bone of cancellous bone becomes thinner, broken, and reduced in number) and increased risk of fracture. It is a comprehensive reflection of bone density and bone quality. Osteoporosis can be divided into two categories: primary OP and secondary OP. Both postmenopausal OP and senile OP belong to primary OP. Patients with osteoporosis generally have no special clinical manifestations, but severe hip, Fractures of the vertebral body or distal radius. Currently commonly used OP treatment drugs include estrogens, bone resorption inhibitors, bone formation accelerators, and bone mineralizers.
围绝经期是女性必经经历的一个特殊阶段。在此期间女性因卵巢功能减退,雌激素水平下降,造成内分泌系统、心血管系统、神经系统等多系统功能紊乱,引发一系列不同程度的症状统称为围绝经期综合征(Perimenopausal Syndrome,PS)。围绝经期综合症具体表现因人而异,绝大多数症状可通过自身调节和心理疏导得到改善
[1]。但是围绝经期骨质疏松症作为围绝经期综合症中非常严重的并发症,不仅会给女性的心理和生理带来极大的伤害,甚至危及患者生命
[2]。
Perimenopause is a special stage that women must go through. During this period, women's ovarian function declines and estrogen levels drop, causing multi-system dysfunction such as the endocrine system, cardiovascular system, and nervous system, causing a series of symptoms of varying degrees collectively known as perimenopausal syndrome (Perimenopausal Syndrome, PS) . The specific manifestations of perimenopausal syndrome vary from person to person, and most symptoms can be improved through self-regulation and psychological counseling [1] . However, perimenopausal osteoporosis, as a very serious complication of perimenopausal syndrome, will not only bring great harm to women's psychology and physiology, but even endanger the lives of patients [2] .
据统计,我国围绝经期女性患骨质疏松的人数约占围绝经期总人数的25%。其发病特点是病程长,且早期不易被发觉,直到发生严重骨痛,椎骨变性甚至骨折等情况才会引起重视,而且愈后差,非常容易造成患者终生残疾甚至死亡
[3,4]。
According to statistics, the number of perimenopausal women suffering from osteoporosis accounts for about 25% of the total number of perimenopausal women in my country. Its onset is characterized by a long course of disease, and it is not easy to be detected in the early stage. It will not be paid attention until severe bone pain, vertebral degeneration or even fracture occurs, and the prognosis is poor, which is very likely to cause lifelong disability or even death of the patient [3,4] .
目前临床常用雌激素替代疗法(HRT)治疗围绝经期骨质疏松症,疗效尚佳但不良反应颇多。研究结果显示,长期服用雌激素治疗会增加乳腺癌、子宫内膜癌的发病几率,同时加重脑卒中、冠脉硬化、肺栓塞和深静脉血栓的风险
[5-7]。此外,据统计其他类型的治疗骨质疏松的药物也会造成不同类型的不良反应,严重的甚至会危及到患者生命。因此中药因其治疗效果好,毒副作用小且依从性好逐渐进入人们的视线,中药治疗围绝经期诸症的研究日益受到重视。
At present, estrogen replacement therapy (HRT) is commonly used clinically to treat perimenopausal osteoporosis. The curative effect is good but there are many adverse reactions. Research results show that long-term use of estrogen therapy will increase the incidence of breast cancer and endometrial cancer, and at the same time increase the risk of stroke, coronary arteriosclerosis, pulmonary embolism and deep vein thrombosis [5-7] . In addition, according to statistics, other types of drugs for the treatment of osteoporosis will also cause different types of adverse reactions, which may even endanger the lives of patients. Therefore, Chinese medicine has gradually entered people's sight because of its good therapeutic effect, small side effects and good compliance, and the research on Chinese medicine treatment of perimenopausal diseases has attracted increasing attention.
二至方由女贞子和墨旱莲等质量配伍组成,女贞子以果实入药,冬至时节采收,而墨旱莲以全草入药,夏至季节采收;制成丸剂称为二至丸,其中,女贞子常采用酒女贞子即女贞子的炮制品。二至方具有补益肝肾、滋阴止血之功。现代研究表明,二至方的药理作用主要包括免疫调节作用、抗氧化以及抗衰老作用、保肝作用、抗骨质疏松的作用、抗炎作用、抗肿瘤作用,激素样作用等
[8]。
Erzhi Fang is composed of Ligustrum lucidum and Eclipta chinensis. The fruit of Ligustrum lucidum is used as medicine, which is harvested during the winter solstice, while the whole herb of Eclipta edulis is used as medicine, which is harvested during the summer solstice; the pills are called Erzhi pills. Among them, Ligustrum lucidum often uses wine Ligustrum lucidum, that is, the processed product of Ligustrum lucidum. Erzhi Fang has the functions of nourishing the liver and kidney, nourishing yin and stopping bleeding. Modern studies have shown that the pharmacological effects of Erzhi Fang mainly include immune regulation, anti-oxidation, anti-aging, liver protection, anti-osteoporosis, anti-inflammatory, anti-tumor, hormone-like effects, etc. [8] .
方中女贞子为木樨草科植物女贞的果实,味甘,性凉,归肝、肾经,具有滋补肝肾,明目乌发之功,多用于肝肾阴虚,眩晕耳鸣,腰膝酸软,须发早白,目暗不明等症的治疗。现代研究表明女贞子含有丰富的药效物质主要包括三萜类化合物,环烯醚萜类化合物,苯乙醇类化合物,黄酮类化合物,女贞子多糖等,2015年版《中国药典》将环烯醚萜苷类化合物特女贞苷作为女贞子的质量检测成分
[9]。
Ligustrum lucidum in the prescription is the fruit of privet privet of Osmanthus fragrans. It is sweet in taste and cool in nature. It returns to the liver and kidney meridian. The treatment of sore knees, premature graying of beard and hair, and blurred eyesight. Modern studies have shown that Ligustrum lucidum is rich in medicinal substances, mainly including triterpenoids, iridoids, phenethyl alcohols, flavonoids, Ligustrum lucidum polysaccharides, etc., and the 2015 edition of "Chinese Pharmacopoeia" will The iridoid glycoside compound privetin is used as the quality detection component of Ligustrum lucidum [9] .
方中墨旱莲(俗称旱莲草)是菊科植物鳢肠的全草,味甘酸,性凉,归肝、肾经。具有滋补肝肾、凉血止血的功效,主要用于凉血,止血,补肾,益阴等疾病的治疗。现代研究表明其药效物质主要包括黄酮类化合物,三萜及其衍生物、香草醚类化合物、噻吩类化合物、甾体类化合物、挥发油等。2015年版《中国药典》将香草醚类化合物蟛蜞菊内酯作为墨旱莲的质量检测成分
[10]。
In the recipe, Eclipta (commonly known as Eclipta) is the whole herb of the Compositae plant, which is sweet and sour, cool in nature, and returns to the liver and kidney meridians. It has the effects of nourishing liver and kidney, cooling blood and stopping bleeding, and is mainly used for the treatment of diseases such as cooling blood, stopping bleeding, nourishing kidney, and benefiting yin. Modern studies have shown that its medicinal substances mainly include flavonoids, triterpenes and their derivatives, vanillin compounds, thiophenes, steroids, and volatile oils. The 2015 edition of the "Chinese Pharmacopoeia" used the vanillin compound wedelolide as the quality detection component of Eclipta japonica [10] .
鸡血藤是活血化瘀常用中药,归肝、肾经,具有舒筋活络、活血补血、调经止痛的功效。《本草备要》指出“鸡血藤,活血舒筋,治男女干血劳,一切虚损劳伤……”。临床主要用于月经不调,血虚萎黄,麻木瘫痪,风湿痹痛。现代研究发现,鸡血藤化学成分复杂,含有黄烷类(如儿茶素)、萜类(如羽扇豆醇)、甾醇类(β-谷甾醇)、蒽醌类(如大黄素)等十余种类型的化合物。Spatholobus Spatholobus is a commonly used traditional Chinese medicine for promoting blood circulation and removing blood stasis. It belongs to the liver and kidney channels. "Compendium of Materia Medica" points out that "Spathiphyllum japonica, promotes blood circulation and relaxes tendons, treats dry blood labor of men and women, and all fatigue injuries...". Clinically, it is mainly used for irregular menstruation, blood deficiency and chlorosis, numbness and paralysis, and rheumatic arthralgia. Modern studies have found that the chemical composition of Spatholobus is complex, containing ten types of flavans (such as catechin), terpenoids (such as lupeol), sterols (β-sitosterol), anthraquinones (such as emodin), etc. other types of compounds.
牛膝为苋科牛膝属植物牛膝的根。性苦、酸、平,归肝、肾经,具有补肝肾、强筋骨、活血通经、引气血下行、利尿通淋等功效。始载于《神农本草经》:“主寒湿痿痹,四肢拘挛,膝痛不可屈伸,逐血气,伤热火烂,久服轻身耐老。”Achyranthes bidentata is the root of Achyranthes bidentata plant of Amaranthaceae. Bitter, sour, flat in nature, it returns to the liver and kidney meridian, and has the effects of nourishing the liver and kidney, strengthening muscles and bones, promoting blood circulation and stimulating menstruation, leading qi and blood to descend, diuresis and treating stranguria. It was first recorded in "Shen Nong's Materia Medica": "It is mainly used for cold-damp impotence, spasms of limbs, knee pain that cannot be flexed and stretched, expels blood, hurts heat and burns, and long-term use makes light of body and endures old age."
目前尚需要开发更为有效的能够防治骨质疏松症等病症的药物手段。At present, there is still a need to develop more effective drug means that can prevent and treat diseases such as osteoporosis.
发明内容Contents of the invention
本发明人经过深入的研究和创造性的劳动,得到了一种防治骨质疏松症等病症的药物组合物及其提取物。本发明人惊奇地发现,该药物组合或其提取物能够有效地防治骨质疏松症特别是围绝经期骨质疏松症、防治便秘和/或降血脂。本发明的药物组合物或提取物的效果优于二至方(二至丸),长期使用的安全性良好。由此提供了下述 发明:After intensive research and creative work, the present inventor has obtained a pharmaceutical composition for preventing and treating diseases such as osteoporosis and an extract thereof. The inventors surprisingly found that the drug combination or its extract can effectively prevent and treat osteoporosis, especially perimenopausal osteoporosis, prevent and treat constipation and/or lower blood lipid. The effect of the pharmaceutical composition or extract of the invention is better than that of Erzhi Fang (Erzhi Pill), and the safety of long-term use is good. The following inventions are thus provided:
本发明的一个方面涉一种药物组合物,包括:One aspect of the present invention relates to a pharmaceutical composition comprising:
女贞子 2-8重量份Ligustrum 2-8 parts by weight
墨旱莲 2-8重量份Eclipta 2-8 parts by weight
鸡血藤 1-5重量份Spatholobus 1-5 parts by weight
牛膝 1-5重量份。Achyranthes knuckle 1-5 parts by weight.
在本发明的一些实施方式中,所述的药物组合物,其包括:In some embodiments of the present invention, the pharmaceutical composition includes:
女贞子 2-8重量份Ligustrum 2-8 parts by weight
墨旱莲 2-8重量份Eclipta 2-8 parts by weight
鸡血藤 2-4重量份Spatholobus 2-4 parts by weight
牛膝 1-3重量份;Achyranthes knuckle 1-3 parts by weight;
优选地,包括:Preferably, include:
女贞子 4-6重量份Ligustrum 4-6 parts by weight
墨旱莲 4-6重量份Eclipta 4-6 parts by weight
鸡血藤 2-4重量份Spatholobus 2-4 parts by weight
牛膝 1-3重量份;Achyranthes knuckle 1-3 parts by weight;
更优选地,包括:More preferably, including:
女贞子 4.5-5.5重量份Ligustrum 4.5-5.5 parts by weight
墨旱莲 4.5-5.5重量份Eclipta 4.5-5.5 parts by weight
鸡血藤 2.5-3.5重量份Spatholobus 2.5-3.5 parts by weight
牛膝 1.5-2.5重量份;Achyranthes knuckle 1.5-2.5 parts by weight;
进一步优选地,包括:Further preferably, including:
女贞子 4.8-5.2重量份Ligustrum 4.8-5.2 parts by weight
墨旱莲 4.8-5.2重量份Eclipta 4.8-5.2 parts by weight
鸡血藤 2.8-3.2重量份Spatholobus 2.8-3.2 parts by weight
牛膝 1.8-2.2重量份;Achyranthes knuckle 1.8-2.2 parts by weight;
特别优选地,包括:Particularly preferably, include:
女贞子 5重量份 Ligustrum 5 parts by weight
墨旱莲 5重量份 Eclipta 5 parts by weight
鸡血藤 3重量份 Spatholobus 3 parts by weight
牛膝 2重量份。 Achyranthes knuckle 2 parts by weight.
