WO2019134534A1 - Use of e-10-hydroxyl-2-decylenic acid in preparation of medicine or health care product for preventing and treating osteoporosis - Google Patents
Use of e-10-hydroxyl-2-decylenic acid in preparation of medicine or health care product for preventing and treating osteoporosis Download PDFInfo
- Publication number
- WO2019134534A1 WO2019134534A1 PCT/CN2018/122533 CN2018122533W WO2019134534A1 WO 2019134534 A1 WO2019134534 A1 WO 2019134534A1 CN 2018122533 W CN2018122533 W CN 2018122533W WO 2019134534 A1 WO2019134534 A1 WO 2019134534A1
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- Prior art keywords
- calcium
- health care
- osteoporosis
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- care product
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
- A61K31/201—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having one or two double bonds, e.g. oleic, linoleic acids
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/115—Fatty acids or derivatives thereof; Fats or oils
- A23L33/12—Fatty acids or derivatives thereof
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
Definitions
- the invention relates to the technical field of medicines or health care products for preventing and treating osteoporosis, in particular to the application of E-10-hydroxy-2-decenoic acid in preparing medicines or health care products for preventing and treating osteoporosis .
- Osteoporosis is a systemic bone disease characterized by low bone mass, bone microstructural destruction, increased bone fragility, and prone to fracture. According to the National Health and Nutrition Examination Survey III (NHANES III), more than 9.9 million Americans suffer from osteoporosis, and approximately 43.1 million Americans suffer from osteopenia. One in every two white women had an osteoporotic fracture in one lifetime, and one in every five men had an osteoporotic fracture. With the extension of human life and the advent of an aging society, osteoporosis has become a global health problem, and China is no exception. Studies have shown that in China, the number of people suffering from osteoporosis increases year by year at a rate of 20%, and the number of patients has expanded from the elderly to adolescents.
- the drugs approved by the Food and Drug Administration (FDA) for the treatment of osteoporosis include bisphosphonates, calcitonin, estrogen receptor modulators (raloxifene), and estrogen. , tissue selective estrogen complex (binding estrogen / apeledoxifene), PTH 1-34 (teriparatide) and RANKL mAb.
- bisphosphonates are FDA-approved indications for the treatment of osteoporosis in postmenopausal women and middle-aged men, as well as glucocorticoid-induced osteoporosis, but all bisphosphonates have similar adverse effects.
- Raloxifene is approved by the FDA for the prevention and treatment of osteoporosis in postmenopausal women.
- the overall safety of the drug is good, it will increase the incidence of hot flashes, in addition to slightly increase the risk of deep vein thrombosis, so there is a history of venous thrombosis and thrombosis (such as long-term bed rest and sedentary period); Although the above-mentioned drug treatment has a good control effect, there are many side effects in long-term use, so these drugs are mainly used as a phased therapeutic drug, and for those who need long-term use for the prevention and treatment of osteoporosis, Various conventional calcium preparations with no toxic side effects will still be selected, such as "calcium carbonate, calcium chloride, calcium phosphate, calcium acetate recommended in "Guidelines for the diagnosis and treatment of primary osteoporosis” (Chinese Journal of General Medicine, 2017.10).
- Calcium lactate, calcium citrate, calcium citrate, calcium gluconate, etc. mainly through sufficient calcium intake to obtain relatively better bone peaks, slow bone loss, improve bone mineralization, and maintain bone health.
- calcium carbonate has the highest calcium content (40%), followed by calcium phosphate (38.76%) and calcium acetate (36%), while calcium lactate and gluconic acid have calcium contents of 18.37% and 9.30, respectively. %, which is a type of calcium with a low calcium content.
- inorganic calcium such as calcium carbonate, calcium phosphate, calcium chloride and the like has low water solubility, small degree of ionization, and relatively poor absorption
- organic calcium acid such as calcium lactate, calcium acetate and calcium gluconate has good water solubility and degree of ionization.
- absorption rate is relatively higher than inorganic calcium.
- calcium organic acid due to the low calcium content, calcium organic acid must take a large amount of preparation to meet the calcium requirement, but the high dose is costly and has some side effects. In order to overcome these drawbacks, in recent years, technicians in the industry have been continuously researching and developing various organic calcium salts.
