WO2016110167A1 - Applications of 20(r)-ginsenosides rg3 in preparing medicament or healthcare product for use in treatment of osteoporosis and medicament - Google Patents

Applications of 20(r)-ginsenosides rg3 in preparing medicament or healthcare product for use in treatment of osteoporosis and medicament Download PDF

Info

Publication number
WO2016110167A1
WO2016110167A1 PCT/CN2015/096989 CN2015096989W WO2016110167A1 WO 2016110167 A1 WO2016110167 A1 WO 2016110167A1 CN 2015096989 W CN2015096989 W CN 2015096989W WO 2016110167 A1 WO2016110167 A1 WO 2016110167A1
Authority
WO
WIPO (PCT)
Prior art keywords
ginsenoside
extract
osteoporosis
medicament
group
Prior art date
Application number
PCT/CN2015/096989
Other languages
French (fr)
Chinese (zh)
Inventor
富力
刘正贤
鲁明明
王凯乾
惠敏
鲁岐
王硕
柳洋
冯雪
盖鑫
付强
付文斐
周庆丰
Original Assignee
富力
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 富力 filed Critical 富力
Publication of WO2016110167A1 publication Critical patent/WO2016110167A1/en

Links

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/70Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin

Definitions

  • the invention belongs to the field of medicine, and relates to a medicine or health food for treating osteoporosis, in particular to an application of a traditional Chinese medicine ginseng extract component in treating osteoporosis medicine or health food.
  • Osteoporosis is mainly divided into primary and secondary, primary except for idiopathic, divided into type I and type II, type I, also known as postmenopausal osteoporosis, is a high conversion type, the main reason It is a deficiency of estrogen; type II, also known as senile osteoporosis, is a low-transformation type due to ageing. Osteoporosis is caused by many factors. Its basic pathological mechanism is the defect of coupling of bone resorption and bone formation during bone metabolism, resulting in imbalance of calcium and phosphorus metabolism in the human body and causing a decrease in bone density. Clinical symptoms.
  • the most common symptom of primary osteoporosis is more common in low back pain, accounting for 70% to 80% of patients with pain.
  • the pain spreads along the spine to the sides, and the pain is relieved when lying on the back or sitting.
  • the pain is exacerbated during sedentary, the pain during the day is light, and the night and morning wake up, the waist bends, the muscles move, the cough, The stool is aggravated when it is hard. Bone pain can occur when the bone mass is lost by more than 12%.
  • New thoracolumbar vertebral compression fractures can also produce acute pain.
  • Spinal spinous processes in the corresponding sites can have strong tenderness and snoring pain. Generally, they can be gradually relieved after 2 to 3 weeks, and some patients may have chronic low back pain.
  • the corresponding spinal nerves can cause radiation pain in the extremities, sensory dyskinesia in both lower extremities, intercostal neuralgia, post-sternal pain similar to angina pectoris, and upper abdominal pain similar to acute abdomen. If the spinal cord and the horsetail are pressed, the bladder and rectum function will be affected. More often after the pain.
  • the front part of the vertebral body is composed of cancellous bone, and this part is the pillar of the body. It has a large weight, especially the 11th and 12th thoracic vertebrae and the 3rd lumbar vertebrae. The load is larger, it is easy to compress and deform, and the spine is tilted forward.
  • the back curvature is intensified, forming a hunchback.
  • the osteoporosis increases, and the kyphosis curvature increases, causing the knee joint to be significantly restrained.
  • Each person has 24 vertebral bodies.
  • the height of each vertebral body is about 2cm.
  • the vertebral body is compressed when the elderly are osteoporosis.
  • Each vertebral body is shortened by about 2mm, and the body length is shortened by an average of 3 ⁇ 6cm. Chest and lumbar compression fractures, posterior curvature of the spine, and thoracic deformity can significantly reduce lung capacity and maximum ventilation. Patients often have symptoms such as chest tightness, shortness of breath, and difficulty breathing.
  • the diagnosis of postmenopausal and senile osteoporosis first need to rule out secondary osteoporosis caused by various other reasons, such as hyperparathyroidism and multiple myeloma, osteomalacia, renal bone Malnutrition, osteogenesis in children, metastases, leukemia, and lymphoma.
  • Graded diagnosis of osteoporosis normal BMD or BMC within 1 standard deviation (SD) of normal adult bone mineral density; osteopenia for BMD or BMC is 1 to 2.5 lower than normal adult bone mineral density Standard deviation; osteoporosis is more than 2.5 standard deviations of BMD or BMC than normal adult bone mineral density; severe osteoporosis is more than 2.5 standard deviations lower than BMD or BMC than normal adult bone mineral density with One or more fragility fractures.
  • BMD or BMC can be measured in the central axis or peripheral bone in this diagnostic criteria.
  • Clinically used drugs for the prevention and treatment of osteoporosis include: calcium preparations, including Yidile, Kaisili, Calcium D, Leli, calcium gluconate oral solution, Longchang calcium + D oral solution, Jinde calcium , giant energy calcium and ultra-micro calcium; inhibit bone resorption drugs, such as dehydrogenation, Premarin tablets and Li Weiai; bisphosphonates, such as Fushanmei, Linlin, Bondlin and Gili Shuning; Osteogenic drugs, such as levidine; vitamins that promote mineralization, such as Fa-en (l ⁇ -hydroxyvitamin D3), Luo calcium (calcium triol), Menggewang (alfacalcitol), Qing (Alpha Calcium Tablets).
  • calcium preparations including Yidile, Kaisili, Calcium D, Leli, calcium gluconate oral solution, Longchang calcium + D oral solution, Jinde calcium , giant energy calcium and ultra-micro calcium
  • inhibit bone resorption drugs such as dehydrogenation, Premarin tablets and Li Weia
  • Surgical treatment is required only after fractures due to osteoporosis.
  • the purpose is to treat the fracture and restore normal function as soon as possible.
  • ginseng Chinese medicine modern medical research shows that the main functions and effects of ginseng are: the role of the central nervous system, anti-cancer anti-tumor effect, immune function regulation, anti-diabetes effect, enhance liver function, cardiovascular and cerebrovascular disorders Improvement, anti-arteriosclerosis, blood pressure regulation, and menopausal disorders and anti-osteoporosis, anti-fatigue, anti-oxidation, anti-aging and so on.
  • ginsenoside is widely studied and used. Among them, 20(R)-ginsenoside Rg3 is the most attractive. It is the main active ingredient of ginseng and has good safety. It has been made into anti-tumor oral preparation. It has been used clinically and has been intensively studied as an injection.
  • the inventors have extracted the active ingredient 20(R)-ginsenoside Rg3, and 20(R)-ginsenoside Rg3, from the ginseng medicinal materials by a large number of modern scientific researches using advanced separation and purification techniques.
  • the corresponding pharmaceutical preparations have been studied for pharmacodynamics and pharmacology of osteoporosis.
  • the results show that 20(R)-ginsenoside Rg3 monomer has clear pharmacological effects, strong efficacy in treating osteoporosis, low toxicity and safety. High in sex, it can provide a highly effective and low-toxic drug for the treatment of osteoporosis.
  • the primary object of the present invention is to provide the performance and efficacy of 20(R)-ginsenoside Rg3 in the treatment of osteoporosis in view of the technical problems existing in the above-mentioned drugs or health care products for treating osteoporosis, and to address the above-mentioned existing
  • a problem with the technology provides a new medicinal use of 20(R)-ginsenoside Rg3, a new application in the treatment of osteoporosis drugs or health foods.
  • an aspect of the present invention provides a use of 20(R)-ginsenoside Rg3 for the preparation of a medicament or a health care product for treating osteoporosis.
  • the medicament or health care product consists of 20(R)-ginsenoside Rg3 and a pharmaceutically acceptable carrier.
  • the 20(R)-ginsenoside Rg3 content is ⁇ 1%, preferably ⁇ 30%, further preferably ⁇ 60%, still more preferably ⁇ 80%, still more preferably ⁇ 98%.
  • the 20(R)-ginsenoside Rg3 content is from 1% to 98%; preferably from 30% to 80%, more preferably 60%.
  • pharmaceutically acceptable carriers are generally approved by health care professionals for this purpose and as inactive ingredients of the agent.
  • a compilation of pharmaceutically acceptable carriers can be found in the Handbook of Pharmaceutical excipients, 2nd edition, edited by A. Wade and PJ Weller; published by the American Pharmaceutical Association, Washington and The Pharmaceutical Press, London, 1994) found in the reference book.
  • the carrier comprises an excipient such as starch, water or the like; a lubricant such as magnesium stearate or the like; a disintegrating agent such as microcrystalline cellulose; a filler such as lactose; and a binder, Such as pregelatinized starch, dextrin, etc.; sweeteners; antioxidants; preservatives, flavors, spices, etc.
  • the medicament is in the form of a tablet, a capsule, a pill, a powder, a granule, a syrup, a solution, an emulsion, an injection, a spray, an aerosol, a gel, a cream, a tincture, a cataplasm, a rubber. It is in the form of a plaster or a plaster.
  • the 20(R)-ginsenoside Rg3 content is ⁇ 1%, preferably ⁇ 30%, further preferably ⁇ 60%, still more preferably ⁇ 80%, still more preferably ⁇ 98%.
  • Another aspect of the present invention provides a medicament or a health care product for treating osteoporosis containing 20(R)-ginsenoside Rg3.