在本发明的一些实施方式中,所述的药物组合物,其单位剂量为10-60g,优选为15-40g、20-30g、22-28g或24-26g,更优选为25g。In some embodiments of the present invention, the unit dose of the pharmaceutical composition is 10-60g, preferably 15-40g, 20-30g, 22-28g or 24-26g, more preferably 25g.
本发明的药物组合物中,各味药材(例如其中的2种、3种或者4种)可以是混合的,也可以是相对独立的(不混合)。In the pharmaceutical composition of the present invention, various medicinal materials (for example, 2, 3 or 4 of them) may be mixed or relatively independent (not mixed).
在本发明的一些实施方式中,所述的药物组合物,其由上述4味药材组成。In some embodiments of the present invention, the pharmaceutical composition is composed of the above four herbs.
在本发明的一些实施方式中,所述的药物组合物,其由上述4味药材和药学上可接受的辅料组成。In some embodiments of the present invention, the pharmaceutical composition is composed of the above four herbs and pharmaceutically acceptable excipients.
本发明的另一方面涉及一种提取物,其由本发明中任一项所述的药物组合物制得。Another aspect of the present invention relates to an extract prepared from any one of the pharmaceutical compositions of the present invention.
在本发明的一些实施方式中,所述的提取物,其通过包含如下步骤的制备方法制得:In some embodiments of the present invention, the extract is prepared by a preparation method comprising the following steps:
(1)用水或乙醇溶液对前面任一项所述重量份的女贞子、墨旱莲、鸡血藤和牛膝进行提取,得到提取液;(1) Extracting the Ligustrum lucidum, Eclipta chinensis, Millipeda and Achyranthes bidentata in any one of the parts by weight described above with water or ethanol solution, to obtain an extract;
(2)将所述提取液浓缩,得到浓缩物,为提取物。(2) Concentrating the extract to obtain a concentrate, which is an extract.
在本发明的一些实施方式中,所述的提取物,其特征在于如下的①-⑧项中的任意一项或者多项:In some embodiments of the present invention, the extract is characterized by any one or more of the following items ①-⑧:
①步骤(1)中,所述提取为一次或多次,当为多次时,合并各次的提取液;1. In step (1), the extraction is one or more times, and when it is multiple times, the extracts of each time are combined;
②步骤(1)中,将女贞子、墨旱莲、鸡血藤和牛膝的混合物进行提取;或者将其中的任意1味以及其余3味的混合物分别提取得到各提取液,合并或不合并各提取液;或者将其中的任意2味的混合物以及其余2味的混合物分别提取得到各提取液,合并或不合并各提取液;或者将其中的任意1味、另外一味以及其余2味的混合物分别提取得到各提取液,合并或不合并各提取液;或者将4味药材分别提取得到各提取液,合并或不合并各提取液;② In step (1), extract the mixture of Ligustrum lucidum, Eclipta chinensis, Caulis Spatholobus and Achyranthes bidentata; or extract any 1 flavor and the mixture of the remaining 3 flavors to obtain the respective extracts, combined or not Each extract; or extract the mixture of any 2 flavors and the mixture of the remaining 2 flavors separately to obtain the extracts, combine or not combine the extracts; or extract any 1 flavor, the other 1 flavor and the mixture of the remaining 2 flavors extracting separately to obtain each extract, merging or not merging each extract; or extracting 4 medicinal materials separately to obtain each extract, merging or not merging each extract;
③步骤(1)中,所述乙醇的浓度为10%-99%、20%-90%、30%-80%、40%-80%、50%-80%、50%-70%或者60%-80%;③ In step (1), the concentration of the ethanol is 10%-99%, 20%-90%, 30%-80%, 40%-80%, 50%-80%, 50%-70% or 60% %-80%;
④步骤(1)中,所述提取为回流提取或者煎煮;④ In step (1), the extraction is reflux extraction or decoction;
⑤步骤(1)中,提取时间为至少0.5小时、至少1小时、至少2小时或者1-5小 时;5. In step (1), the extraction time is at least 0.5 hour, at least 1 hour, at least 2 hours or 1-5 hours;
⑥步骤(1)中,水或乙醇溶液的用量为5-20倍量(ml/g),优选为8-16倍量;6. In step (1), the consumption of water or ethanol solution is 5-20 times the amount (ml/g), preferably 8-16 times the amount;
⑦步骤(2)中,所述浓缩为减压浓缩;7. In step (2), the concentration is concentration under reduced pressure;
⑧步骤(2)中,所述浓缩物为浸膏。8. In the step (2), the concentrate is an extract.
在本发明的一些实施方式中,所述的提取物,其中,步骤(2)中,所述浓缩物是一种或者几种(例如2种、3种或4种)。在第②项中不合并提取液的情况下,有几种提取液,就会得到几种浓缩物;此时所述几种浓缩物为提取物。In some embodiments of the present invention, the extract, wherein, in step (2), the concentrate is one or more ( eg 2, 3 or 4). In the case of not combining extracts in item ②, if there are several extracts, several concentrates will be obtained; at this time, the several concentrates are extracts.
在本发明的一些实施方式中,所述的提取物,其中,将女贞子、墨旱莲分别提取,得到女贞子浓缩物和墨旱莲浓缩物;将女贞子提取后的药渣与鸡血藤和牛膝的混合物进行提取,得到女贞子鸡血藤牛膝浓缩物;得到的这三种浓缩物为本发明的提取物。In some embodiments of the present invention, the extract, wherein Ligustrum lucidum and Eclipta chinensis are respectively extracted to obtain Ligustrum lucidum concentrate and Eclipta edulis extract; Extract with the mixture of Spatholobus Spatholobus and Achyranthes bidentata to obtain the concentrate of Ligustrum lucidum Spatholobus Spatholobus and Achyranthes bidentata; the three obtained concentrates are the extracts of the present invention.
在本发明的一些实施方式中,所述的提取物,其中,In some embodiments of the present invention, the extract, wherein,
步骤(1)包括如下步骤:Step (1) comprises the following steps:
将女贞子、墨旱莲分别提取,得到女贞子提取液和墨旱莲提取液;将女贞子提取后的药渣与鸡血藤和牛膝的混合物进行提取,得到女贞子鸡血藤牛膝提取液;Extracting Ligustrum lucidum and Eclipta edulis separately to obtain Ligustrum lucidum extract and Eclipta edulis extract; extracting the mixture of Ligustrum lucidum extract and the mixture of Spatholobus Spatholobus and Achyranthes bidentata to obtain Ligustrum lucidum Spatholobus Spatholobus Achyranthes knuckle extract;
优选地,步骤(2)包括如下步骤:Preferably, step (2) comprises the steps of:
将女贞子提取液、墨旱莲提取液和女贞子鸡血藤牛膝提取液分别浓缩后混合或者合并各提取液后浓缩,得到提取物。Concentrate the Ligustrum lucidum extract, the Eclipta chinensis extract and the Ligustrum lucidum Caulis Spatholobus Achyranthes extract respectively and then mix or combine the extracts and then concentrate to obtain the extract.
本发明的再一方面涉及一种药物制剂,其包含本发明中任一项所述的提取物,以及一种或多种药学上可接受的辅料;Another aspect of the present invention relates to a pharmaceutical preparation, which comprises the extract described in any one of the present invention, and one or more pharmaceutically acceptable excipients;
优选地,按照生药的质量计算,所述药物制剂的单位剂量为10-60g,优选为15-40g或20-30g,更优选为25g。Preferably, the unit dose of the pharmaceutical preparation is 10-60 g, preferably 15-40 g or 20-30 g, more preferably 25 g, calculated according to the mass of the crude drug.
在本发明的一些实施方式中,所述的药物制剂,其中所述提取物为唯一活性成分。In some embodiments of the present invention, the pharmaceutical preparation, wherein the extract is the only active ingredient.
在本发明的一些实施方式中,所述的药物制剂,其由所述提取物和一种或多种药学上可接受的辅料组成。In some embodiments of the present invention, the pharmaceutical preparation consists of the extract and one or more pharmaceutically acceptable excipients.
在本发明的一些实施方式中,所述的药物制剂,其为丸剂、片剂、颗粒剂、胶囊剂、酊剂或混悬剂。In some embodiments of the present invention, the pharmaceutical preparation is a pill, tablet, granule, capsule, tincture or suspension.
在本发明的一些实施方式中,所述的药物制剂,其还包含选自如下药物中的一种或多种:In some embodiments of the present invention, the pharmaceutical preparation further comprises one or more selected from the following drugs:
钙剂、维生素D、双磷酸盐、雌激素例如雌二醇、雌激素受体调节剂、降钙素、甲状旁腺激素和骨保护素。Calcium, vitamin D, bisphosphonates, estrogens such as estradiol, estrogen receptor modulators, calcitonin, parathyroid hormone, and osteoprotegerin.
根据本发明中任一项所述的药物组合物、本发明中任一项所述的提取物或者本发明中任一项所述的药物制剂,其用于治疗和/或预防骨质疏松症、围绝经期综合症、便秘或肥胖或者降血脂;According to the pharmaceutical composition according to any one of the present invention, the extract according to any one of the present invention or the pharmaceutical preparation according to any one of the present invention, it is used for treating and/or preventing osteoporosis , perimenopausal syndrome, constipation or obesity or hypolipidemia;
优选地,所述骨质疏松症为原发性骨质疏松症或继发性骨质疏松症;Preferably, the osteoporosis is primary osteoporosis or secondary osteoporosis;
优选地,所述骨质疏松症为绝经后骨质疏松症或老年性骨质疏松症;Preferably, the osteoporosis is postmenopausal osteoporosis or senile osteoporosis;
优选地,所述骨质疏松症为围绝经期骨质疏松症;Preferably, the osteoporosis is perimenopausal osteoporosis;
优选地,所述肥胖为更年期肥胖。Preferably, the obesity is climacteric obesity.
本发明的再一方面涉及一种组合药物产品,其包含独立包装的第一产品和第二产品,Yet another aspect of the present invention relates to a combination pharmaceutical product comprising a first product and a second product in separate packages,
其中,in,
所述第一产品包含本发明中任一项所述的药物组合物、本发明中任一项所述的提取物或者本发明中任一项所述的药物制剂;The first product comprises the pharmaceutical composition according to any one of the present invention, the extract according to any one of the present invention or the pharmaceutical preparation according to any one of the present invention;
所述第二产品包含选自如下药物中的一种或多种:The second product contains one or more selected from the following drugs:
钙剂、维生素D、双磷酸盐、雌激素例如雌二醇、雌激素受体调节剂、降钙素、甲状旁腺激素和骨保护素;Calcium, vitamin D, bisphosphonates, estrogens such as estradiol, estrogen receptor modulators, calcitonin, parathyroid hormone, and osteoprotegerin;
优选地,所述第二产品还包含一种或多种药学上可接受的辅料;Preferably, the second product further comprises one or more pharmaceutically acceptable excipients;
优选地,按照生药的质量计算,所述第一产品的单位剂量为10-60g,优选为15-40g或20-30g,更优选为25g。Preferably, the unit dose of the first product is 10-60g, preferably 15-40g or 20-30g, more preferably 25g, calculated according to the mass of the crude drug.
所述“第一产品”或“第二产品”中的“第一”或“第二”仅仅是为了区分或者指代清楚,并不具有次序上的含义。The "first" or "second" in the "first product" or "second product" is only for distinguishing or clearly denoting, and has no order meaning.
本发明的再一方面涉及本发明中任一项所述的药物组合物、本发明中任一项所述的提取物或者本发明中任一项所述的药物制剂在制备治疗和/或预防骨质疏松症、围绝经期综合症、便秘或肥胖的药物、或者降血脂的药物中的用途;Another aspect of the present invention relates to the pharmaceutical composition described in any one of the present invention, the extract described in any one of the present invention or the pharmaceutical preparation described in any one of the present invention in preparation treatment and/or prophylaxis Osteoporosis, perimenopausal syndrome, constipation or obesity drugs, or the use of blood lipid-lowering drugs;
优选地,所述骨质疏松症为原发性骨质疏松症或继发性骨质疏松症;Preferably, the osteoporosis is primary osteoporosis or secondary osteoporosis;
优选地,所述骨质疏松症为绝经后骨质疏松症或老年性骨质疏松症;Preferably, the osteoporosis is postmenopausal osteoporosis or senile osteoporosis;
优选地,所述骨质疏松症为围绝经期骨质疏松症;Preferably, the osteoporosis is perimenopausal osteoporosis;
优选地,所述肥胖为更年期肥胖。Preferably, the obesity is climacteric obesity.
在本发明的一些实施方式中,所述的用途,其中,每千克体重每天的给药剂量为 0.1g-2g、0.2g-1g或0.4g-0.8g,优选为0.5g。In some embodiments of the present invention, the use, wherein the dosage per kilogram of body weight per day is 0.1g-2g, 0.2g-1g or 0.4g-0.8g, preferably 0.5g.
本发明的再一方面涉及一种制备提取物的方法,包括如下步骤:Another aspect of the present invention relates to a method for preparing an extract, comprising the steps of:
(1)用水或乙醇溶液对本发明中任一项要求所述重量份的女贞子、墨旱莲、鸡血藤和牛膝进行提取,得到提取液;(1) extract Ligustrum lucidum, Eclipta chinensis, Millipeda and Achyranthes bidentata in any one of the present invention by using water or ethanol solution to obtain an extract;
(2)将提取液浓缩,得到浓缩物,为提取物。(2) Concentrate the extract to obtain a concentrate, which is the extract.
在本发明的一些实施方案中,所述的制备方法,其特征在于如下的①-⑧项中的任意一项或者多项:In some embodiments of the present invention, the preparation method is characterized in that any one or more of the following items ①-⑧:
①步骤(1)中,所述提取为一次或多次,当为多次时,合并各次的提取液;1. In step (1), the extraction is one or more times, and when it is multiple times, the extracts of each time are combined;
②步骤(1)中,将女贞子、墨旱莲、鸡血藤和牛膝的混合物进行提取;或者将其中的任意1味以及其余3味的混合物分别提取得到各提取液,合并或不合并各提取液;或者将其中的任意2味的混合物以及其余2味的混合物分别提取得到各提取液,合并或不合并各提取液;或者将其中的任意1味、另外一味以及其余2味的混合物分别提取得到各提取液,合并或不合并各提取液;或者将4味药材分别提取得到各提取液,合并或不合并各提取液;② In step (1), extract the mixture of Ligustrum lucidum, Eclipta chinensis, Caulis Spatholobus and Achyranthes bidentata; or extract any 1 flavor and the mixture of the remaining 3 flavors to obtain the respective extracts, combined or not Each extract; or extract the mixture of any 2 flavors and the mixture of the remaining 2 flavors separately to obtain the extracts, combine or not combine the extracts; or extract any 1 flavor, the other 1 flavor and the mixture of the remaining 2 flavors extracting separately to obtain each extract, merging or not merging each extract; or extracting 4 medicinal materials separately to obtain each extract, merging or not merging each extract;
③步骤(1)中,所述乙醇的浓度为10%-99%、20%-90%、30%-80%、40%-80%、50%-80%、50%-70%或者60%-80%;③ In step (1), the concentration of the ethanol is 10%-99%, 20%-90%, 30%-80%, 40%-80%, 50%-80%, 50%-70% or 60% %-80%;
④步骤(1)中,所述提取为回流提取或者煎煮;④ In step (1), the extraction is reflux extraction or decoction;
⑤步骤(1)中,提取时间为至少0.5小时、至少1小时、至少2小时或者1-5小时;⑤ In step (1), the extraction time is at least 0.5 hour, at least 1 hour, at least 2 hours or 1-5 hours;
⑥步骤(1)中,水或乙醇溶液的用量为5-20倍量(ml/g),优选为8-16倍量;6. In step (1), the consumption of water or ethanol solution is 5-20 times the amount (ml/g), preferably 8-16 times the amount;
⑦步骤(2)中,所述浓缩为减压浓缩;7. In step (2), the concentration is concentration under reduced pressure;
⑧步骤(2)中,所述浓缩物为浸膏。8. In the step (2), the concentrate is an extract.
在本发明的一些实施方案中,所述的制备方法,其中,In some embodiments of the present invention, the preparation method, wherein,
步骤(1)包括如下步骤:Step (1) comprises the following steps:
将女贞子、墨旱莲分别提取,得到女贞子提取液和墨旱莲提取液;将女贞子提取后的药渣与鸡血藤和牛膝的混合物进行提取,得到女贞子鸡血藤牛膝提取液;Extracting Ligustrum lucidum and Eclipta edulis separately to obtain Ligustrum lucidum extract and Eclipta edulis extract; extracting the mixture of Ligustrum lucidum extract and the mixture of Spatholobus Spatholobus and Achyranthes bidentata to obtain Ligustrum lucidum Spatholobus Spatholobus Achyranthes knuckle extract;
优选地,步骤(2)包括如下步骤:Preferably, step (2) comprises the steps of:
将女贞子提取液、墨旱莲提取液和女贞子鸡血藤牛膝提取液分别浓缩后混合或者合并各提取液后浓缩,得到提取物。Concentrate the Ligustrum lucidum extract, the Eclipta chinensis extract and the Ligustrum lucidum Caulis Spatholobus Achyranthes extract respectively and then mix or combine the extracts and then concentrate to obtain the extract.
本发明中涉及的乙醇溶液,如果没有特别说明,均指乙醇的水溶液。The ethanol solution involved in the present invention refers to the aqueous solution of ethanol unless otherwise specified.
本发明中,如果没有特别说明,所述乙醇的浓度或乙醇溶液的浓度为体积百分比浓度(v/v)%。In the present invention, unless otherwise specified, the concentration of the ethanol or the concentration of the ethanol solution is the volume percent concentration (v/v)%.
本发明中,如果没有特别说明,术语“二至方”是指女贞子和墨旱莲(俗称旱莲草)构成的方剂,术语“二至丸”是指通过工业生产获得的制剂。In the present invention, unless otherwise specified, the term "Erzhi Fang" refers to a prescription composed of Ligustrum lucidum and Eclipta chinensis (commonly known as Eclipta), and the term "Erzhi Wan" refers to a preparation obtained through industrial production.
本发明中,本发明的药物组合物或提取物,有时也称为加味二至方。In the present invention, the pharmaceutical composition or extract of the present invention is also sometimes referred to as Jiawei Erzhifang.
通常本发明的药物制剂含有作为主药的0.1重量%-90重量%的本发明的提取物。药物制剂可根据本领域已知的方法制备。用于此目的时,如果需要,可将主药与一种或多种固体或液体药物赋形剂和/或辅剂结合,制成可作为人用的适当的施用形式或剂量形式。Usually, the pharmaceutical preparation of the present invention contains 0.1% by weight to 90% by weight of the extract of the present invention as the main ingredient. Pharmaceutical formulations can be prepared according to methods known in the art. For this purpose, if necessary, the main drug can be combined with one or more solid or liquid pharmaceutical excipients and/or adjuvants to prepare an appropriate administration form or dosage form for human use.
术语“辅料”在本申请中是指用以将主药给药的赋形剂或者媒介物,其包括但不限于稀释剂、崩解剂、沉淀抑制剂、表面活性剂、助流剂、粘合剂、润滑剂、包衣材料等。辅料在E.W.Martin的“Remington's Pharmaceutical Sciences”中被一般性描述。辅料的实例包括但不限于单硬脂酸铝、硬脂酸铝、羧甲基纤维素、羧甲基纤维素钠、交聚维酮、异硬脂酸甘油酯、单硬脂酸甘油酯、羟基乙基纤维素、羟基甲基纤维素、羟基硬脂酸羟基二十八酯、羟基丙基纤维素、羟基丙基甲基纤维素、乳糖、乳糖一水合物、硬脂酸镁、甘露醇、微晶纤维素等。The term "adjuvant" in this application refers to the excipient or vehicle used to administer the main drug, which includes but not limited to diluents, disintegrating agents, precipitation inhibitors, surfactants, glidants, viscose Mixtures, lubricants, coating materials, etc. Excipients are generally described in "Remington's Pharmaceutical Sciences" by E.W. Martin. Examples of excipients include, but are not limited to, aluminum monostearate, aluminum stearate, carboxymethylcellulose, sodium carboxymethylcellulose, crospovidone, glyceryl isostearate, glyceryl monostearate, Hydroxyethyl Cellulose, Hydroxy Methyl Cellulose, Hydroxy Octacyl Hydroxystearate, Hydroxy Propyl Cellulose, Hydroxy Propyl Methyl Cellulose, Lactose, Lactose Monohydrate, Magnesium Stearate, Mannitol , microcrystalline cellulose, etc.
本发明的提取物可配制成药物制剂,包括适用于口服给药的剂型,适用于胃肠外注射(例如静脉注射、皮下注射)的剂型(例如作为溶液剂),适用于表面给药的剂型(例如作为软膏剂、贴剂或者乳膏剂),以及适用于直肠给药的剂型(例如作为栓剂)等。The extracts of the present invention can be formulated into pharmaceutical preparations, including dosage forms suitable for oral administration, dosage forms suitable for parenteral injection (such as intravenous injection, subcutaneous injection) (such as as a solution), dosage forms suitable for topical administration (for example as an ointment, patch or cream), and formulations suitable for rectal administration (for example as a suppository) and the like.
本发明的再一方面涉及一种治疗和/或预防骨质疏松症、围绝经期综合症、便秘或肥胖或者降血脂的方法,包括给予有需求的受试者以有效量的本发明中任一项所述的药物组合物、本发明中任一项所述的提取物或者本发明中任一项所述的药物制剂的步骤;Another aspect of the present invention relates to a method for treating and/or preventing osteoporosis, perimenopausal syndrome, constipation or obesity or lowering blood lipids, comprising administering an effective amount of any of the present invention to a subject in need Steps of one of the pharmaceutical compositions described in the present invention, the extracts described in any one of the present invention or the pharmaceutical preparations described in any one of the present invention;
优选地,所述骨质疏松症为原发性骨质疏松症或继发性骨质疏松症;Preferably, the osteoporosis is primary osteoporosis or secondary osteoporosis;
优选地,所述骨质疏松症为绝经后骨质疏松症或老年性骨质疏松症;Preferably, the osteoporosis is postmenopausal osteoporosis or senile osteoporosis;
优选地,所述骨质疏松症为围绝经期骨质疏松症;Preferably, the osteoporosis is perimenopausal osteoporosis;
优选地,所述肥胖为更年期肥胖。Preferably, the obesity is climacteric obesity.
在本发明的一些实施方式中,所述的方法,其中,每千克体重每天的给药剂量为0.1g-2g、0.2g-1g或0.4g-0.8g,优选为0.5g。In some embodiments of the present invention, the method, wherein the dosage per kilogram of body weight per day is 0.1g-2g, 0.2g-1g or 0.4g-0.8g, preferably 0.5g.
取决于待治疗的疾病和患者以及给药途径,本发明的药物制剂可以以不同剂量每日一次或者多次给药。给药剂量取决于许多因素,例如所要治疗或预防的骨质疏松症的严重程度,患者的性别、年龄、体重及个体反应,给药途径及给药次数等。上述剂量可以单一剂量形式或分成几个,例如二、三、四个剂量形式给药。Depending on the disease to be treated and the patient and the route of administration, the pharmaceutical preparations according to the invention can be administered once or several times a day in different doses. The dosage depends on many factors, such as the severity of the osteoporosis to be treated or prevented, the sex, age, body weight and individual response of the patient, the route of administration and the frequency of administration, etc. The above dose can be administered as a single dose or divided into several, eg two, three or four doses.