  • the 20(R)-ginsenoside Rg3 content is ⁇ 1%, preferably ⁇ 30%, further preferably ⁇ 60%, still more preferably ⁇ 80%, still more preferably ⁇ 98%.
  • the 20(R)-ginsenoside Rg3 content is preferably from 1% to 98%, more preferably from 30% to 80%, still more preferably from 60%.
  • the ratio of the weight of the 20(R)-ginsenoside Rg3 to the total weight of the pharmaceutical or nutraceutical product is from 0.01 to 10:100, preferably from 0.1 to 10:100, further preferably from 1 to 10:100. .
  • the medicine or health care product is also extracted from Astragalus membranaceus, Salvia miltiorrhiza extract, Epimedium extract, Hawthorn extract, licorice extract, black sesame extract, ginger extract, grape seed extract, and pomegranate extract.
  • a plant a plant essential oil, arbutin, vitamin C and its derivatives, or vitamin E and its derivatives.
  • the medicament can be prepared into various dosage forms by methods well known in the art, such as tablets, capsules, pills, powders, granules, syrups, solutions, injections, sprays, aerosols, gels, creams. Agent, expectorant, cataplasm, rubber plaster or plaster.
  • the present invention also provides a method of treating osteoporosis comprising administering to a subject a therapeutically effective amount of a pharmaceutical composition of 20(R)-ginsenoside Rg3, wherein the therapeutically effective amount is 0.6 to 12 mg/kg ⁇ d. It is preferably 1 to 6 mg/kg ⁇ d, and more preferably 1.5 to 3 mg/kg ⁇ d.
  • terapéuticaally effective amount as used herein, unless otherwise indicated, is the amount of the agent in need of an effective effect; the “therapeutically effective amount” is adjustable and variable, and is ultimately determined by the medical personnel, the factors considered including the route of administration. And the general nature of the formulation, the recipient's weight, age, etc., and the nature and severity of the condition being treated.
  • the present invention has the following distinct advantages:
  • the present invention excavates a new medicinal value for the known compound 20(R)-ginsenoside Rg3, which is used for preventing and treating osteoporosis, and can be prepared into a medicament for treating osteoporosis or a health food. , thus opening up a new field for the application of ginseng herbs.
  • the 20(R)-ginsenoside Rg3 of the invention has strong pharmacological action, has remarkable efficacy in treating osteoporosis, has quick effect, small toxic and side effects, good safety, and can be taken for a long time, and has good medicinal prospects.
  • the raw materials of the invention have rich sources, low cost, safe clinical use, simple preparation process, can be made into various dosage forms, and have small dosage and convenient use, so it is easy to promote.
  • the invention can prepare a medicament for treating osteoporosis by using a single component of 20(R)-ginsenoside Rg3 active ingredient, and can also use 20(R)-ginsenoside Rg3 and other active ingredients (for example, with astragalus and salvia miltiorrhiza) , Epimedium, hawthorn, licorice, black sesame extract, ginger extract, grape seed extract, garnet extract, plant essential oil, arbutin, vitamin C and its derivatives or vitamin E and its derivatives) Recipe to prepare a compound drug for the treatment of osteoporosis.
  • ginsenoside Rg3 and starch were uniformly mixed, granules were prepared, and talc powder and magnesium stearate were added and uniformly mixed, and then pressed into 10,000 tablets.
  • Ginsenoside Rg3 (content 63%) 200g
  • the ginsenoside Rg3 and the starch were uniformly mixed, and then filled into capsules to prepare 10,000 tablets.
  • Ginsenoside Rg3 (content 98%) 10g
  • the ginsenoside Rg3 and the microcrystalline cellulose were uniformly mixed to form granules, which were bagged and made into 10,000 bags.
  • ginsenoside rg3, licorice extract, vitamin C and starch were uniformly mixed, granulation was carried out, and talc powder and magnesium stearate were added and mixed, and then pressed into 10,000 tablets.
  • Ginsenoside Rg3 Astragalus membranaceus extract, vitamin C and starch were uniformly mixed and filled into capsules to prepare 10,000 tablets.
  • Ginsenoside Rg3, hawthorn extract, vitamin C and sucrose powder were mixed and granulated, and then bagged to prepare 10,000 bags.
  • ginsenoside Rg3 is dissolved in a small amount of ethanol, Danshen extract, black sesame extract and glucose syrup are added, and finally deionized water is added to 100 ml to obtain.
  • Nilestriol tablets were produced by Beijing Sihuan Pharmaceutical Co., Ltd., National Pharmaceutical Standard Hl1020123, lmg/tablet, 10 tablets/box. The mixture was ground in a mortar before use and suspended in a suspension of 0.5% CMC-Na to form a 0.05 mg/ml suspension;
  • Negative control drug normal saline, provided by Ningxia Qiyuan National Medicine Co., Ltd., batch number 100221-1;
  • BIO-RAD type washing machine Model-680 type microplate reader, DHP-9082 type electrothermal constant temperature incubator, Olympus AU2700 automatic biochemical analyzer, TD5A-WS desktop low speed centrifuge, etc. are provided by Ningxia Medical University.
  • Ovariectomized model rats 10% chloral hydrate 30mg/kg intraperitoneal injection anesthesia, strict aseptic operation, take the midline incision into the abdominal cavity, completely remove the bilateral ovaries, completely stop bleeding, suture the muscles and skin in two layers, remove The ovary was confirmed by pathology: the sham operation group had the same incision as before, and the left and right mesenteric segments were removed after entering the abdominal cavity. The bilateral ovaries were removed and placed in vitro for 1 min. The weight was basically the same as that of the bilateral ovaries. , hemostasis suture. The wound was sprinkled with penicillin powder, and the wound was not infected after the operation, and healed on schedule. There was no periodic change in the continuous vaginal smear 5 days after oophorectomy, and the uterus was atrophied at autopsy.
  • RG3 high-dose group high-dose group
  • RG3 middle-dose group middle-dose group
  • RG3 low-dose group low-dose group
  • the model group was given normal saline, 2 ml/kg body weight, once daily for 12 weeks, and the sham operation group was treated with the same model group.
  • the high, medium and low dose groups of RG3 were given 6 mg/kg, 3 mg/kg and 1.5 mg/kg, respectively. Once a day for 12 consecutive weeks.
  • the positive control group was intragastrically administered with nylestriol 0.15 mg/kg once a week, and distilled water 6 times per week, 2 ml/kg for 12 weeks. Freely drink water and eat for 12 weeks in the same environment to control the amount of food.
  • each group of animals was anesthetized by intraperitoneal injection of 10% chloral hydrate (30 ml/kg) after the last administration.
  • the prone position was placed on the dual-energy X-ray bone density diagnostic apparatus, and the small animal measurement software was used.
  • the 1-5 lumbar vertebrae and femur were scanned in the resolution mode.
  • the scanning parameters were: l.0xl.0mm, 60mm/s, 12.00cm REV3.9.3/2.1.0, precision 1.5%, accuracy 90%. .
  • Positive control drug Nilestriol tablets were produced by Beijing Sihuan Pharmaceutical Co., Ltd., National Pharmaceutical Standard Hl1020123, lmg/tablet, 10 tablets/box.
  • Retinoic acid tablets produced by Shandong Liangfu Pharmaceutical Co., Ltd., national medicine quasi-word H20083494, 10mg / piece, 20 pieces / box.
  • Estradiol (E2) Quantitative Assay Kit (Chemiluminescence Method) Xiamen Bosheng Biotechnology Co., Ltd.
  • Insulin-like growth factor-receptor I/II (IGF-I/IIR) ELISA kit Shanghai Jianglai Biotechnology Co., Ltd.
  • Wistar rats 50 females, half male and half female, weighing 180g ⁇ 220, 3 months old, purchased from Experimental Animal Center of Dalian Medical University, quality certificate number: SCXK (13) 2012-0003.
  • the rats were fed adaptively for 3 days, 10 were randomly selected as the normal control group, and the remaining 40 were modeled. 75 mg/kg.d retinoic acid was administered for 15 days, and the control group was orally administered with the same amount of distilled water.
  • mice Thirty mice were randomly divided into model group, RG3 group, nylestriol treatment group, plus normal group, a total of 4 groups, 10 in each group.
  • each group of rats began to be treated with lml/100g dose.
  • the normal group 0.9% normal saline; the model group: 0.9% normal saline; rg3 group: 6mg/1kg Body weight of rg3; the above four groups of rats were intragastrically administered once a day, the control group: nylestriol was administered, and a suspension of 0.2 mg/ml was prepared with physiological saline before use, and 1 ml/100 g was administered once a week.
  • the stomach is not restricted to eating and drinking, and the cycle is 8 weeks.
  • Rat serological examination After the end of the experiment, the rats in each group were taken with eyeballs, centrifuged, and stored in a refrigerator at -20 °C.
  • the radioimmunoassay method was used to determine the serum of the rats: estradiol (E2), osteocalcin (BGP), calcitonin (CT), and insulin-like growth factor-I (IGI-I), all of which were performed strictly according to the kit instructions.
  • IGI-I insulin-like growth factor-I

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Epidemiology (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Molecular Biology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines Containing Plant Substances (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

Applications of 20(R)-ginsenosides Rg3 in preparing a medicament for use in treatment of osteoporosis and the medicament or a healthcare product comprising 20(R)-ginsenosides Rg3, where the content of 20(R)-ginsenosides Rg3 is ≥ 1%.