可改变本发明药物制剂中主药(提取物)的实际剂量水平,以便能有效针对具体患者、组合物和给药方式得到所需的治疗反应。剂量水平须根据给药途径、所治疗病况的严重程度以及待治疗患者的病况和既往病史来选定。但是,本领域的做法是,给药剂量从低于为得到所需治疗效果而要求的水平开始,逐渐增加剂量,直到得到所需的效果。The actual dosage level of the principal ingredient (extract) in the pharmaceutical formulations of the present invention can be varied to effectively achieve the desired therapeutic response for a particular patient, composition and mode of administration. Dosage levels will be selected based on the route of administration, the severity of the condition being treated and the condition and previous medical history of the patient being treated. However, it is the practice in the art to start doses below that required to obtain the desired therapeutic effect and to gradually increase the dosage until the desired effect is obtained.
术语“有效量”是指可在受试者中实现治疗、预防、减轻和/或缓解本发明所述疾病或病症的剂量。The term "effective amount" refers to a dose that can achieve treatment, prevention, alleviation and/or alleviation of the diseases or conditions described in the present invention in a subject.
发明的有益效果Beneficial Effects of the Invention
本发明取得了如下的技术效果(1)-(6)中的任意一项或者多项:The present invention achieves any one or more of the following technical effects (1)-(6):
(1)本发明的药物组合物或提取物能够有效地治疗或预防骨质疏松症。(1) The pharmaceutical composition or extract of the present invention can effectively treat or prevent osteoporosis.
(2)本发明的药物组合物或提取物能够有效地治疗或预防便秘。(2) The pharmaceutical composition or extract of the present invention can effectively treat or prevent constipation.
(3)本发明的药物组合物或提取物能够有效地降血脂,治疗或预防高血脂症。(3) The pharmaceutical composition or extract of the present invention can effectively lower blood fat, treat or prevent hyperlipidemia.
(4)本发明的药物组合物或提取物治疗或预防骨质疏松症的效果优于二至方(二至丸)。(4) The effect of the pharmaceutical composition or extract of the present invention in treating or preventing osteoporosis is better than that of Erzhi Fang (Erzhi Wan).
(5)本发明的药物组合物或提取物长期使用的安全性好。(5) The long-term use safety of the pharmaceutical composition or extract of the present invention is good.
(6)本发明的制备方法优于传统的二至方(二至丸)制备工艺,例如,在同样组方的情况下,本发明的制备方法制得的提取物具有更优的抗骨质疏松效果,例如能够更好地提高骨密度。(6) The preparation method of the present invention is superior to the traditional Erzhifang (Erzhiwan) preparation process, for example, under the same prescription, the extract prepared by the preparation method of the present invention has better anti-osteogeny Porous effects, such as better bone density.
图1:各组动物体重随时间变化的曲线图。Figure 1: Curves of body weight of animals in each group over time.
图2:各组动物取材前(动物处死前)体重的柱状图。Figure 2: Histogram of body weight of animals in each group before sampling (before sacrifice).
图3:各组动物肝重指数的柱状图。Figure 3: Histogram of liver mass index of animals in each group.
图4:各组动物脾脏指数的柱状图。Figure 4: Histogram of spleen index of animals in each group.
图5:各组动物肾脏指数的柱状图。Figure 5: Histogram of kidney indices of animals in each group.
图6:各组动物子宫指数的柱状图。Figure 6: Histogram of uterine index of animals in each group.
图7:各组动物的代表性子宫图。Figure 7: Representative hysterograms of animals in each group.
图8:各组动物脂肪指数的柱状图。Figure 8: Histogram of animal fat index for each group.
图9:各组动物白色脂肪指数的柱状图。Figure 9: Histogram of white fat index of animals in each group.
图10:各组动物血清LDL-C水平的柱状图。Figure 10: Histogram of serum LDL-C levels of animals in each group.
图11:各组动物骨密度的柱状图。Figure 11: Histogram of bone density of animals in each group.
下面将结合实施例对本发明的实施方案进行详细描述,但是本领域技术人员将会理解,下列实施例仅用于说明本发明,而不应视为限定本发明的范围。实施例中未注明具体条件者,按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者,均为可以通过市购获得的常规产品。Embodiments of the present invention will be described in detail below in conjunction with examples, but those skilled in the art will understand that the following examples are only used to illustrate the present invention, and should not be considered as limiting the scope of the present invention. Those who do not indicate the specific conditions in the examples are carried out according to the conventional conditions or the conditions suggested by the manufacturer. The reagents or instruments used were not indicated by the manufacturer, and they were all commercially available conventional products.
制备例1:加味二至方提取物制备工艺示例(1)Preparation Example 1: Example of Preparation Process of Flavored Erzhifang Extract (1)
1.女贞子提取物的制备和分析1. Preparation and analysis of Ligustrum lucidum extract
1.1女贞子提取物的制备1.1 Preparation of Ligustrum lucidum extract
实验仪器:真空干燥箱、加热套、旋转蒸发仪。Experimental equipment: vacuum drying oven, heating mantle, rotary evaporator.
实验过程:experiment procedure:
取女贞子药材300g,放入20L的圆底烧瓶内,加入80%(v/v)乙醇10L,放在加热套上进行加热回流提取,从液体微沸计时,2小时后关闭加热套冷却,用纱布滤出烧瓶中液体,再次加入10L 80%乙醇提取,合并两次提取液,50℃减压浓缩至稠浸膏,放入45℃真空干燥箱中烘干、称重。Take 300g of Ligustrum lucidum medicinal material, put it into a 20L round-bottomed flask, add 10L of 80% (v/v) ethanol, put it on a heating mantle for heating and reflux extraction, count from the slight boiling of the liquid, and turn off the heating mantle to cool after 2 hours , filter out the liquid in the flask with gauze, add 10L 80% ethanol again for extraction, combine the two extracts, concentrate under reduced pressure at 50°C to a thick extract, put it in a vacuum oven at 45°C for drying, and weigh.
实验结果:共得干燥样品72.0g,出膏率为24%。Experimental results: A total of 72.0 g of dried samples were obtained, and the paste yield was 24%.
1.2检测方法及单因素试验结果1.2 Detection method and single factor test results
1.2.1 HPLC条件:仪器:waters2695、色谱柱:Agilent 4.6×250mm,5μm、温度:25℃、流动相:A:水,B:甲醇,检测波长224nm。1.2.1 HPLC conditions: instrument: waters2695, chromatographic column: Agilent 4.6×250mm, 5μm, temperature: 25°C, mobile phase: A: water, B: methanol, detection wavelength 224nm.
1.2.2液相方法:1.2.2 Liquid phase method:
如下面的表1所示。As shown in Table 1 below.
表1Table 1
对照品溶液的制备:精密称取特女贞苷对照品,使用甲醇溶解后制成对照品溶液。Preparation of the reference substance solution: Accurately weigh the privetin reference substance, and dissolve it in methanol to make a reference substance solution.
对照品溶液和样品液分别进样10μl,计算指标成分的含量,并统计。女贞子提取物含有特女贞苷含量19.82mg/g。Inject 10 μl of reference substance solution and sample solution respectively, calculate the content of index components, and make statistics. Ligustrum lucidum extract contains privetin 19.82mg/g.
2.墨旱莲提取物的制备和分析2. Preparation and Analysis of Eclipta Eclipta Extract
2.1墨旱莲60%乙醇加热回流提取2.1 Eclipta 60% ethanol heating reflux extraction
实验仪器:真空干燥箱、加热套、旋转蒸发仪。Experimental equipment: vacuum drying oven, heating mantle, rotary evaporator.
实验过程:experiment procedure:
称取墨旱莲药材300g,放入20L的圆底烧瓶内,加入60%乙醇10L,放在加热套上进行加热回流提取,从液体微沸计时,2小时后关闭加热套冷却,用纱布滤出烧瓶中液体,再次加入10L 60%乙醇提取,合并两次提取液,55℃减压浓缩至稠浸膏,放入45℃真空干燥箱中烘干、称重。Weigh 300g of Eclipta medicinal material, put it into a 20L round-bottomed flask, add 10L of 60% ethanol, put it on a heating mantle for heating and reflux extraction, count from the slight boiling of the liquid, turn off the heating mantle to cool after 2 hours, filter with gauze Take out the liquid in the flask, add 10L of 60% ethanol again for extraction, combine the two extracts, concentrate under reduced pressure at 55°C to a thick extract, dry in a vacuum oven at 45°C, and weigh.
实验结果:共得干燥样品53.25g,出膏率为17.75%。Experimental results: A total of 53.25 g of dried samples were obtained, and the paste yield was 17.75%.
2.2检测方法及单因素试验结果2.2 Detection method and single factor test results
2.2.1 HPLC条件:仪器:waters2695、色谱柱:Agilent 4.6×250mm,5μm、温度:25℃、流动相:A:0.5%醋酸水,B:甲醇,检测波长351nm。2.2.1 HPLC conditions: instrument: waters2695, chromatographic column: Agilent 4.6×250mm, 5μm, temperature: 25°C, mobile phase: A: 0.5% acetic acid water, B: methanol, detection wavelength 351nm.
2.2.2液相方法:2.2.2 Liquid phase method:
如下面的表2所示。As shown in Table 2 below.
表2Table 2
对照品溶液的制备:精密称取蟛蜞菊内酯对照品,使用甲醇溶解后制成对照品溶液。Preparation of the reference substance solution: Accurately weigh the wedelia lactone reference substance, dissolve it in methanol to prepare the reference substance solution.
对照品溶液和样品液分别进样10μl,计算指标成分的含量,并统计。墨旱莲提取物蟛蜞菊内酯含量0.8mg/g。Inject 10 μl of reference substance solution and sample solution respectively, calculate the content of index components, and make statistics. The content of wedelolide in the extract of Eclipta chinensis is 0.8mg/g.
3.鸡血藤提取物的制备和分析3. Preparation and Analysis of Spatholobus Extract
3.1鸡血藤60%乙醇加热回流3.1 Heat reflux with 60% ethanol from Spatholobus Spatholobus
实验仪器:真空干燥箱、加热套、旋转蒸发仪。Experimental equipment: vacuum drying oven, heating mantle, rotary evaporator.
实验过程:experiment procedure:
称取鸡血藤药材300g,放入5L的圆底烧瓶内,加入60%乙醇3000ml,放在加热套上进行加热回流提取,从液体微沸计时,2小时后关闭加热套冷却,用纱布滤出烧瓶中液体,再次加入3000ml 60%乙醇提取,合并两次提取液,55℃减压浓缩至稠浸膏,放入45℃真空干燥箱中烘干、称重。Weigh 300g of Mildew Spatholobus medicinal material, put it into a 5L round-bottomed flask, add 3000ml of 60% ethanol, put it on a heating mantle for heating and reflux extraction, count from the slight boiling of the liquid, turn off the heating mantle to cool after 2 hours, filter with gauze Take out the liquid in the flask, add 3000ml of 60% ethanol again for extraction, combine the two extracts, concentrate under reduced pressure at 55°C to a thick extract, put it in a vacuum oven at 45°C for drying, and weigh.
实验结果:得干燥固体60.24g,出膏率20.08%。Experimental results: 60.24 g of dry solid was obtained, and the paste yield was 20.08%.
4.牛膝提取物的制备和分析4. Preparation and analysis of Achyranthes bidentata extract
4.1牛膝60%乙醇提取4.1 Achyranthes bidentata 60% ethanol extraction
牛膝饮片250g,加入8倍量60%乙醇2000ml回流提取2h,倒出提取液后,药渣再加入2000ml 60%乙醇回流提取2h,两次提取液合并,浓缩干燥得牛膝提取物126.4g,出膏率50.6%。Achyranthes bidentata decoction pieces 250g, add 8 times the amount of 60% ethanol 2000ml to reflux for extraction for 2 hours, pour out the extract, then add 2000ml of 60% ethanol to reflux and extract for 2 hours, combine the two extracts, concentrate and dry to obtain 126.4g of Achyranthes bidentata extract , The cream yield is 50.6%.