Description

20(R)-人参皂苷Rg3在制备用于治疗骨质疏松症的药物或保健品中的应用及药物Application of 20(R)-ginsenoside Rg3 in preparing medicines or health care products for treating osteoporosis 技术领域Technical field
本发明属于医药领域,涉及一种治疗骨质疏松症的药物或保健食品,特别涉及一种中药人参提取成分在治疗骨质疏松症药物或保健食品中的应用。The invention belongs to the field of medicine, and relates to a medicine or health food for treating osteoporosis, in particular to an application of a traditional Chinese medicine ginseng extract component in treating osteoporosis medicine or health food.
背景技术Background technique
骨质疏松症主要分为原发性和继发性,原发性除特发性外,分为I型和II型,I型又称为绝经后骨质疏松,为高转换型,主要原因为雌性激素缺乏;II型又称为老年性骨质疏松,为低转换型,由于年龄的老化。骨质疏松症由多种因素所致,它的基本病理机理是骨代谢过程中骨吸收和骨形成的偶联出现缺陷,导致人体内的钙磷代谢不平衡,使骨密度逐渐减少而引起的临床症状。Osteoporosis is mainly divided into primary and secondary, primary except for idiopathic, divided into type I and type II, type I, also known as postmenopausal osteoporosis, is a high conversion type, the main reason It is a deficiency of estrogen; type II, also known as senile osteoporosis, is a low-transformation type due to ageing. Osteoporosis is caused by many factors. Its basic pathological mechanism is the defect of coupling of bone resorption and bone formation during bone metabolism, resulting in imbalance of calcium and phosphorus metabolism in the human body and causing a decrease in bone density. Clinical symptoms.
原发性骨质疏松症最常见的症症,以腰背痛多见,占疼痛患者中的70%~80%。疼痛沿脊柱向两侧扩散,仰卧或坐位时疼痛减轻,直立时后伸或久立、久坐时疼痛加剧,日间疼痛轻,夜间和清晨醒来时加重,弯腰、肌肉运动、咳嗽、大便用力时加重。一般骨量丢失12%以上时即可出现骨痛。老年骨质疏松症时,椎体骨小梁萎缩,数量减少,椎体压缩变形,脊柱前屈,腰疹肌为了纠正脊柱前屈,加倍收缩,肌肉疲劳甚至痉挛,产生疼痛。新近胸腰椎压缩性骨折,亦可产生急性疼痛,相应部位的脊柱棘突可有强烈压痛及叩击痛,一般2~3周后可逐渐减轻,部分患者可呈慢性腰痛。若压迫相应的脊神经可产生四肢放射痛、双下肢感觉运动障碍、肋间神经痛、胸骨后疼痛类似心绞痛,也可出现上腹痛类似急腹症。若压迫脊髓、马尾还中影响膀胱、直肠功能。多在疼痛后出现。脊椎椎体前部几乎多为松质骨组成,而且此部位是身体的支柱,负重量大,尤其第11、12胸椎及第3腰椎,负荷量更大,容易压缩变形,使脊椎前倾,背曲加剧,形成驼背,随着年龄增长,骨质疏松加重,驼背曲度加大,致使膝关节挛拘显著。每人有24节椎体,正常人每一椎体高度约2cm左右,老年人骨质疏松时椎体压缩,每椎体缩短2mm左右,身长平均缩短3~6cm。胸、腰椎压缩性骨折,脊椎后弯,胸廓畸形,可使肺活量和最大换气量显著减少,患者往往可出现胸闷、气短、呼吸困难等症状。 The most common symptom of primary osteoporosis is more common in low back pain, accounting for 70% to 80% of patients with pain. The pain spreads along the spine to the sides, and the pain is relieved when lying on the back or sitting. When standing up or standing upright, the pain is exacerbated during sedentary, the pain during the day is light, and the night and morning wake up, the waist bends, the muscles move, the cough, The stool is aggravated when it is hard. Bone pain can occur when the bone mass is lost by more than 12%. In elderly osteoporosis, the vertebral trabecular bone atrophy, the number is reduced, the vertebral body is compressed and deformed, the spine is flexed, and the back rash muscle is used to correct the flexion of the spine, double the contraction, muscle fatigue and even paralysis. New thoracolumbar vertebral compression fractures can also produce acute pain. Spinal spinous processes in the corresponding sites can have strong tenderness and snoring pain. Generally, they can be gradually relieved after 2 to 3 weeks, and some patients may have chronic low back pain. If the corresponding spinal nerves are compressed, it can cause radiation pain in the extremities, sensory dyskinesia in both lower extremities, intercostal neuralgia, post-sternal pain similar to angina pectoris, and upper abdominal pain similar to acute abdomen. If the spinal cord and the horsetail are pressed, the bladder and rectum function will be affected. More often after the pain. The front part of the vertebral body is composed of cancellous bone, and this part is the pillar of the body. It has a large weight, especially the 11th and 12th thoracic vertebrae and the 3rd lumbar vertebrae. The load is larger, it is easy to compress and deform, and the spine is tilted forward. The back curvature is intensified, forming a hunchback. As the age increases, the osteoporosis increases, and the kyphosis curvature increases, causing the knee joint to be significantly restrained. Each person has 24 vertebral bodies. The height of each vertebral body is about 2cm. The vertebral body is compressed when the elderly are osteoporosis. Each vertebral body is shortened by about 2mm, and the body length is shortened by an average of 3~6cm. Chest and lumbar compression fractures, posterior curvature of the spine, and thoracic deformity can significantly reduce lung capacity and maximum ventilation. Patients often have symptoms such as chest tightness, shortness of breath, and difficulty breathing.
绝经后和老年性骨质疏松症的诊断,首先需排除其他各种原因所致的继发性骨质疏松症,如甲状旁腺功能亢进和多发性骨髓瘤、骨质软化症、肾性骨营养不良、儿童的成骨不全、转移瘤、白血病以及淋巴瘤等。The diagnosis of postmenopausal and senile osteoporosis, first need to rule out secondary osteoporosis caused by various other reasons, such as hyperparathyroidism and multiple myeloma, osteomalacia, renal bone Malnutrition, osteogenesis in children, metastases, leukemia, and lymphoma.
骨质疏松症进行分级诊断:正常为BMD或BMC在正常成人骨密度平均值的1个标准差(SD)之内;骨质减少为BMD或BMC较正常成人骨密度平均值降低1~2.5个标准差;骨质疏松症为BMD或BMC较正常成人骨密度平均值降低2.5个标准差以上;严重骨质疏松症为BMD或BMC较正常成人骨密度平均值降低2.5个标准差以上并伴有1个或1个以上的脆性骨折。该诊断标准中BMD或BMC可在中轴骨或外周骨骼测定。Graded diagnosis of osteoporosis: normal BMD or BMC within 1 standard deviation (SD) of normal adult bone mineral density; osteopenia for BMD or BMC is 1 to 2.5 lower than normal adult bone mineral density Standard deviation; osteoporosis is more than 2.5 standard deviations of BMD or BMC than normal adult bone mineral density; severe osteoporosis is more than 2.5 standard deviations lower than BMD or BMC than normal adult bone mineral density with One or more fragility fractures. BMD or BMC can be measured in the central axis or peripheral bone in this diagnostic criteria.
临床上用来防治骨质疏松的药物有:钙制剂,包括有逸得乐、凯思立,钙尔奇D、乐力、葡萄糖酸钙口服液、龙昌钙+D口服液、劲得钙、巨能钙和超微钙;抑制骨吸收药物,如去氢孕嗣、倍美力片和利维爱等;双膦酸盐类,如福善美、骨麟、邦得林和吉力舒宁;成骨治疗药物,如特乐定;促进矿化的维生素类药物,如法能(lα-羟基维生素D3)、罗钙全(钙三醇)、萌格旺(阿法骨化醇)、立庆(阿法骨化醇片)。Clinically used drugs for the prevention and treatment of osteoporosis include: calcium preparations, including Yidile, Kaisili, Calcium D, Leli, calcium gluconate oral solution, Longchang calcium + D oral solution, Jinde calcium , giant energy calcium and ultra-micro calcium; inhibit bone resorption drugs, such as dehydrogenation, Premarin tablets and Li Weiai; bisphosphonates, such as Fushanmei, Linlin, Bondlin and Gili Shuning; Osteogenic drugs, such as levidine; vitamins that promote mineralization, such as Fa-en (lα-hydroxyvitamin D3), Luo calcium (calcium triol), Menggewang (alfacalcitol), Qing (Alpha Calcium Tablets).
只有在因骨质疏松症发生骨折以后,才需外科治疗,其目的在于治疗骨折,尽早恢复正常功能。Surgical treatment is required only after fractures due to osteoporosis. The purpose is to treat the fracture and restore normal function as soon as possible.
人参中药中名贵药材,现代医学研究表明人参的主要功效和作用有:对于神经中枢系统的作用,抗癌抗肿瘤作用,免疫功能调节作用,抗糖尿病的作用,增强肝功能作用,心脑血管障碍改善,抗动脉硬化作用,血压调节作用,以及更年期障碍和抗骨质疏松作用,抗疲劳,抗氧化,抑制衰老等。人参皂苷作为人参的主要有效成分,被广泛研究和使用,其中以20(R)-人参皂苷Rg3最为引人瞩目,其作为人参的主要有效成分,安全性良好,已经被制成抗肿瘤口服制剂应用于临床,作为注射剂被深入研究。The famous medicinal materials of ginseng Chinese medicine, modern medical research shows that the main functions and effects of ginseng are: the role of the central nervous system, anti-cancer anti-tumor effect, immune function regulation, anti-diabetes effect, enhance liver function, cardiovascular and cerebrovascular disorders Improvement, anti-arteriosclerosis, blood pressure regulation, and menopausal disorders and anti-osteoporosis, anti-fatigue, anti-oxidation, anti-aging and so on. As the main active ingredient of ginseng, ginsenoside is widely studied and used. Among them, 20(R)-ginsenoside Rg3 is the most attractive. It is the main active ingredient of ginseng and has good safety. It has been made into anti-tumor oral preparation. It has been used clinically and has been intensively studied as an injection.
本发明人通过大量的现代科学研究,采用先进的分离纯化技术从人参药材中提取其治疗骨质疏松症的有效成分20(R)-人参皂苷Rg3,并对20(R)-人参皂苷Rg3及其相应的药物制剂进行了治疗骨质疏松症的药效学、药理学研究,结果表明20(R)-人参皂苷Rg3单体药理作用清楚,治疗骨质疏松症功效强,毒副作用低,安全性高,可以为治疗骨质疏松症提供一种高效低毒的药物。 The inventors have extracted the active ingredient 20(R)-ginsenoside Rg3, and 20(R)-ginsenoside Rg3, from the ginseng medicinal materials by a large number of modern scientific researches using advanced separation and purification techniques. The corresponding pharmaceutical preparations have been studied for pharmacodynamics and pharmacology of osteoporosis. The results show that 20(R)-ginsenoside Rg3 monomer has clear pharmacological effects, strong efficacy in treating osteoporosis, low toxicity and safety. High in sex, it can provide a highly effective and low-toxic drug for the treatment of osteoporosis.
发明内容Summary of the invention
本发明的首要目的是针对上述现有治疗骨质疏松症的药物或保健品中存在的技术问题,提供20(R)-人参皂苷Rg3治疗骨质疏松症的性能和功效,并针对上述现有技术存在的问题,提供20(R)-人参皂苷Rg3新的药用用途,即在治疗骨质疏松症的药物或保健食品中的新应用。The primary object of the present invention is to provide the performance and efficacy of 20(R)-ginsenoside Rg3 in the treatment of osteoporosis in view of the technical problems existing in the above-mentioned drugs or health care products for treating osteoporosis, and to address the above-mentioned existing A problem with the technology provides a new medicinal use of 20(R)-ginsenoside Rg3, a new application in the treatment of osteoporosis drugs or health foods.