制备例2:加味二至方提取物制备工艺示例(2)Preparation example 2: Example of preparation process of flavored Erzhifang extract (2)
1.取200g女贞子药材,置圆底烧瓶中,加入2400毫升60%乙醇,加热回流提取2小时,倒出滤液得女贞子第一次提取液,再加入2400毫升60%乙醇,加热回流提取2小时,倒出滤液得女贞子第二次提取物,女贞子药渣备用,合并两次提取液,浓缩干燥得女贞子提取物48.78g。1. Take 200g of Ligustrum lucidum medicinal material, put it in a round bottom flask, add 2400ml of 60% ethanol, heat and reflux for extraction for 2 hours, pour out the filtrate to obtain the first extract of Ligustrum lucidum, then add 2400ml of 60% ethanol, heat Reflux extraction for 2 hours, pour out the filtrate to obtain the second extract of Ligustrum lucidum, and the medicinal residue of Ligustrum lucidum for later use, combine the two extracts, concentrate and dry to obtain 48.78 g of Ligustrum lucidum extract.
2.取200g墨旱莲药材,置圆底烧瓶中,加入2000毫升70%乙醇,加热回流提取物3小时,倒出滤液得墨旱莲第一次提取液,再加入2000毫升70%乙醇,加热回流提取3小时,倒出滤液得墨旱莲第二次提取液,合并两次提取液,浓缩干燥得墨旱莲提取物28.52g。2. Get 200g Eclipta medicinal material, put in a round bottom flask, add 2000 milliliters of 70% ethanol, heat and reflux the extract for 3 hours, pour out the filtrate to obtain the first extract of Eclipta, then add 2000 milliliters of 70% ethanol, Heated and refluxed for 3 hours, poured out the filtrate to obtain the second extract of Eclipta chinensis, combined the two extracts, concentrated and dried to obtain 28.52 g of Eclipta eclipta extract.
3.取前面步骤1制得的女贞子药渣,加入120g鸡血藤、80g牛膝,置圆底烧瓶中,加入3200毫升水,加热回流提取2小时,倒出溶液得第一次提取液,再加入3200毫升水,加热回流提取2小时,倒出溶液得第二次提取液,合并两次提取液浓缩干燥得女贞子鸡血藤牛膝提取物67.56g。3. Take the medicinal residue of Ligustrum lucidum obtained in the previous step 1, add 120g of Caulis Spatholobus and 80g of Achyranthes bidentata, put it in a round bottom flask, add 3200ml of water, heat and reflux for extraction for 2 hours, pour out the solution to obtain the first extraction solution, then add 3200 ml of water, heat and reflux for extraction for 2 hours, pour out the solution to obtain the second extract, combine the two extracts, concentrate and dry to obtain 67.56 g of Ligustrum lucidum Spatholobi Spatholobus Achyranthes bidentata extract.
将上述制得的女贞子提取物48.78g、墨旱莲提取物28.52g和女贞子鸡血藤牛膝提取物67.56g混合,即得本发明的提取物,代号为XGY。Mix 48.78g of Ligustrum lucidum extract, 28.52g of Eclipta chinensis extract and 67.56g of Ligustrum lucidum Caulis Spatholobus Achyranthes extract to obtain the extract of the present invention, code-named XGY.
不拘于理论的限制,本发明人发现,制备例2的制备方法制备的样品有利于制剂 成型、提取的可能有效成分含量更高(女贞子多糖、毛蕊花糖苷和/或旱莲苷A等)、药效更优。Without being bound by theory, the inventors found that the sample prepared by the preparation method of Preparation Example 2 is conducive to the formation of the preparation and the extraction of possible active ingredients with higher content (Ligustrum lucidum polysaccharide, verbascoside and/or ecclidene glycoside A, etc.) , Better efficacy.
另外,也可以将4味药材中的任意两味药材或者任意三味药材混合进行提取。In addition, any two or any three of the four medicinal materials may be mixed for extraction.
制备例3:加味二至方提取物制备工艺示例(3)Preparation example 3: Example of preparation process of flavored Erzhifang extract (3)
取200g女贞子药材、200g墨旱莲药材、鸡血藤120g以及牛膝80g,置圆底烧瓶中,加入6000毫升70%乙醇,加热回流提取,提取2次,每次2小时,合并两次提取液,浓缩干燥得加味二至方提取物140.58g,代号为XF。Take 200g of Ligustrum lucidum medicinal material, 200g of Eclipta chinensis medicinal material, 120g of Millet Spatholobus and 80g of Achyranthes bidentata, put them in a round bottom flask, add 6000ml of 70% ethanol, heat and reflux for extraction, extract twice, each time for 2 hours, combine the two The secondary extract was concentrated and dried to obtain 140.58 g of flavored Erzhi Fang extract, code-named XF.
实验例1:抗骨质疏松症实验Experimental example 1: Anti-osteoporosis experiment
1.材料与方法1. Materials and methods
1.1实验动物1.1 Experimental animals
SPF级别雌性C57BL/6小鼠,8周龄,体重19-20g。购自斯贝福(北京)生物技术有限公司,合格证号SCXK(京)2016-0002。饲养于天津市中国医学科学院放射医学研究所,饲养温度23-25℃,湿度50%-60%,光线为12小时明暗循环。SPF grade female C57BL/6 mice, 8 weeks old, weighing 19-20g. Purchased from Speiford (Beijing) Biotechnology Co., Ltd., certificate number SCXK (Beijing) 2016-0002. They were raised in the Institute of Radiation Medicine, Chinese Academy of Medical Sciences, Tianjin, with a temperature of 23-25°C, a humidity of 50%-60%, and a 12-hour cycle of light and dark.
1.2药物1.2 Drugs
加味二至方组:女贞子提取物、墨旱莲提取物、鸡血藤提取物、牛膝提取物均按照制备例1的方法制备。Flavored Erzhi Prescription Group: Ligustrum lucidum extract, Eclipta chinensis extract, Caulis Spatholobus extract, and Achyranthes bidentata extract were all prepared according to the method of Preparation Example 1.
配制方法:称取女贞子提取物14.4g、墨旱莲提取物10.65g、鸡血藤提取物7.23、牛膝提取物12.14g,用0.2%CMCNa溶解,定容至100mL,作为加味二至方组给药溶液。4℃保存。Preparation method: Weigh 14.4g of Ligustrum lucidum extract, 10.65g of Eclipta officinalis extract, 7.23g of Caulis Spatholobus extract, and 12.14g of Achyranthes bidentata extract, dissolve in 0.2% CMCNa, and dilute to 100mL, as the flavored two to Prescription group administration solution. Store at 4°C.
1.3去卵巢动物模型的制备1.3 Preparation of ovariectomized animal model
小鼠适应性喂养一周后,按体重随机分为假手术组(sham)和手术组(OVX)。手术时采用三溴乙醇对动物进行麻醉,将小鼠固定于手术板上,将小鼠背部中下部1/3处去毛备皮,碘伏消毒,在双侧背部中央纵向切开约2cm的切口,分离皮肤层和肌肉层,有无菌眼科镊轻轻拉出卵巢,用手术线在输卵管末端进行结扎(防止术后出血),用眼科剪将卵巢全部切除,最后将子宫缓慢纳入腹腔,同法摘除双侧卵巢,分别缝合肌肉层和皮肤层。假手术组采用同样的方法进行操作,但只需要摘除卵巢周围的脂肪组织即可,不需要摘除卵巢。手术后连续腹腔注射青霉素钠(0.1mL/只,20万单位/mL)三天以防止手术造成的体内感染。After one week of adaptive feeding, the mice were randomly divided into a sham operation group (sham) and an operation group (OVX) according to body weight. During the operation, the animals were anesthetized with tribromoethanol, the mice were fixed on the operating board, the middle and lower 1/3 of the back of the mice were depilated and skinned, disinfected with povidone iodine, and about 2 cm was cut longitudinally in the center of the bilateral backs. Make an incision, separate the skin layer and muscle layer, gently pull out the ovary with sterile ophthalmic forceps, ligate the end of the fallopian tube with surgical thread (to prevent postoperative bleeding), remove all the ovaries with ophthalmic scissors, and finally slowly bring the uterus into the abdominal cavity. The bilateral ovaries were removed in the same way, and the muscle layer and skin layer were sutured separately. The sham operation group was operated in the same way, but only the adipose tissue around the ovaries was removed, and the ovaries did not need to be removed. Continuous intraperitoneal injection of penicillin sodium (0.1 mL/cause, 200,000 units/mL) for three days after operation to prevent internal infection caused by operation.
1.4实验分组给药1.4 Experimental group administration
如下面的表3所示。As shown in Table 3 below.
表3table 3
实验动物按0.1mL/10g/d灌胃给药8周,给药期间观察小鼠生长情况,每周称重记录,全程标准饲料喂养,自由进食、进水。The experimental animals were given 0.1mL/10g/d orally for 8 weeks. During the period of administration, the growth of the mice was observed, and the weight was recorded every week. The whole process was fed with standard feed, and they had free access to food and water.
2.实验结果2. Experimental results
2.1加味二至方给药对去势小鼠体重及各脏器的影响2.1 Effects of Modified Erzhi Recipe on Body Weight and Viscera of Ovariectomized Mice
每天进行1次灌胃给药,连续灌胃8周,观察各组小鼠体重及脏器的变化情况,结果显示,Model组小鼠体重显著升高,加味二至方组可以显著降低去势小鼠体重升高的现象(P<0.05)。各组小鼠体内脏器无显著变化。Gastrointestinal administration was carried out once a day for 8 consecutive weeks, and the changes in the body weight and organs of the mice in each group were observed. The results showed that the weight of the mice in the Model group increased significantly, and the modified Erzhifang group could significantly reduce the castration rate. The body weight of the mice increased (P<0.05). There were no significant changes in internal organs of mice in each group.
2.2加味二至方给药对去势小鼠子宫的影响2.2 Effects of Modified Erzhi Recipe Administration on the Uterus of Ovariectomized Mice
去势后小鼠子宫重量显著降低(P<0.01),子宫出现萎缩的现象,给予加味二至方后具有改善子宫萎缩的现象。After castration, the weight of the uterus of the mice was significantly reduced (P<0.01), and the uterus appeared to shrink, and the uterine atrophy could be improved after being given the modified Erzhi Formula.
2.3加味二至方给药对去势小鼠脂肪含量的影响2.3 Effects of Modified Erzhi Recipe on Fat Content in Castrated Mice
结果显示,与假手术组相比,去势后小鼠背部脂肪含量无显著变化,而加味二至方能够显著升高背部脂肪含量(P<0.01)。腹部脂肪含量结果表明,去势后小鼠腹部脂肪含量显著升高(P<0.01),其中加味二至方能够显著降低腹部脂肪的含量(P<0.01)。The results showed that compared with the sham operation group, there was no significant change in the fat content of the back of the mice after castration, but the modified Erzhi Recipe could significantly increase the fat content of the back of the mice (P<0.01). The results of the abdominal fat content showed that the abdominal fat content of the castrated mice increased significantly (P<0.01), and the modified Erzhi Fang could significantly reduce the abdominal fat content (P<0.01).
2.4加味二至方给药对去势小鼠骨密度的影响2.4 Effect of Modified Erzhi Prescription on Bone Density of Ovariectomized Mice
采用双能X射线骨密度仪对小鼠胫骨的骨矿物密度进行检测,结果显示,与假手术组相比,模型组中小鼠胫骨的骨矿物密度(BMD)显著降低(P<0.01)。加味二至方给药能升高胫骨的骨密度。The bone mineral density (BMD) of the mouse tibia was detected by dual-energy X-ray absorptiometry, and the results showed that, compared with the sham operation group, the bone mineral density (BMD) of the mouse tibia in the model group decreased significantly (P<0.01). The administration of the modified Erzhi Fang can increase the bone density of the tibia.
实验例2:抗骨质疏松症实验Experimental example 2: Anti-osteoporosis experiment
1.材料与方法1. Materials and methods
1.1实验动物1.1 Experimental animals
SPF级别雌性C57BL/6小鼠,8周龄,体重19-20g。购自北京维通利华实验动物技术有限公司,合格证号SCXK(京)2016-0006。饲养于天津中医药大学动物中心,饲养温度23-25℃,湿度50%-60%,光线为12小时明暗循环。SPF grade female C57BL/6 mice, 8 weeks old, weighing 19-20g. Purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd., certificate number SCXK (Beijing) 2016-0006. They were raised in the Animal Center of Tianjin University of Traditional Chinese Medicine, with a temperature of 23-25°C, a humidity of 50%-60%, and a 12-hour cycle of light and dark.
1.2药物1.2 Drugs
加味二至方组(XGY):女贞子提取物、墨旱莲提取物、女贞子鸡血藤牛膝混提物均按照制备例2的方法制备。配制方法:称取女贞子提取物14.63g、墨旱莲提取物8.56g、女贞子鸡血藤牛膝混提物20.27g,用0.2%CMCNa溶解,定容至100mL,作为加味二至方组(XGY)给药溶液。4℃保存。Modified Erzhi Formula Group (XGY): Ligustrum lucidum extract, Eclipta chinensis extract, and Ligustrum lucidum, Caulis Spatholobus and Achyranthes bidentata mixed extracts were all prepared according to the method of Preparation Example 2. Preparation method: weigh 14.63g of Ligustrum lucidum extract, 8.56g of Eclipta officinalis extract, and 20.27g of mixed extract of Ligustrum lucidum and Caulis Spatholobus Achyranthes bidentata, dissolve in 0.2% CMCNa, dilute to 100mL, and use it as flavored Erzhi recipe Group (XGY) was administered the solution. Store at 4°C.
加味二至方组(XF):取女贞子、墨旱莲、鸡血藤及牛膝混合药材按照制备例3的方法制备。配制方法:称取上述XF提取物42.2g,用0.2%CMCNa溶解,定容至100mL,作为加味二至方组(XF)给药溶液。4℃保存。Added flavored Erzhi formula group (XF): take the mixed medicinal materials of Ligustrum lucidum, Eclipta chinensis, Caulis Spatholobus and Achyranthes bidentata, and prepare according to the method of Preparation Example 3. Preparation method: Weigh 42.2 g of the above-mentioned XF extract, dissolve it with 0.2% CMCNa, and dilute to 100 mL, and use it as the dosing solution of the flavored Erzhifang group (XF). Store at 4°C.
二至方组(EZF):女贞子提取物和墨旱莲提取物均按照制备例1的方法制备。配制方法:称取上述女贞子提取物14.4g和墨旱莲提取物10.65g,用0.2%CMCNa溶解,定容至100mL,作为二至方组(EZF)给药溶液。4℃保存。Erzhifang Group (EZF): Ligustrum lucidum extract and Eclipta chinensis extract were both prepared according to the method of Preparation Example 1. Preparation method: Weigh 14.4 g of the above-mentioned Ligustrum lucidum extract and 10.65 g of the Eclipta chinensis extract, dissolve them in 0.2% CMCNa, and dilute to 100 mL, as the administration solution for the Erzhifang group (EZF). Store at 4°C.
1.3去卵巢动物模型的制备1.3 Preparation of ovariectomized animal model
小鼠适应性喂养一周后,按体重随机分为假手术组(sham)和手术组(OVX)。手术时采用三溴乙醇对动物进行麻醉,将小鼠固定于手术板上,将小鼠背部中下部1/3处去毛备皮,碘伏消毒,在双侧背部中央纵向切开约2cm的切口,分离皮肤层和肌肉层,有无菌眼科镊轻轻拉出卵巢,用手术线在输卵管末端进行结扎(防止术后出血),用眼科剪将卵巢全部切除,最后将子宫缓慢纳入腹腔,同法摘除双侧卵巢,分别缝合肌肉层和皮肤层。假手术组采用同样的方法进行操作,但只需要摘除卵巢周围的脂肪组织即可,不需要摘除卵巢。手术后连续腹腔注射青霉素钠(0.1mL/只,20万单位/mL)三天以防止手术造成的体内感染。After one week of adaptive feeding, the mice were randomly divided into a sham operation group (sham) and an operation group (OVX) according to body weight. During the operation, the animals were anesthetized with tribromoethanol, the mice were fixed on the operating board, the middle and lower 1/3 of the back of the mice were depilated and skinned, disinfected with povidone iodine, and about 2 cm was cut longitudinally in the center of the bilateral backs. Make an incision, separate the skin layer and muscle layer, gently pull out the ovary with sterile ophthalmic forceps, ligate the end of the fallopian tube with surgical thread (to prevent postoperative bleeding), remove all the ovaries with ophthalmic scissors, and finally slowly bring the uterus into the abdominal cavity. The bilateral ovaries were removed in the same way, and the muscle layer and skin layer were sutured separately. The sham operation group was operated in the same way, but only the adipose tissue around the ovaries was removed, and the ovaries did not need to be removed. Continuous intraperitoneal injection of penicillin sodium (0.1 mL/cause, 200,000 units/mL) for three days after operation to prevent internal infection caused by operation.
1.4实验分组给药1.4 Experimental group administration
如下面的表4所示。As shown in Table 4 below.
表4Table 4
实验动物按0.1mL/10g/d灌胃给药8周,给药期间观察小鼠生长情况,每周称重记录,全程标准饲料喂养,自由进食、进水。The experimental animals were given 0.1mL/10g/d orally for 8 weeks. During the period of administration, the growth of the mice was observed, and the weight was recorded every week. The whole process was fed with standard feed, and they had free access to food and water.
1.5血清中LDL-C含量检测1.5 Detection of LDL-C content in serum
检测前将小鼠血清样本从-80℃冰箱取出并平衡至室温,采用全自动生化分析仪(型号:BS-240VET,深圳迈瑞生物医疗电子股份有限公司)和低密度脂蛋白胆固醇(LDL-C)测定试剂盒(批号:142020006)检测小鼠血清中LDL-C含量。Before the test, the mouse serum samples were taken out from the -80°C refrigerator and equilibrated to room temperature, and the low-density lipoprotein cholesterol (LDL-C ) assay kit (batch number: 142020006) to detect LDL-C content in mouse serum.
2.实验结果2. Experimental results
2.1加味二至方给药对去势小鼠体重及各脏器的影响2.1 Effects of Modified Erzhi Recipe on Body Weight and Viscera of Ovariectomized Mice
每天进行1此灌胃给药,连续灌胃8周,观察各组小鼠体重及脏器的变化情况,结果如图1至图5所示。The intragastric administration was carried out once a day for 8 consecutive weeks, and the changes in the body weight and organs of the mice in each group were observed. The results are shown in Figures 1 to 5.
结果显示,Model组小鼠体重显著升高,二至方组、加味二至方组(XGY)和加味二至方组(XF)均可以显著降低去势小鼠体重升高的现象(图1和图2,P<0.05)。各组小鼠体内脏器无显著变化(图3至图5)。The results showed that the weight of the mice in the Model group increased significantly, and the Erzhifang group, the flavored Erzhifang group (XGY) and the flavored Erzhifang group (XF) could all significantly reduce the weight gain of castrated mice (Figure 1 and Figure 2, P<0.05). There were no significant changes in internal organs of the mice in each group (Fig. 3 to Fig. 5).
2.2加味二至方给药对去势小鼠子宫的影响2.2 Effects of Modified Erzhi Recipe Administration on the Uterus of Ovariectomized Mice
结果如图6和图7所示。The results are shown in Figure 6 and Figure 7.
结果显示,去势后小鼠子宫重量显著降低(P<0.01),子宫出现萎缩的现象,给予加味二至方(XGY)和加味二至方(XF)后具有改善子宫萎缩的现象。The results showed that the weight of the uterus of the castrated mice was significantly reduced (P<0.01), and the uterus appeared atrophy, and the uterine atrophy could be improved after administration of Jiawei Erzhifang (XGY) and Jiawei Erzhifang (XF).
从图6至图7结果分析,加味二至方(XGY)组和加味二至方(XF)组的子宫指标比二至方组(EZF)更趋于正常组,提示加味二至方(XGY)组和加味二至方(XF)组比二至方组更具营养子宫的作用,表现出比二至方组更强的雌激素样作用。From the analysis of the results in Figure 6 to Figure 7, the uterine indicators of the Jiawei Erzhifang (XGY) group and the Jiawei Erzhifang (XF) group are more normal than those of the Erzhifang group (EZF), suggesting that the Jiawei Erzhifang (XGY ) group and modified Erzhifang (XF) group had more uterine nourishing effect than Erzhifang group, and showed stronger estrogen-like effect than Erzhifang group.
2.3二至方配伍给药对去势小鼠脂肪含量的影响2.3 Effects of Erzhi Fang Compatible Administration on Fat Content in Castrated Mice
结果如图8和图9所示。The results are shown in Figure 8 and Figure 9.
结果显示,与假手术组相比,去势后小鼠腹部脂肪含量显著升高(P<0.01),其中二至方及加味二至方(XGY)和加味二至方(XF)能够显著降低腹部脂肪的含量 (P<0.01)。同时,体脂成分含量检测表明去势后小鼠体脂成分显著升高(P<0.01),二至方、加味二至方(XGY)和加味二至方(XF)能够显著降低去势小鼠体脂成分的含量(P<0.01)。此外,图8的结果表明,加味二至方(XF)比二至方(EZF)抗去势小鼠脂肪增多的作用更强,提示加味二至方(XF)具有更强的防治更年期肥胖的作用。The results showed that, compared with the sham operation group, the abdominal fat content of castrated mice was significantly increased (P<0.01), among which Erzhifang, Jiawei Erzhifang (XGY) and Jiawei Erzhifang (XF) could significantly reduce Abdominal fat content (P<0.01). At the same time, the detection of body fat composition showed that the body fat composition of castrated mice increased significantly (P<0.01), and Erzhifang, Jiawei Erzhifang (XGY) and Jiawei Erzhifang (XF) could significantly reduce the weight of castrated mice. The content of body fat components in rats (P<0.01). In addition, the results in Figure 8 show that the flavored Erzhi Formula (XF) has a stronger effect on preventing fat gain in castrated mice than Erzhi Formula (EZF), suggesting that the flavored Erzhi Formula (XF) has a stronger effect on preventing and treating menopausal obesity. effect.
2.4二至方配伍给药对去势小鼠LDL-C水平的影响2.4 Effects of Erzhifang Compatible Administration on LDL-C Levels in Castrated Mice
与假手术组相比,模型组血清LDL-C水平升高,而二至方、加味二至方(XGY)和加味二至方(XF)均具有降低LDL-C的作用(图10)。Compared with the sham operation group, the serum LDL-C level in the model group increased, while Erzhifang, Jiawei Erzhifang (XGY) and Jiawei Erzhifang (XF) all had the effect of lowering LDL-C (Figure 10).
2.5二至方配伍给药对去势小鼠骨密度的影响2.5 Effects of Erzhifang Compatible Administration on Bone Density of Ovariectomized Mice
采用双能X射线骨密度仪对小鼠股骨的骨矿物密度进行检测,结果如图11所示。The bone mineral density of the mouse femur was detected by dual-energy X-ray absorptiometry, and the results are shown in FIG. 11 .
结果显示,与假手术组相比,模型组中小鼠股骨的骨矿物密度(BMD)显著降低(P<0.01)。二至方、加味二至方(XGY)和加味二至方(XF)给药均能升高股骨的骨密度(P<0.05或P<0.01)。结果还显示,与二至方组(EZF)相比,加味二至方组(XGY)提高骨密度的作用更明显;加味二至方组(XGY)的效果甚至优于采用4味中药合并提取工艺的加味二至方组(XF)。The results showed that, compared with the sham operation group, the bone mineral density (BMD) of the mouse femur in the model group was significantly decreased (P<0.01). The administration of Erzhifang, Modified Erzhifang (XGY) and Modified Erzhifang (XF) could increase the BMD of femur (P<0.05 or P<0.01). The results also showed that, compared with the Erzhifang group (EZF), the modified Erzhifang group (XGY) had a more obvious effect on improving bone mineral density; the effect of the modified Erzhifang group (XGY) was even better than that of four traditional Chinese medicine combined Craft's flavored two-to-square set (XF).