为实现本发明的目的,本发明一方面提供一种20(R)-人参皂苷Rg3在制备用于治疗骨质疏松症的药物或保健品中的应用。In order to achieve the object of the present invention, an aspect of the present invention provides a use of 20(R)-ginsenoside Rg3 for the preparation of a medicament or a health care product for treating osteoporosis.
在筛选具有治疗骨质疏松症作用的天然活性成分的过程中,发明人发现人参的化学成分中20(R)-人参皂苷Rg3具有强烈的治疗骨质疏松症的作用。In the process of screening natural active ingredients having an effect of treating osteoporosis, the inventors found that 20(R)-ginsenoside Rg3 in the chemical composition of ginseng has a strong therapeutic effect on osteoporosis.
其中,所述药物或保健品由20(R)-人参皂苷Rg3和药学上可接受的载体组成。Wherein the medicament or health care product consists of 20(R)-ginsenoside Rg3 and a pharmaceutically acceptable carrier.
其中,所述的20(R)-人参皂苷Rg3含量≥1%,优选为≥30%,进一步优选为≥60%,更进一步优选为≥80%,再更进一步优选为≥98%。Wherein the 20(R)-ginsenoside Rg3 content is ≥1%, preferably ≥30%, further preferably ≥60%, still more preferably ≥80%, still more preferably ≥98%.
特别是,所述的20(R)-人参皂苷Rg3含量为1%~98%;优选为30~80%,进一步优选为60%。In particular, the 20(R)-ginsenoside Rg3 content is from 1% to 98%; preferably from 30% to 80%, more preferably 60%.
特别是,药学上可接受的载体通常被保健专家认可用于这一目的且作为药剂的非活性成分。有关药学上可接受的载体的汇编可以在《药物赋形剂手册》(Handbook of Pharmaceutical excipients,第2版,由A.Wade和P.J.Weller编辑;American Pharmaceutical Association出版,Washington and The Pharmaceutical Press,London,1994)等工具书中找到。In particular, pharmaceutically acceptable carriers are generally approved by health care professionals for this purpose and as inactive ingredients of the agent. A compilation of pharmaceutically acceptable carriers can be found in the Handbook of Pharmaceutical excipients, 2nd edition, edited by A. Wade and PJ Weller; published by the American Pharmaceutical Association, Washington and The Pharmaceutical Press, London, 1994) found in the reference book.
尤其是,所述的载体包括赋形剂,如淀粉、水等;润滑剂,如硬脂酸镁等;崩解剂,如微晶纤维素等;填充剂,如乳糖等;粘结剂,如预胶化淀粉、糊精等;甜味剂;抗氧化剂;防腐剂、矫味剂、香料等。In particular, the carrier comprises an excipient such as starch, water or the like; a lubricant such as magnesium stearate or the like; a disintegrating agent such as microcrystalline cellulose; a filler such as lactose; and a binder, Such as pregelatinized starch, dextrin, etc.; sweeteners; antioxidants; preservatives, flavors, spices, etc.
其中,所述药物以片剂、胶囊剂、丸剂、散剂、颗粒剂、糖浆剂、溶液剂、乳剂、注射剂、喷雾剂、气雾剂、凝胶型、霜剂、酊剂、巴布剂、橡胶贴膏剂或贴膏剂形式存在。Wherein the medicament is in the form of a tablet, a capsule, a pill, a powder, a granule, a syrup, a solution, an emulsion, an injection, a spray, an aerosol, a gel, a cream, a tincture, a cataplasm, a rubber. It is in the form of a plaster or a plaster.
特别是,所述的20(R)-人参皂苷Rg3含量≥1%,优选为≥30%,进一步优选为≥60%,更进一步优选为≥80%,再更进一步优选为≥98%。In particular, the 20(R)-ginsenoside Rg3 content is ≥1%, preferably ≥30%, further preferably ≥60%, still more preferably ≥80%, still more preferably ≥98%.
本发明另一方面提供一种含有20(R)-人参皂苷Rg3的治疗骨质疏松症的药物或保健品。 Another aspect of the present invention provides a medicament or a health care product for treating osteoporosis containing 20(R)-ginsenoside Rg3.
其中,所述的20(R)-人参皂苷Rg3含量≥1%,优选为≥30%,进一步优选为≥60%,更进一步优选为≥80%,再更进一步优选为≥98%。Wherein the 20(R)-ginsenoside Rg3 content is ≥1%, preferably ≥30%, further preferably ≥60%, still more preferably ≥80%, still more preferably ≥98%.
特别是,所述的20(R)-人参皂苷Rg3含量优选为1%~98%;进一步优选为30~80%,更进一步优选为60%。In particular, the 20(R)-ginsenoside Rg3 content is preferably from 1% to 98%, more preferably from 30% to 80%, still more preferably from 60%.
特别是,所述20(R)-人参皂苷Rg3的重量与所述药物或保健品的总重量之比为0.01-10:100,优选为0.1~10:100,进一步优选为1~10:100。In particular, the ratio of the weight of the 20(R)-ginsenoside Rg3 to the total weight of the pharmaceutical or nutraceutical product is from 0.01 to 10:100, preferably from 0.1 to 10:100, further preferably from 1 to 10:100. .
特别是,所述药物或保健品中还黄芪提取物、丹参提取物、淫羊藿提取物、山茱萸提取物、甘草提取物、黑芝麻提取物、生姜提取物、葡萄子提取物、石榴子提取物、植物精油、熊果苷、维生素C及其衍生物或维生素E及其衍生物中的一种或多种。In particular, the medicine or health care product is also extracted from Astragalus membranaceus, Salvia miltiorrhiza extract, Epimedium extract, Hawthorn extract, licorice extract, black sesame extract, ginger extract, grape seed extract, and pomegranate extract. One or more of a plant, a plant essential oil, arbutin, vitamin C and its derivatives, or vitamin E and its derivatives.
所述药物可以采用本领域公知的方法制成各种剂型,如片剂、胶囊剂、丸剂、散剂、颗粒剂、糖浆剂、溶液剂、注射剂、喷雾剂、气雾剂、凝胶型、霜剂、酊剂、巴布剂、橡胶贴膏剂或贴膏剂等。The medicament can be prepared into various dosage forms by methods well known in the art, such as tablets, capsules, pills, powders, granules, syrups, solutions, injections, sprays, aerosols, gels, creams. Agent, expectorant, cataplasm, rubber plaster or plaster.
本发明还提供了一种治疗骨质疏松症的方法,包括向受试者给予治疗有效量的20(R)-人参皂苷Rg3的药物组合物,其治疗有效量为0.6~12mg/kg·d,优选为1~6mg/kg·d,进一步优选为1.5~3mg/kg·d。The present invention also provides a method of treating osteoporosis comprising administering to a subject a therapeutically effective amount of a pharmaceutical composition of 20(R)-ginsenoside Rg3, wherein the therapeutically effective amount is 0.6 to 12 mg/kg·d. It is preferably 1 to 6 mg/kg·d, and more preferably 1.5 to 3 mg/kg·d.
除非另外说明,本文所用的术语“治疗有效量”为需要产生有效作用的药物的用量;“治疗有效量”是可以调整和变化的,最终由医务人员确定,其所考虑的因素包括给药途径和制剂的性质、接受者的体重、年龄等一般情况以及所治疗疾病的性质和严重程度。The term "therapeutically effective amount" as used herein, unless otherwise indicated, is the amount of the agent in need of an effective effect; the "therapeutically effective amount" is adjustable and variable, and is ultimately determined by the medical personnel, the factors considered including the route of administration. And the general nature of the formulation, the recipient's weight, age, etc., and the nature and severity of the condition being treated.
与现有技术相比,本发明具有如下的明显优点:Compared with the prior art, the present invention has the following distinct advantages:
1、本发明对已知化合物20(R)-人参皂苷Rg3发掘了新的药用价值,将其用于预防、治疗骨质疏松症,并可制备成治疗骨质疏松症的药物或保健食品,从而为人参药材的应用开拓了一个新的领域。1. The present invention excavates a new medicinal value for the known compound 20(R)-ginsenoside Rg3, which is used for preventing and treating osteoporosis, and can be prepared into a medicament for treating osteoporosis or a health food. , thus opening up a new field for the application of ginseng herbs.
2、本发明的系列试验研究证明20(R)-人参皂苷Rg3具有显著的治疗骨质疏松症的功效。2. A series of experimental studies of the present invention demonstrate that 20(R)-ginsenoside Rg3 has significant efficacy in the treatment of osteoporosis.
3、本发明的20(R)-人参皂苷Rg3药理作用强,治疗骨质疏松症的功效显著,见效快、毒副作用小、安全性好,能够长期服用,具有良好的药用前景。3. The 20(R)-ginsenoside Rg3 of the invention has strong pharmacological action, has remarkable efficacy in treating osteoporosis, has quick effect, small toxic and side effects, good safety, and can be taken for a long time, and has good medicinal prospects.
4、本发明的产品原料来源丰富、价廉、临床使用安全,制备工艺简单,可制成各种剂型,且服量小,使用方便,因此易于推广。 4. The raw materials of the invention have rich sources, low cost, safe clinical use, simple preparation process, can be made into various dosage forms, and have small dosage and convenient use, so it is easy to promote.
5、本发明既可采用单一成分的20(R)-人参皂苷Rg3活性成分制备治疗骨质疏松症的药物,又可采用20(R)-人参皂苷Rg3与其它活性成分(例如与黄芪、丹参、淫羊藿、山茱萸、甘草、黑芝麻提取物、生姜提取物、葡萄子提取物、石榴子提取物、植物精油、熊果苷、维生素C及其衍生物或维生素E及其衍生物)共同组方,制备治疗骨质疏松症的复方药物。5. The invention can prepare a medicament for treating osteoporosis by using a single component of 20(R)-ginsenoside Rg3 active ingredient, and can also use 20(R)-ginsenoside Rg3 and other active ingredients (for example, with astragalus and salvia miltiorrhiza) , Epimedium, hawthorn, licorice, black sesame extract, ginger extract, grape seed extract, garnet extract, plant essential oil, arbutin, vitamin C and its derivatives or vitamin E and its derivatives) Recipe to prepare a compound drug for the treatment of osteoporosis.
具体实施例方式Specific embodiment
下面通过具体实施方式来进一步描述本发明所述配方的有益效果。这些实施例仅是范例性的,并不对本发明的范围构成任何限制。本领域技术人员应该理解的是,在不偏离本发明的配方思路、用途范围下可以对本发明技术方案的细节和形式进行修改或替换,但这些修改和替换均落入本发明的保护范围内The beneficial effects of the formulations of the present invention are further described below by way of specific embodiments. These examples are merely illustrative and are not intended to limit the scope of the invention in any way. It should be understood by those skilled in the art that the details and forms of the technical solutions of the present invention may be modified or replaced without departing from the spirit and scope of the invention, but such modifications and substitutions fall within the scope of the present invention.
下列实施例中未注明具体实验条件的实验方法,通常按照常规条件,或按照厂商所建议的条件。以下通过试验例来进一步阐述本发明所述药物的有益效果,这些试验例包括了本发明药物的药效学试验。The experimental methods in the following examples which do not specify the specific experimental conditions are usually in accordance with conventional conditions or according to the conditions recommended by the manufacturer. The beneficial effects of the medicament of the present invention are further illustrated by the following test examples, which include the pharmacodynamic test of the medicament of the present invention.
实施例1Rg3片剂Example 1 Rg3 tablet
1、按照如下配比准备原料1. Prepare raw materials according to the following ratio
Figure PCTCN2015096989-appb-000001
Figure PCTCN2015096989-appb-000001
将人参皂苷Rg3和淀粉混合均匀后,制成颗粒,加入滑石粉和硬脂酸镁混合均匀后压制成10000片。After ginsenoside Rg3 and starch were uniformly mixed, granules were prepared, and talc powder and magnesium stearate were added and uniformly mixed, and then pressed into 10,000 tablets.
实施例2Rg3胶囊剂Example 2 Rg3 capsule
1、按照如下配比准备原料1. Prepare raw materials according to the following ratio
人参皂苷Rg3(含量63%) 200gGinsenoside Rg3 (content 63%) 200g
淀粉                  1000gStarch 1000g
将人参皂苷Rg3和淀粉混合均匀后,装入胶囊,制成10000粒。 The ginsenoside Rg3 and the starch were uniformly mixed, and then filled into capsules to prepare 10,000 tablets.
实施例3Rg3颗粒剂Example 3 Rg3 granules
1、按照如下配比准备原料1. Prepare raw materials according to the following ratio
人参皂苷Rg3(含量98%) 10gGinsenoside Rg3 (content 98%) 10g
微晶纤维素            1000gMicrocrystalline cellulose 1000g
将人参皂苷Rg3和微晶纤维素混合均匀后制成颗粒,装袋,制成10000袋。The ginsenoside Rg3 and the microcrystalline cellulose were uniformly mixed to form granules, which were bagged and made into 10,000 bags.
实施例4Rg3片剂Example 4 Rg3 tablet
1、按照如下配比准备原料1. Prepare raw materials according to the following ratio
Figure PCTCN2015096989-appb-000002
Figure PCTCN2015096989-appb-000002
将人参皂苷rg3、甘草提取物、维生素C和淀粉混合均匀后,制粒,加入滑石粉和硬脂酸镁混匀后压制成10000片。After ginsenoside rg3, licorice extract, vitamin C and starch were uniformly mixed, granulation was carried out, and talc powder and magnesium stearate were added and mixed, and then pressed into 10,000 tablets.
实施例5Rg3胶囊剂Example 5 Rg3 capsule
Figure PCTCN2015096989-appb-000003
Figure PCTCN2015096989-appb-000003
将人参皂苷Rg3、黄芪提取物、维生素C和淀粉混合均匀后装入胶囊,制成10000粒。Ginsenoside Rg3, Astragalus membranaceus extract, vitamin C and starch were uniformly mixed and filled into capsules to prepare 10,000 tablets.
实施例6Rg3颗粒剂Example 6 Rg3 granules
Figure PCTCN2015096989-appb-000004
Figure PCTCN2015096989-appb-000004
Figure PCTCN2015096989-appb-000005
Figure PCTCN2015096989-appb-000005
将人参皂苷Rg3、山茱萸提取物、维生素C和蔗糖粉混合均匀制成颗粒后装袋,制成10000袋。Ginsenoside Rg3, hawthorn extract, vitamin C and sucrose powder were mixed and granulated, and then bagged to prepare 10,000 bags.
实施例7Rg3口服液Example 7 Rg3 oral solution
1、按照如下配比准备原料1. Prepare raw materials according to the following ratio
Figure PCTCN2015096989-appb-000006
Figure PCTCN2015096989-appb-000006
全方最终加去离子水至1000mlThe whole party will eventually add deionized water to 1000ml.
取人参皂苷Rg3用少量乙醇溶解后,加入丹参提取物、黑芝麻提取物和葡萄糖糖浆,最后补加去离子水至100ml,即得。After ginsenoside Rg3 is dissolved in a small amount of ethanol, Danshen extract, black sesame extract and glucose syrup are added, and finally deionized water is added to 100 ml to obtain.
试验例1 20(R)-人参皂苷Rg3抗骨质疏松症药效学实验Test Example 1 20(R)-ginsenoside Rg3 anti-osteoporosis pharmacodynamic experiment
1实验材料1 experimental material
1.1药物与试剂1.1 drugs and reagents
20(R)-人参皂苷Rg3,大连富生天然药物开发有限公司药物制剂研究室提供,批号:2012303;以中国药品生物制品检定所提供的人参皂苷Rg3标准品对照并进行HPLC标定,含量为98.2%;20(R)-ginsenoside Rg3, provided by Dalian Fusheng Natural Medicine Development Co., Ltd., Pharmaceutical Preparation Laboratory, batch number: 2012303; ginsenoside Rg3 standard provided by China National Institute for the Control of Pharmaceutical and Biological Products, and HPLC calibration, 98.2% ;
阳性对照药物:尼尔雌醇片由北京四环制药有限公司生产,国药准字Hl1020123号,lmg/片,10片/盒。使用前在碾钵中碾细后并以0.5%CMC-Na助悬配成0.05mg/m1混悬液;Positive control drug: Nilestriol tablets were produced by Beijing Sihuan Pharmaceutical Co., Ltd., National Pharmaceutical Standard Hl1020123, lmg/tablet, 10 tablets/box. The mixture was ground in a mortar before use and suspended in a suspension of 0.5% CMC-Na to form a 0.05 mg/ml suspension;
阴性对照药物:生理盐水,宁夏启元国药有限公司提供,批号员100221-1;Negative control drug: normal saline, provided by Ningxia Qiyuan National Medicine Co., Ltd., batch number 100221-1;
麻醉药:10%水合氯醛;Anesthetic: 10% chloral hydrate;
其余试剂均为分析纯。The remaining reagents were of analytical grade.
1.2实验动物1.2 experimental animals
8月龄Wistar雌性大鼠、体重220-310g,购自大连医科大学实验动物中心,质量合格证号:SCXK(13)2012-0003。Eight-month-old Wistar female rats weighing 220-310 g were purchased from Experimental Animal Center of Dalian Medical University, and the quality certificate number was SCXK (13) 2012-0003.
1.3实验仪器 1.3 experimental instruments
BIO-RAD型洗板机、Model-680型酶标仪、DHP-9082型电热恒温培养箱、Olympus AU2700全自动生化分析仪、TD5A-WS台式低速离心机等由宁夏医科大学提供。BIO-RAD type washing machine, Model-680 type microplate reader, DHP-9082 type electrothermal constant temperature incubator, Olympus AU2700 automatic biochemical analyzer, TD5A-WS desktop low speed centrifuge, etc. are provided by Ningxia Medical University.
2实验方法2 experimental methods
2.1造模方法2.1 modeling method
去卵巢模型鼠:10%水合氯醛30mg/kg腹腔注射麻醉,严格无菌操作,取腹部正中切口,进入腹腔,完整摘除双侧卵巢,彻底止血后,分两层依次缝合肌肉和皮肤,切除的卵巢均经病理学证实:假手术组切口同前,进入腹腔后切除左、右肠系膜各一段,取出双侧卵巢于体外放置lmin后还纳,其重量基本与两侧卵巢一致,不去卵巢,止血缝合。伤口撒青霉素粉末,术后伤口无感染,按期愈合。卵巢切除后5天连续阴道涂片无周期性的变化,尸检时子宫萎缩。Ovariectomized model rats: 10% chloral hydrate 30mg/kg intraperitoneal injection anesthesia, strict aseptic operation, take the midline incision into the abdominal cavity, completely remove the bilateral ovaries, completely stop bleeding, suture the muscles and skin in two layers, remove The ovary was confirmed by pathology: the sham operation group had the same incision as before, and the left and right mesenteric segments were removed after entering the abdominal cavity. The bilateral ovaries were removed and placed in vitro for 1 min. The weight was basically the same as that of the bilateral ovaries. , hemostasis suture. The wound was sprinkled with penicillin powder, and the wound was not infected after the operation, and healed on schedule. There was no periodic change in the continuous vaginal smear 5 days after oophorectomy, and the uterus was atrophied at autopsy.
2.2动物分组及给药方法2.2 Animal grouping and administration methods
造模后将48只Wistar大鼠按体重分层随机分为RG3高剂量组(简称高剂量组)、RG3中剂量组(简称中剂量组),RG3低剂量组(简称低剂量组)、阳性对照组、模型空白组、假手术组共6组,每组均8只大鼠,均于术后半月给药。模型组给予生理盐水灌胃,2ml/kg体重,每日一次连续12周,假手术组处理同模型组。RG3高、中、低剂量组分别给予6mg/kg、3mg/kg、1.5mg/kg。每日一次,连续12周。阳性对照组,以尼尔雌醇0.15mg/kg每周灌胃一次,另每周灌蒸馏水6次,2ml/kg,连续12周。在同样环境中自由饮水、摄食12周,控制食量。After modeling, 48 Wistar rats were randomly divided into RG3 high-dose group (high-dose group), RG3 middle-dose group (middle-dose group), RG3 low-dose group (low-dose group), and positive. There were 6 groups in the control group, model blank group and sham operation group, and 8 rats in each group were administered half a month after operation. The model group was given normal saline, 2 ml/kg body weight, once daily for 12 weeks, and the sham operation group was treated with the same model group. The high, medium and low dose groups of RG3 were given 6 mg/kg, 3 mg/kg and 1.5 mg/kg, respectively. Once a day for 12 consecutive weeks. The positive control group was intragastrically administered with nylestriol 0.15 mg/kg once a week, and distilled water 6 times per week, 2 ml/kg for 12 weeks. Freely drink water and eat for 12 weeks in the same environment to control the amount of food.
药物干预12周月后,各组动物于末次给药后,腹腔注射10%水合氯醛(30ml/kg)麻醉后,俯卧位置于双能X线骨密度诊断仪,用小动物测量软件在高分辨率模式下对大鼠第1-5腰椎和股骨进行扫描,扫描参数为:l.0xl.0mm,60mm/s,12.00cm REV3.9.3/2.1.0,精密度1.5%,准确度90%。After 12 weeks of drug intervention, each group of animals was anesthetized by intraperitoneal injection of 10% chloral hydrate (30 ml/kg) after the last administration. The prone position was placed on the dual-energy X-ray bone density diagnostic apparatus, and the small animal measurement software was used. The 1-5 lumbar vertebrae and femur were scanned in the resolution mode. The scanning parameters were: l.0xl.0mm, 60mm/s, 12.00cm REV3.9.3/2.1.0, precision 1.5%, accuracy 90%. .
3实验结果3 experimental results
采用SPSS11.0处理,所有数据先行正态性和方差齐性检验。各组大鼠骨密度测定结果的比较采用单因素方差分析,组间两两比较采用SNK-q检验,检验水准α=0.05,测定结果如表1所示。With SPSS11.0 processing, all data were tested for normality and homogeneity of variance. The results of bone mineral density measurement in each group were compared by one-way analysis of variance. The SNK-q test was used to compare the two groups. The test level was α=0.05. The results are shown in Table 1.
表1 RG3对去势雌鼠骨密度的影响(x±s n=8)Table 1 Effect of RG3 on bone mineral density in ovariectomized female rats (x±s n=8)
Figure PCTCN2015096989-appb-000007
Figure PCTCN2015096989-appb-000007
Figure PCTCN2015096989-appb-000008
Figure PCTCN2015096989-appb-000008
注:与模型组比较*:P<0.01,**:P<0.001。Note: Compared with the model group *: P < 0.01, **: P < 0.001.