参考文献references
[1]刘恩令,周玉秀.雌二醇屈螺酮片激素替代治疗更年期综合征的疗效[J].中国老年学杂志,2014,26(19):5566-5567.[1] Liu Enling, Zhou Yuxiu. Efficacy of hormone replacement therapy with estradiol and drospirenone tablets for menopausal syndrome [J]. Chinese Journal of Gerontology, 2014, 26(19): 5566-5567.
[2]陈伟,刘东灵,姜兴鹏.回阳针法治疗脾肾阳虚型更年期综合症临床疗效观察[J].中国中医基础医学杂志,2016,22(3):401-403.[2] Chen Wei, Liu Dongling, Jiang Xingpeng. Observation on the clinical efficacy of Huiyang Acupuncture in the treatment of menopausal syndrome of spleen and kidney yang deficiency [J]. Chinese Journal of Basic Medicine of Traditional Chinese Medicine, 2016, 22(3): 401-403.
[3]申浩,谢雁鸣.骨质疏松性骨折的危险因素及中医证候要素风险评估研究现状[J].中国骨伤,2014,27(3):261-265.[3] Shen Hao, Xie Yanming. Research status of risk factors for osteoporotic fractures and risk assessment of TCM syndrome elements [J]. Chinese Orthopedics, 2014, 27(3): 261-265.
[4]郭华平,郁嫣嫣,陈文华,余波,祁奇.绝经后骨质疏松症发病相关危险因素分析及预防措施探讨[J].中国康复医学杂志,2011,26(5):424-428.[4] Guo Huaping, Yu Yanyan, Chen Wenhua, Yu Bo, Qi Qi. Analysis of related risk factors and preventive measures for postmenopausal osteoporosis [J]. Chinese Journal of Rehabilitation Medicine, 2011, 26(5): 424-428 .
[5]黄建立,王岗,李林涛.中西药治疗老年性骨质疏松症的效果观察[J].中国骨质疏松杂志,2016,22(12):1573-1575+1584.[5] Huang Jianli, Wang Gang, Li Lintao. Observation on the Effect of Chinese and Western Medicine in Treating Senile Osteoporosis [J]. Chinese Journal of Osteoporosis, 2016, 22(12): 1573-1575+1584.
[6]张建祥.中西药治疗抑郁症的不良反应比较[J].中国实用医药,2010,5(19):130-131.[6] Zhang Jianxiang. Comparison of adverse reactions of Chinese and Western medicine in the treatment of depression [J]. Chinese Practical Medicine, 2010,5(19):130-131.
[7]白俊丽.激素替代疗法联合阿仑膦酸钠治疗围绝经期妇女骨质疏松症临床观察[J].临床医药实践,2017,26(2):107-109.[7] Bai Junli. Clinical observation of hormone replacement therapy combined with alendronate sodium in the treatment of perimenopausal women with osteoporosis [J]. Clinical Medicine Practice, 2017,26(2):107-109.
[8]邹勇,左铮云,赵海梅,等.二至丸药理作用研究进展[J].江西中医药.2015,46(03):75-76+80.[8] Zou Yong, Zuo Zhengyun, Zhao Haimei, et al. Research progress on pharmacological effects of Erzhi Pills [J]. Jiangxi Traditional Chinese Medicine. 2015, 46(03): 75-76+80.
[9]刘亭亭,王萌.女贞子化学成分与药理作用研究进展[J].中国实验方剂学杂志.2014,20(14):228-234.[9] Liu Tingting, Wang Meng. Research progress on chemical constituents and pharmacological effects of Ligustrum lucidum [J]. Chinese Journal of Experimental Formulas. 2014,20(14):228-234.
[10]方悦,李熙晨,张朝凤.墨旱莲化学成分与药理活性的研究进展[J].海峡药学.2015,27(06):1-3.[10] Fang Yue, Li Xichen, Zhang Chaofeng. Research progress on chemical constituents and pharmacological activities of Eclipta chinensis [J]. Strait Pharmacy. 2015,27(06):1-3.
尽管本发明的具体实施方式已经得到详细的描述,本领域技术人员将会理解。根据已经公开的所有教导,可以对那些细节进行各种修改和替换,这些改变均在本发明的保护范围之内。本发明的全部范围由所附权利要求及其任何等同物给出。Although specific embodiments of the present invention have been described in detail, those skilled in the art will understand. Based on all the teachings that have been disclosed, various modifications and substitutions can be made to those details, and these changes are all within the scope of the invention. The full scope of the invention is given by the appended claims and any equivalents thereof.
Claims (19)
- 根据权利要求1至2中任一权利要求所述的药物组合物,其单位剂量为10-60g,优选为15-40g或20-30g,更优选为25g。According to any one of claims 1 to 2, the pharmaceutical composition has a unit dose of 10-60 g, preferably 15-40 g or 20-30 g, more preferably 25 g.
- 一种提取物,其由权利要求1至3中任一权利要求所述的药物组合物制得。An extract prepared from the pharmaceutical composition according to any one of claims 1 to 3.
- 根据权利要求4所述的提取物,其通过包含如下步骤的制备方法制得:Extract according to claim 4, it is made by the preparation method comprising the following steps:(1)用水或乙醇溶液对权利要求1至3中任一权利要求所述重量份的女贞子、墨旱莲、鸡血藤和牛膝进行提取,得到提取液;(1) Extracting Ligustrum lucidum, Eclipta chinensis, Gallis Spatholobus and Achyranthes bidentata of any one of claims 1 to 3 by weight with water or ethanol solution, to obtain an extract;(2)将提取液浓缩,得到浓缩物,为提取物。(2) Concentrate the extract to obtain a concentrate, which is the extract.
- 根据权利要求5所述的提取物,其特征在于如下的①-⑧项中的任意一项或者多项:The extract according to claim 5, characterized in that any one or more of the following ①-⑧ items:①步骤(1)中,所述提取为一次或多次,当为多次时,合并各次的提取液;1. In step (1), the extraction is one or more times, and when it is multiple times, the extracts of each time are combined;②步骤(1)中,将女贞子、墨旱莲、鸡血藤和牛膝的混合物进行提取;或者将其中的任意1味以及其余3味的混合物分别提取得到各提取液,合并或不合并各提取液;或者将其中的任意2味的混合物以及其余2味的混合物分别提取得到各提取液,合并或不合并各提取液;或者将其中的任意1味、另外一味以及其余2味的混合物分别提取得到各提取液,合并或不合并各提取液;或者将4味药材分别提取得到各提取液,合并或不合并各提取液;② In step (1), extract the mixture of Ligustrum lucidum, Eclipta chinensis, Caulis Spatholobus and Achyranthes bidentata; or extract any 1 flavor and the mixture of the remaining 3 flavors to obtain the respective extracts, combined or not Each extract; or extract the mixture of any 2 flavors and the mixture of the remaining 2 flavors separately to obtain the extracts, combine or not combine the extracts; or extract any 1 flavor, the other 1 flavor and the mixture of the remaining 2 flavors extracting separately to obtain each extract, merging or not merging each extract; or extracting 4 medicinal materials separately to obtain each extract, merging or not merging each extract;③步骤(1)中,所述乙醇的浓度为10%-99%、20%-90%、30%-80%、40%-80%、50%-80%、50%-70%或者60%-80%;③ In step (1), the concentration of the ethanol is 10%-99%, 20%-90%, 30%-80%, 40%-80%, 50%-80%, 50%-70% or 60% %-80%;④步骤(1)中,所述提取为回流提取或者煎煮;④ In step (1), the extraction is reflux extraction or decoction;⑤步骤(1)中,提取时间为至少0.5小时、至少1小时、至少2小时或者1-5小时;⑤ In step (1), the extraction time is at least 0.5 hour, at least 1 hour, at least 2 hours or 1-5 hours;⑥步骤(1)中,水或乙醇溶液的用量为5-20倍量(ml/g),优选为8-16倍量;6. In step (1), the consumption of water or ethanol solution is 5-20 times the amount (ml/g), preferably 8-16 times the amount;⑦步骤(2)中,所述浓缩为减压浓缩;7. In step (2), the concentration is concentration under reduced pressure;⑧步骤(2)中,所述浓缩物为浸膏。8. In the step (2), the concentrate is an extract.
- 根据权利要求5至6中任一权利要求所述的提取物,其中,The extract according to any one of claims 5 to 6, wherein,步骤(1)包括如下步骤:Step (1) comprises the following steps:将女贞子、墨旱莲分别提取,得到女贞子提取液和墨旱莲提取液;将女贞子提取后的药渣与鸡血藤和牛膝的混合物进行提取,得到女贞子鸡血藤牛膝提取液;Extracting Ligustrum lucidum and Eclipta edulis separately to obtain Ligustrum lucidum extract and Eclipta edulis extract; extracting the mixture of Ligustrum lucidum extract and the mixture of Spatholobus Spatholobus and Achyranthes bidentata to obtain Ligustrum lucidum Spatholobus Spatholobus Achyranthes knuckle extract;优选地,步骤(2)包括如下步骤:Preferably, step (2) comprises the steps of:将女贞子提取液、墨旱莲提取液和女贞子鸡血藤牛膝提取液分别浓缩后混合或者合并各提取液后浓缩,得到提取物。Concentrate the Ligustrum lucidum extract, the Eclipta chinensis extract and the Ligustrum lucidum Caulis Spatholobus Achyranthes extract respectively and then mix or combine the extracts and then concentrate to obtain the extract.
- 一种药物制剂,其包含权利要求4至7中任一权利要求所述的提取物,以及一种或多种药学上可接受的辅料;A pharmaceutical preparation comprising the extract according to any one of claims 4 to 7, and one or more pharmaceutically acceptable excipients;优选地,按照生药的质量计算,所述药物制剂的单位剂量为10-60g,优选为15-40g或20-30g,更优选为25g。Preferably, the unit dose of the pharmaceutical preparation is 10-60 g, preferably 15-40 g or 20-30 g, more preferably 25 g, calculated according to the mass of the crude drug.
- 根据权利要求8所述的药物制剂,其为丸剂、片剂、颗粒剂、胶囊剂、酊剂或混悬剂。The pharmaceutical preparation according to claim 8, which is pill, tablet, granule, capsule, tincture or suspension.
- 根据权利要求8至9中任一权利要求所述的药物制剂,其还包含选自如下药物中的一种或多种:The pharmaceutical preparation according to any one of claims 8 to 9, further comprising one or more selected from the following drugs:钙剂、维生素D、双磷酸盐、雌激素例如雌二醇、雌激素受体调节剂、降钙素、甲状旁腺激素和骨保护素。Calcium, vitamin D, bisphosphonates, estrogens such as estradiol, estrogen receptor modulators, calcitonin, parathyroid hormone, and osteoprotegerin.
- 一种组合药物产品,其包含独立包装的第一产品和第二产品,A combination pharmaceutical product comprising a first product and a second product in separate packages,其中,in,所述第一产品包含权利要求1至3中任一权利要求所述的药物组合物、权利要求4至7中任一权利要求所述的提取物或者权利要求8至9中任一权利要求所述的药物制剂;The first product comprises the pharmaceutical composition according to any one of claims 1 to 3, the extract according to any one of claims 4 to 7, or the extract according to any one of claims 8 to 9. the above-mentioned pharmaceutical preparations;所述第二产品包含选自如下药物中的一种或多种:The second product contains one or more selected from the following drugs:钙剂、维生素D、双磷酸盐、雌激素例如雌二醇、雌激素受体调节剂、降钙素、 甲状旁腺激素和骨保护素;Calcium, vitamin D, bisphosphonates, estrogens such as estradiol, estrogen receptor modulators, calcitonin, parathyroid hormone, and osteoprotegerin;优选地,所述第二产品还包含一种或多种药学上可接受的辅料;Preferably, the second product further comprises one or more pharmaceutically acceptable excipients;优选地,按照生药的质量计算,所述第一产品的单位剂量为10-60g,优选为15-40g或20-30g,更优选为25g。Preferably, the unit dose of the first product is 10-60g, preferably 15-40g or 20-30g, more preferably 25g, calculated according to the mass of the crude drug.