由表1的实验结果可知:模型组与假手术组比较,股骨、腰椎骨及全身的骨密度明显下降(p<0.01),表明去卵巢雌鼠的骨矿含量明显下降;RG3高、中剂量组与模型组比较,显著提高了去卵巢雌鼠雌鼠相应部位的骨密度(p<0.01,p<0.001),表明RG3与尼尔雌醇都能明显增加去卵巢大鼠的骨矿含量。From the experimental results in Table 1, it can be seen that the bone density of femur, lumbar vertebrae and whole body decreased significantly in the model group compared with the sham operation group (p<0.01), indicating that the bone mineral content of the ovariectomized female rats decreased significantly; the high and medium doses of RG3 Compared with the model group, the bone density of the corresponding parts of female rats in ovariectomized rats was significantly increased (p<0.01, p<0.001), indicating that both RG3 and Nilestriol significantly increased the bone mineral content of ovariectomized rats.
试验例2 20(R)-人参皂苷Rg3对骨质疏松作用的实验研究Test Example 2 Experimental study on the effect of 20(R)-ginsenoside Rg3 on osteoporosis
1实验材料1 experimental material
1.1药物与试剂1.1 drugs and reagents
20(R)-人参皂苷Rg3(含量>98%),大连富生天然药物开发有限公司生产,批号:2012303;以中国药品生物制品检定所提供的人参皂苷Rg3标准品对照并进行HPLC标定,含量为98.2%;20(R)-ginsenoside Rg3 (content>98%), produced by Dalian Fusheng Natural Medicine Development Co., Ltd., batch number: 2012303; ginsenoside Rg3 standard provided by China National Institute for the Control of Pharmaceutical and Biological Products, and HPLC calibration, the content is 98.2%;
阳性对照药:尼尔雌醇片由北京四环制药有限公司生产,国药准字Hl1020123号,lmg/片,10片/盒。Positive control drug: Nilestriol tablets were produced by Beijing Sihuan Pharmaceutical Co., Ltd., National Pharmaceutical Standard Hl1020123, lmg/tablet, 10 tablets/box.
维甲酸片,山东良福制药有限公司生产,国药准字H20083494,10mg/片,20片/盒。Retinoic acid tablets, produced by Shandong Liangfu Pharmaceutical Co., Ltd., national medicine quasi-word H20083494, 10mg / piece, 20 pieces / box.
雌二醇(E2)定量测定试剂盒(化学发光法)厦门波生生物技术有限公司。Estradiol (E2) Quantitative Assay Kit (Chemiluminescence Method) Xiamen Bosheng Biotechnology Co., Ltd.
骨钙素(BGP)检测试剂盒  上海谷研实业有限公司。Osteocalcin (BGP) test kit Shanghai Guyan Industrial Co., Ltd.
人降钙素(CT)酶联免疫检测试剂盒  上海朗顿生物科技有限公司。Human calcitonin (CT) enzyme-linked immunosorbent assay kit Shanghai Langton Biotechnology Co., Ltd.
胰岛素样生长因子-受体I/Ⅱ(IGF-I/ⅡR)ELISA试剂盒  上海江莱生物科技有限公司。Insulin-like growth factor-receptor I/II (IGF-I/IIR) ELISA kit Shanghai Jianglai Biotechnology Co., Ltd.
1.2实验动物1.2 experimental animals
Wistar大鼠,50只,雌雄各半,体重180g~220,3月龄,购自大连医科大学实验动物中心,质量合格证号:SCXK(13)2012-0003。Wistar rats, 50 females, half male and half female, weighing 180g ~ 220, 3 months old, purchased from Experimental Animal Center of Dalian Medical University, quality certificate number: SCXK (13) 2012-0003.
2实验方法2 experimental methods
2.1动物模型制作2.1 Animal model making
大鼠适应性喂养3天,随机挑选10只作为正常对照组,其余40只造模,每只按 75mg/kg.d维甲酸灌喂15d,对照组用同等量的蒸馏水灌胃。The rats were fed adaptively for 3 days, 10 were randomly selected as the normal control group, and the remaining 40 were modeled. 75 mg/kg.d retinoic acid was administered for 15 days, and the control group was orally administered with the same amount of distilled water.
2.2动物分组2.2 Animal grouping
选择30只成模鼠随机分为模型组、RG3组、尼尔雌醇治疗对照组,另加正常组,共4组,每组10只。Thirty mice were randomly divided into model group, RG3 group, nylestriol treatment group, plus normal group, a total of 4 groups, 10 in each group.
2.3治疗方法2.3 treatment methods
造模成功并分组后,各组大鼠即开始按lml/100g剂量灌胃治疗,正常组:灌服0.9%生理盐水;模型组:灌服0.9%生理盐水;rg3组:灌服6mg/1kg体重的rg3;上述四组大鼠每日灌胃一次,对照组:灌服尼尔雌醇,使用前用生理盐水配成浓度为0.2mg/m1的混悬液,lml/100g每周一次灌胃,均不限制进食及饮水,周期为8周。After successful modeling and grouping, each group of rats began to be treated with lml/100g dose. The normal group: 0.9% normal saline; the model group: 0.9% normal saline; rg3 group: 6mg/1kg Body weight of rg3; the above four groups of rats were intragastrically administered once a day, the control group: nylestriol was administered, and a suspension of 0.2 mg/ml was prepared with physiological saline before use, and 1 ml/100 g was administered once a week. The stomach is not restricted to eating and drinking, and the cycle is 8 weeks.
2.4观察指标与指标检测方法2.4 Observation indicators and indicators detection methods
大鼠血清学检查:实验结束后,各组大鼠分别采用摘眼球取血,离心分离血清,放于-20℃冰箱中保存,应用放免测定法,分别测定大鼠血清如下指标:雌二醇(E2)、骨钙素(BGP)、降钙素(CT)、胰岛素样生长因子-I(IGI-I),以上均严格按试剂盒说明书进行。Rat serological examination: After the end of the experiment, the rats in each group were taken with eyeballs, centrifuged, and stored in a refrigerator at -20 °C. The radioimmunoassay method was used to determine the serum of the rats: estradiol (E2), osteocalcin (BGP), calcitonin (CT), and insulin-like growth factor-I (IGI-I), all of which were performed strictly according to the kit instructions.
3实验结果3 experimental results
3.1RG3对大鼠血清E2的影响Effect of 3.1RG3 on serum E2 in rats
大鼠血清中雌二醇(E2)的测定结果见表2。The results of the determination of estradiol (E2) in rat serum are shown in Table 2.
表2 RG3对大鼠血清E2的影响(x±s)Table 2 Effect of RG3 on serum E2 in rats (x±s)
组别Group 例数Number of cases E2(ng/L)E2(ng/L)
正常对照组Normal control group 1010 49.13±3.4249.13±3.42
模型对照组Model control group 1010 4.28±0.89*4.28±0.89*
RG3组RG3 group 1010 31.07±3.16*△□31.07±3.16*△□
阳性药物对照组Positive drug control group 1010 23.25±2.84*△23.25±2.84*△
注:与正常组比较*:P<0.01,与模型组比较△:P<0.01,与尼尔雌醇组比较□:P<0.01。Note: Compared with the normal group *: P <0.01, compared with the model group △: P <0.01, compared with the nylestriol group □: P <0.01.
表1的实验结果表明:给药8周后,正常对照组大鼠血清雌二醇含量最高,RG3组给药后可明显升高动物雌二醇含量,与模型组比较,有显著性差异(P<0.01)并明显优于对照组(P<0.01)说明RG3能明显升高实验动物雌二醇含量。The experimental results in Table 1 showed that the serum estradiol content was the highest in the normal control group after 8 weeks of administration, and the estradiol content in the RG3 group was significantly increased after administration. Compared with the model group, there was a significant difference ( P <0.01) and significantly better than the control group (P<0.01), indicating that RG3 can significantly increase the estradiol content of experimental animals.
3.2RG3对大鼠血清骨钙素(BGP)的影响的影响Effect of 3.2RG3 on the effect of serum osteocalcin (BGP) in rats
大鼠血清中骨钙素(BGP)的测定结果见表3。The results of the determination of osteocalcin (BGP) in rat serum are shown in Table 3.
表3 RG3对大鼠血清骨钙素(BGP)的影响(x±s) Table 3 Effect of RG3 on serum osteocalcin (BGP) in rats (x±s)
Figure PCTCN2015096989-appb-000009
Figure PCTCN2015096989-appb-000009
注:与正常组比较*:P<0.01,与模型组比较△:P<0.01,与尼尔雌醇组比较□:P<0.01。Note: Compared with the normal group *: P <0.01, compared with the model group △: P <0.01, compared with the nylestriol group □: P <0.01.
由表3可见:药物治疗后,大鼠血清骨钙素水平比较,模型对照组与正常对照组比较,有非常显著性差异(P<0.01),RG3治疗组与模型组及阳性药物(尼尔雌醇)组相比较有显著性差异(P<0.01)。It can be seen from Table 3 that after the drug treatment, the serum osteocalcin levels in the rats were compared, and the model control group was significantly different from the normal control group (P<0.01). The RG3 treatment group and the model group and the positive drug (Neil) There was a significant difference in the estradiol group (P<0.01).
3.3RG3对大鼠血清降钙素(CT)的影响的影响Effect of 3.3RG3 on the effect of serum calcitonin (CT) in rats
大鼠血清中降钙素(CT)的测定结果见表4。The results of measuring calcitonin (CT) in rat serum are shown in Table 4.
表4 RG3对大鼠CT的影响(x±s)Table 4 Effect of RG3 on rat CT (x±s)
Figure PCTCN2015096989-appb-000010
Figure PCTCN2015096989-appb-000010
注:与正常组比较*:P<0.01,与模型组比较△:P<0.01,与尼尔雌醇组比较□:P<0.01。Note: Compared with the normal group *: P <0.01, compared with the model group △: P <0.01, compared with the nylestriol group □: P <0.01.
由表4的测定结果可知:两个治疗组及正常对照组血清降钙素高于模型组(P<0.01),RG3组与阳性药物(尼尔雌醇)组比较效果明显(P<0.01),本实验表明,RG3能够显著提高骨质疏松大鼠血清降钙素水平。From the results of the measurement in Table 4, the serum calcitonin levels in the two treatment groups and the normal control group were higher than those in the model group (P<0.01), and the RG3 group was more effective than the positive drug (nilestriol) group (P<0.01). This experiment shows that RG3 can significantly increase serum calcitonin levels in osteoporotic rats.
3.4RG3对大鼠血清IGI-I(胰岛素样生长因子-I)的影响的影响Effect of 3.4RG3 on the serum IGI-I (insulin-like growth factor-I) in rats
大鼠血清中IGI-I(胰岛素样生长因子-I)的测定结果见表5。The results of measuring IGI-I (insulin-like growth factor-I) in rat serum are shown in Table 5.
表5 RG3对大鼠IGI-I的影响(x±s)Table 5 Effect of RG3 on rat IGI-I (x±s)
Figure PCTCN2015096989-appb-000011
Figure PCTCN2015096989-appb-000011
Figure PCTCN2015096989-appb-000012
Figure PCTCN2015096989-appb-000012
注:与正常组比较*:P<0.01,与模型组△:P<0.01,□与尼尔雌醇组:P<0.01。Note: Compared with the normal group *: P <0.01, and the model group △: P <0.01, □ and nylestriol group: P <0.01.
由表5可见:给药8周后,正常对照组大鼠血清IGI-I含量最高,RG3组给药后可明显升高动物IGI-I含量,与模型组比较,有显著性差异(P<0.01)组间比较,RG3组给药第8周后明显优于对照组(P<0.01),说明RG3能明显升高实验动物IGI-I含量。 It can be seen from Table 5 that the serum IGI-I content in the normal control group was the highest after 8 weeks of administration, and the IGI-I content in the RG3 group was significantly increased after administration. Compared with the model group, there was a significant difference (P< 0.01) Comparison between groups, RG3 group was significantly better than the control group after the 8th week (P<0.01), indicating that RG3 can significantly increase the IGI-I content of experimental animals.

Claims (10)

  1. 20(R)-人参皂苷Rg3在制备用于治疗骨质疏松症的药物或保健品中的应用。20(R)-Application of ginsenoside Rg3 in the preparation of a medicament or health care product for the treatment of osteoporosis.
  2. 根据权利要求1所述的应用,其特征是所述药物由20(R)-人参皂苷Rg3和药学上可接受的载体组成。The use according to claim 1, wherein the drug consists of 20(R)-ginsenoside Rg3 and a pharmaceutically acceptable carrier.
  3. 根据权利要求1或2所述的应用,其特征是所述药物以片剂、胶囊剂、丸剂、散剂、颗粒剂、糖浆剂、溶液剂、乳剂、注射剂、喷雾剂、气雾剂、凝胶型、霜剂、酊剂、巴布剂、橡胶贴膏剂或贴膏剂形式存在。The use according to claim 1 or 2, wherein the medicament is in the form of a tablet, a capsule, a pill, a powder, a granule, a syrup, a solution, an emulsion, an injection, a spray, an aerosol, or a gel. Form, cream, expectorant, cataplasm, rubber plaster or plaster.
  4. 根据权利要求1或2所述的应用,其特征是所述的20(R)-人参皂苷Rg3的含量≥1%。The use according to claim 1 or 2, characterized in that the content of the 20(R)-ginsenoside Rg3 is ≥1%.
  5. 根据权利要求4所述的应用,其特征是所述的20(R)-人参皂苷Rg3的含量为1%~98%。The use according to Claim 4, characterized in that the content of 20(R)-ginsenoside Rg3 is from 1% to 98%.
  6. 一种治疗骨质疏松症的药物或保健品,其特征是含有20(R)-人参皂苷Rg3。A medicament or health care product for treating osteoporosis, characterized by comprising 20(R)-ginsenoside Rg3.
  7. 根据权利要求6所述的药物或保健品,其特征是所述20(R)-人参皂苷Rg3的重量与所述药物或保健品的总重量之比为0.01-10:100。The pharmaceutical or nutraceutical according to claim 6, wherein the ratio of the weight of the 20(R)-ginsenoside Rg3 to the total weight of the drug or health care product is from 0.01 to 10:100.
  8. 根据权利要求6所述的药物或保健品,其特征是所述的20(R)-人参皂苷Rg3的含量为≥1%。The pharmaceutical or nutraceutical according to claim 6, wherein the content of 20(R)-ginsenoside Rg3 is ≥1%.
  9. 根据权利要求8所述的药物或保健品,其特征是所述的20(R)-人参皂苷Rg3的含量为1%~98%。The pharmaceutical or nutraceutical according to claim 8, wherein the 20(R)-ginsenoside Rg3 is contained in an amount of from 1% to 98%.
  10. 根据权利要求6所述的药物或保健品,其特征是还包括黄芪提取物、丹参提取物、淫羊藿提取物、山茱萸提取物、甘草提取物、黑芝麻提取物、生姜提取物、葡萄子提取物、石榴子提取物、植物精油、熊果苷、维生素C及其衍生物或维生素E及其衍生物 中的一种或多种。 The medicine or health care product according to claim 6, which further comprises astragalus extract, salvia miltiorrhiza extract, epimedium extract, hawthorn extract, licorice extract, black sesame extract, ginger extract, grape seed Extract, garnet extract, plant essential oil, arbutin, vitamin C and its derivatives or vitamin E and its derivatives One or more of them.
PCT/CN2015/096989 2015-01-06 2015-12-10 Applications of 20(r)-ginsenosides rg3 in preparing medicament or healthcare product for use in treatment of osteoporosis and medicament WO2016110167A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201510005661.8A CN105816469B (en) 2015-01-06 2015-01-06 Application of 20(R) -ginsenoside Rg3 in preparation of medicine or health product for treating osteoporosis and medicine
CN201510005661.8 2015-01-06