- 权利要求1至3中任一权利要求所述的药物组合物、权利要求4至7中任一权利要求所述的提取物或者权利要求8至9中任一权利要求所述的药物制剂在制备治疗和/或预防骨质疏松症、围绝经期综合症、便秘或肥胖的药物、或者降血脂的药物中的用途;The pharmaceutical composition according to any one of claims 1 to 3, the extract according to any one of claims 4 to 7 or the pharmaceutical preparation according to any one of claims 8 to 9 are prepared Use in medicines for treating and/or preventing osteoporosis, perimenopausal syndrome, constipation or obesity, or medicines for lowering blood lipids;优选地,所述骨质疏松症为原发性骨质疏松症或继发性骨质疏松症;Preferably, the osteoporosis is primary osteoporosis or secondary osteoporosis;优选地,所述骨质疏松症为绝经后骨质疏松症或老年性骨质疏松症;Preferably, the osteoporosis is postmenopausal osteoporosis or senile osteoporosis;优选地,所述骨质疏松症为围绝经期骨质疏松症;Preferably, the osteoporosis is perimenopausal osteoporosis;优选地,所述肥胖为更年期肥胖。Preferably, the obesity is climacteric obesity.
- 根据权利要求12所述的用途,其中,每千克体重每天的给药剂量为0.1g-2g、0.2g-1g或0.4g-0.8g,优选为0.5g。The use according to claim 12, wherein the dosage per kilogram of body weight per day is 0.1g-2g, 0.2g-1g or 0.4g-0.8g, preferably 0.5g.
- 一种制备提取物的方法,包括如下步骤:A method for preparing an extract, comprising the steps of:(1)用水或乙醇溶液对权利要求1至3中任一权利要求所述重量份的女贞子、墨旱莲、鸡血藤和牛膝进行提取,得到提取液;(1) Extracting Ligustrum lucidum, Eclipta chinensis, Gallis Spatholobus and Achyranthes bidentata of any one of claims 1 to 3 by weight with water or ethanol solution, to obtain an extract;(2)将提取液浓缩,得到浓缩物,为提取物。(2) Concentrate the extract to obtain a concentrate, which is the extract.
- 根据权利要求14所述的制备方法,其特征在于如下的①-⑧项中的任意一项或者多项:The preparation method according to claim 14, characterized in that any one or more of the following ①-⑧ items:①步骤(1)中,所述提取为一次或多次,当为多次时,合并各次的提取液;1. In step (1), the extraction is one or more times, and when it is multiple times, the extracts of each time are combined;②步骤(1)中,将女贞子、墨旱莲、鸡血藤和牛膝的混合物进行提取;或者将其中的任意1味以及其余3味的混合物分别提取得到各提取液,合并或不合并各提取液;或者将其中的任意2味的混合物以及其余2味的混合物分别提取得到各提取液,合并或不合并各提取液;或者将其中的任意1味、另外一味以及其余2味的混合物分别提取得到各提取液,合并或不合并各提取液;或者将4味药材分别提取得到各提取 液,合并或不合并各提取液;② In step (1), extract the mixture of Ligustrum lucidum, Eclipta chinensis, Caulis Spatholobus and Achyranthes bidentata; or extract any 1 flavor and the mixture of the remaining 3 flavors to obtain the respective extracts, combined or not Each extract; or extract the mixture of any 2 flavors and the mixture of the remaining 2 flavors separately to obtain the extracts, combine or not combine the extracts; or extract any 1 flavor, the other 1 flavor and the mixture of the remaining 2 flavors extracting separately to obtain each extract, merging or not merging each extract; or extracting 4 medicinal materials separately to obtain each extract, merging or not merging each extract;③步骤(1)中,所述乙醇的浓度为10%-99%、20%-90%、30%-80%、40%-80%、50%-80%、50%-70%或者60%-80%;③ In step (1), the concentration of the ethanol is 10%-99%, 20%-90%, 30%-80%, 40%-80%, 50%-80%, 50%-70% or 60% %-80%;④步骤(1)中,所述提取为回流提取或者煎煮;④ In step (1), the extraction is reflux extraction or decoction;⑤步骤(1)中,提取时间为至少0.5小时、至少1小时、至少2小时或者1-5小时;⑤ In step (1), the extraction time is at least 0.5 hour, at least 1 hour, at least 2 hours or 1-5 hours;⑥步骤(1)中,水或乙醇溶液的用量为5-20倍量(ml/g),优选为8-16倍量;6. In step (1), the consumption of water or ethanol solution is 5-20 times the amount (ml/g), preferably 8-16 times the amount;⑦步骤(2)中,所述浓缩为减压浓缩;7. In step (2), the concentration is concentration under reduced pressure;⑧步骤(2)中,所述浓缩物为浸膏。8. In the step (2), the concentrate is an extract.
- 根据权利要求14至15中任一权利要求所述的制备方法,其中,The preparation method according to any one of claims 14 to 15, wherein,步骤(1)包括如下步骤:Step (1) comprises the following steps:将女贞子、墨旱莲分别提取,得到女贞子提取液和墨旱莲提取液;将女贞子提取后的药渣与鸡血藤和牛膝的混合物进行提取,得到女贞子鸡血藤牛膝提取液;Extracting Ligustrum lucidum and Eclipta edulis separately to obtain Ligustrum lucidum extract and Eclipta edulis extract; extracting the mixture of Ligustrum lucidum extract and the mixture of Spatholobus Spatholobus and Achyranthes bidentata to obtain Ligustrum lucidum Spatholobus Spatholobus Achyranthes knuckle extract;优选地,步骤(2)包括如下步骤:Preferably, step (2) comprises the steps of:将女贞子提取液、墨旱莲提取液和女贞子鸡血藤牛膝提取液分别浓缩后混合或者合并各提取液后浓缩,得到提取物。Concentrate the Ligustrum lucidum extract, the Eclipta chinensis extract and the Ligustrum lucidum Caulis Spatholobus Achyranthes extract respectively and then mix or combine the extracts and then concentrate to obtain the extract.
- 一种治疗和/或预防骨质疏松症、围绝经期综合症、便秘或肥胖或者降血脂的方法,包括给予有需求的受试者以有效量的权利要求1至3中任一权利要求所述的药物组合物、权利要求4至7中任一权利要求所述的提取物或者权利要求8至9中任一权利要求所述的药物制剂的步骤;A method for treating and/or preventing osteoporosis, perimenopausal syndrome, constipation or obesity or lowering blood lipids, comprising administering to a subject in need an effective amount of any one of claims 1 to 3 The steps of the pharmaceutical composition, the extract according to any one of claims 4 to 7, or the pharmaceutical preparation according to any one of claims 8 to 9;优选地,所述骨质疏松症为原发性骨质疏松症或继发性骨质疏松症;Preferably, the osteoporosis is primary osteoporosis or secondary osteoporosis;优选地,所述骨质疏松症为绝经后骨质疏松症或老年性骨质疏松症;Preferably, the osteoporosis is postmenopausal osteoporosis or senile osteoporosis;优选地,所述骨质疏松症为围绝经期骨质疏松症;Preferably, the osteoporosis is perimenopausal osteoporosis;优选地,所述肥胖为更年期肥胖。Preferably, the obesity is climacteric obesity.
- 根据权利要求17所述的方法,其中,每千克体重每天的给药剂量为0.1g-2g、0.2g-1g或0.4g-0.8g,优选为0.5g。The method according to claim 17, wherein the dosage per kilogram of body weight per day is 0.1g-2g, 0.2g-1g or 0.4g-0.8g, preferably 0.5g.
- 根据权利要求1至3中任一权利要求所述的药物组合物、权利要求4至7中任一权利要求所述的提取物或者权利要求8至9中任一权利要求所述的药物制剂,其用于治疗和/或预防骨质疏松症、围绝经期综合症、便秘或肥胖或者降血脂;According to the pharmaceutical composition according to any one of claims 1 to 3, the extract according to any one of claims 4 to 7 or the pharmaceutical preparation according to any one of claims 8 to 9, It is used for the treatment and/or prevention of osteoporosis, perimenopausal syndrome, constipation or obesity or lowering blood lipids;优选地,所述骨质疏松症为原发性骨质疏松症或继发性骨质疏松症;Preferably, the osteoporosis is primary osteoporosis or secondary osteoporosis;优选地,所述骨质疏松症为绝经后骨质疏松症或老年性骨质疏松症;Preferably, the osteoporosis is postmenopausal osteoporosis or senile osteoporosis;优选地,所述骨质疏松症为围绝经期骨质疏松症;Preferably, the osteoporosis is perimenopausal osteoporosis;优选地,所述肥胖为更年期肥胖。Preferably, the obesity is climacteric obesity.
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Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101664480A (en) * | 2009-10-10 | 2010-03-10 | 吴理靖 | Chinese herbal medicine medicament for treating hyperosteogeny |
CN102247420A (en) * | 2011-07-04 | 2011-11-23 | 浙江大学 | Preparation method and application of eclipta extract |
CN107006681A (en) * | 2016-01-28 | 2017-08-04 | 柳泓善 | Animal feed composition containing Chinese medicinal material extract |
CN112755072A (en) * | 2021-02-09 | 2021-05-07 | 天津中医药大学 | Application of two formulas in preparation of medicine for preventing and treating constipation |
CN114344361A (en) * | 2021-05-14 | 2022-04-15 | 天津中医药大学 | Pharmaceutical composition for preventing and treating osteoporosis |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
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CN109602817B (en) * | 2019-02-27 | 2021-06-25 | 兰州大学 | Traditional Chinese medicine composition for treating osteoporosis caused by estrogen deficiency |
CN110613851A (en) * | 2019-10-28 | 2019-12-27 | 天津中医药大学 | Application of two formulas in preparation of medicine for preventing and treating benign prostatic hyperplasia |
-
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Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101664480A (en) * | 2009-10-10 | 2010-03-10 | 吴理靖 | Chinese herbal medicine medicament for treating hyperosteogeny |
CN102247420A (en) * | 2011-07-04 | 2011-11-23 | 浙江大学 | Preparation method and application of eclipta extract |
CN107006681A (en) * | 2016-01-28 | 2017-08-04 | 柳泓善 | Animal feed composition containing Chinese medicinal material extract |
CN112755072A (en) * | 2021-02-09 | 2021-05-07 | 天津中医药大学 | Application of two formulas in preparation of medicine for preventing and treating constipation |
CN114344361A (en) * | 2021-05-14 | 2022-04-15 | 天津中医药大学 | Pharmaceutical composition for preventing and treating osteoporosis |
Non-Patent Citations (3)
Title |
---|
YAO GAN, HE ZONG-YU: "Study of Active Components with Immunoregulation from Erzhi Pill on Lymphocytes and Macrophages in Mice", LISHIZHEN MEDICINE AND MATERIA MEDICA RESEARCH, SHIZHEN GUOYI GUOYAO ZAZHISHE, CN, vol. 17, no. 10, 28 October 2006 (2006-10-28), CN , pages 1921 - 1923, XP093004208, ISSN: 1008-0805 * |
YU QIAOYING: "Clinical Observation of Erzhi Pill in Treating Menopausal Osteoporosis", STRAIT PHARMACEUTICAL JOURNAL = HAIXIA YAOXUE, ZHONGGUO YAOXUEHUI, FUJIAN, CN, vol. 21, no. 11, 15 November 2009 (2009-11-15), Fujian, CN , pages 169 - 170, XP093004209, ISSN: 1006-3765 * |
ZHONG XU, WANG CHEN,WANG AN-CHUN,ET AL.: "Effects of Nüzhenshuxin Formula on the Level of E2 in Serum, the Expression of ER in Arterial Wall and Histomorphology with Ovariectomized and High Fat Rats", ZHONGGUO LAONIANXUE ZAZHI, ZHONGGUO LAONIANXUE ZAZHI BIANJIBU, vol. 31, no. 20, 25 October 2011 (2011-10-25), pages 3949 - 3952, XP093004202, ISSN: 1005-9202 * |
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