Publications (1)

Publication Number Publication Date
WO2016110167A1 true WO2016110167A1 (en) 2016-07-14

Family

ID=56355493

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2015/096989 WO2016110167A1 (en) 2015-01-06 2015-12-10 Applications of 20(r)-ginsenosides rg3 in preparing medicament or healthcare product for use in treatment of osteoporosis and medicament

Country Status (2)

Country Link
CN (1) CN105816469B (en)
WO (1) WO2016110167A1 (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110496131A (en) * 2018-05-18 2019-11-26 上海弘医堂生物医药科技有限公司 The application of total secondary ginseng glycoside composition, ginsenoside Rg 5, ginsenoside Rk1 and ginsenoside ck

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106389493A (en) * 2016-10-12 2017-02-15 王璐林 Drug for treating osteonecrosis and promoting bone repair
CN109170454A (en) * 2018-08-04 2019-01-11 安徽全康药业有限公司 A kind of preventing bone rarefaction ammonia sugar high calcium solid beverage
CN113663047A (en) * 2021-08-31 2021-11-19 广州白云山奇星药业有限公司 Composition with kidney tonifying and bone strengthening effects and preparation method thereof
CN115088833A (en) * 2022-05-20 2022-09-23 唛迪森营养科技(江苏)有限公司 Functional food for preventing and/or treating intestinal injury of tumor patient

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1323588A (en) * 2000-05-16 2001-11-28 广东医学院医药科技开发中心 New use of ginseng and ginseng stalk and leaf extractive in preventing and treating osteoposis
CN1947704A (en) * 2006-08-30 2007-04-18 富力 Medicinal water-soluble compositions contg. 20(R)-ginsenoside (Rg3), and its prepn. method
CN102283877A (en) * 2011-07-26 2011-12-21 上海市中医医院 Application of ginsenoside
CN103845349A (en) * 2012-11-30 2014-06-11 富力 Application of 20(R)-ginsenoside Rg3 in preparation of medicines for treating leucoderma
CN103845348A (en) * 2012-11-30 2014-06-11 富力 Application of 20(R)-ginsenoside Rg3 in preparation of medicines for treating dysmenorrhea

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104643058A (en) * 2013-11-21 2015-05-27 富力 Application of 20(R)-ginsenoside Rg3 in preparation of medicines for improving or/and treating liver cirrhosis diseases
CN104644652A (en) * 2013-11-22 2015-05-27 富力 Application of 20(R)-ginsenoside Rg3 in preparation of drug for treating depression and the drug

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1323588A (en) * 2000-05-16 2001-11-28 广东医学院医药科技开发中心 New use of ginseng and ginseng stalk and leaf extractive in preventing and treating osteoposis
CN1947704A (en) * 2006-08-30 2007-04-18 富力 Medicinal water-soluble compositions contg. 20(R)-ginsenoside (Rg3), and its prepn. method
CN102283877A (en) * 2011-07-26 2011-12-21 上海市中医医院 Application of ginsenoside
CN103845349A (en) * 2012-11-30 2014-06-11 富力 Application of 20(R)-ginsenoside Rg3 in preparation of medicines for treating leucoderma
CN103845348A (en) * 2012-11-30 2014-06-11 富力 Application of 20(R)-ginsenoside Rg3 in preparation of medicines for treating dysmenorrhea

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110496131A (en) * 2018-05-18 2019-11-26 上海弘医堂生物医药科技有限公司 The application of total secondary ginseng glycoside composition, ginsenoside Rg 5, ginsenoside Rk1 and ginsenoside ck
CN110496131B (en) * 2018-05-18 2022-09-06 上海弘医堂生物医药科技有限公司 Total secondary ginseng glycoside composition, ginsenoside Rg5, ginsenoside Rk1 and application of ginsenoside ck

Also Published As

Publication number Publication date
CN105816469A (en) 2016-08-03
CN105816469B (en) 2020-06-26

Similar Documents

Publication Publication Date Title
WO2016110167A1 (en) Applications of 20(r)-ginsenosides rg3 in preparing medicament or healthcare product for use in treatment of osteoporosis and medicament
CN106729599A (en) A kind of pharmaceutical composition for increasing bone density and its production and use
CN110638826A (en) Application of NADH and/or NMN in preparation of medicine or health-care product for strengthening muscle or inhibiting decrease of muscle mass
CN106880839B (en) Deer bone tablet and preparation method thereof
CN104127861B (en) A kind of have pharmaceutical composition increasing bone density effect and preparation method thereof
CN101309692A (en) Application of curbitacin or curbitacin combination in leucocyte increasing medicament preparation
EP3263114A1 (en) Use of albiflorin or pharmaceutically acceptable salt for prevention and/or treatment of irritable bowel syndrome
CN104013817A (en) Conic gymnadenia tuber-sealwort-radix polygonati officinalis preparation and production method thereof
WO2016124080A1 (en) Use of 20(r)-ginsenoside rg3 in preparation of drug for preventing or/and treating obesity and drug
CN104001157B (en) Compound preparation of a kind of protect against osteoporosis and preparation method thereof
WO2022237873A1 (en) Pharmaceutical composition for preventing and treating osteoporosis
WO2019134534A1 (en) Use of e-10-hydroxyl-2-decylenic acid in preparation of medicine or health care product for preventing and treating osteoporosis
US20080254151A1 (en) herbal mixture extract of rehmanniae radix preparata and acanthopanacis cortex and a composition comprising the same for prevention and treatment of osteoporosis
CN109771424B (en) Pharmaceutical composition for preventing and treating senile type II diabetic osteoporosis and application thereof
CN103142568B (en) Calcium acetate-vitamin K pharmaceutical preparation and preparation method thereof
JP2012525412A (en) Methods to reduce fat accumulation and induce weight loss
CN110897152A (en) Composition and capsule for increasing bone mineral density and preparation method thereof
EP3943095A1 (en) Traditional chinese medicine laxative composition for treating constipation, preparation method therefor and application thereof
CN105616581A (en) Glipizide-containing pharmaceutical composition for treating diabetes and preparation method thereof
CN103239543B (en) Chinese medicine effective part composition for treating gastroptosis and preparation method of Chinese medicine effective part composition
JP2019189572A (en) Exercise balance improver and agility improver
CN104161936B (en) A kind of Chinese medicine composition of prevention and treatment postmenopausal osteoporosiss and preparation method thereof
CN114558047B (en) Traditional Chinese medicine composition for preventing and treating osteoporosis and preparation method thereof
CN103877533B (en) Pharmaceutical composition of a kind for the treatment of diabetes containing metformin and preparation method thereof
WO2021179482A1 (en) Traditional chinese medicine compound composition having effect of promoting bone health as well as preparation method therefor and application thereof

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 15876667

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 15876667

Country of ref document: EP

Kind code of ref document: A1