- the application method is 201611131011.9, which discloses a method for preparing calcium caseinate, which is based on traserine. After the solution of the dissolved calcium salt is squeezed and transformed to obtain a calcium caseinate solution, it is naturally cooled and dried, and the calcium caseinate powder is obtained by pulverization, and then the inulin is added. It has no need to add vitamin D, is easy to be absorbed and utilized by the human body, and has good absorption effect, and the calcium supplementing effect is better than the traditional products. Further, as disclosed in Application No.
- L-carnitine calcium fumarate and a use thereof are disclosed, wherein L-carnitine inner salt, fumaric acid and calcium hydroxide are proportioned, added to ethanol, and heated in water. It is refluxed, recovered by ethanol, left to stand, filtered and dried.
- the preparation is suitable for oral and injectable pharmaceutical preparations. It is chemically stable, has good fluidity, is easily soluble in water, is easy for human body to absorb, and has high bioavailability. It can be used clinically for calcium supplementation, cholesterol lowering, and prevention of cerebral arteriosclerosis.
- the industry has also reported the development and application of calcium sulphuric acid.
- ZL200610057359.8 discloses a royal jelly calcium and a preparation method thereof, which specifically adds a calcium agent (calcium lactate or carbonic acid) to the lyophilized powder of royal jelly.
- a calcium agent calcium lactate or carbonic acid
- Calcium, calcium gluconate), yogurt lyophilized powder, mannitol, glucose, dextrin and magnesium stearate are mixed to prepare royal jelly calcium; it is reported that the preparation can not only improve human immunity, delay aging, and fight human body For high temperature, etc., especially through the organic combination of royal jelly acid and calcium, promote the absorption and utilization of calcium in the body, and can treat senile osteoporosis under the synergistic effect.
- ZL201210063350.3 discloses calcium sulphuric acid and anti-atherosclerosis and osteoporosis health supplements made with vitamin K2, specifically by mixing calcium sulphuric acid calcium and vitamin K2 in a certain proportion to prepare middle-aged and elderly people.
- a health care product having good dual functions against atherosclerosis and osteoporosis the patent document describes that the prepared health care product has the effect of preventing and treating osteoporosis mainly because vitamin K2 can significantly increase ⁇ -carboxylated bone Calcium and the synthesis of matrix ⁇ -carboxyglutamic acid protein, from the source to solve the common pathogenic factors of atherosclerosis and osteoporosis - calcium metabolism disorder, while the calcium ion in calcium sulphuric acid is deposited in the bone orientation
- the purpose of prevention and treatment of osteoporosis It can be seen that the inorganic calcium and organic calcium acid preparations developed in the industry are aimed at preventing and treating osteoporosis by promoting the deposition and absorption of calcium ions in the human body.
- the object of the present invention is to provide an application of E-10-hydroxy-2-decenoic acid in the preparation of medicines or health care products for preventing and treating osteoporosis, so as to solve the long-term existence of drugs and health care products for preventing and treating osteoporosis. Taking more side effects and having a poorer effect on preventing and treating osteoporosis.
- the object of the present invention is achieved by the use of an E-10-hydroxy-2-decenoic acid for the preparation of a medicament or a health care product for preventing and treating osteoporosis.
- E-10-hydroxy-2-decenoic acid is a medium chain unsaturated fatty acid having a molecular formula of C 10 H 18 O 3 , abbreviated as 10-HAD, its chemical structure is:
- the E-10-hydroxy-2-decenoic acid is derived from artificial synthesis or extracted from royal jelly; the compound is one of the important components of royal jelly, so it is also called royal jelly acid, and the generally qualified royal jelly contains royal jelly acid (The quality of the superior grade is ⁇ 1.8%, and the content of qualified products is ⁇ 1.4%. It is a bee product with the same medicine and food, safe and suitable for long-term use.
- the E-10-hydroxy-2-decenoic acid provided by the present invention has a remarkable effect on postmenopausal osteoporosis type I and senile osteoporosis type II in osteoporosis.
- E-10-hydroxy-2-decenoic acid When used for preparing a medicine or a health care product for preventing osteoporosis, it may be prepared by adding a pharmaceutically acceptable auxiliary material, such as an excipient, a binder, and a lubricant which are generally used.
- a pharmaceutically acceptable auxiliary material such as an excipient, a binder, and a lubricant which are generally used.
- agents disintegrants, surfactants, glidants, etc.
- excipients include lactose, fructose, glucose, corn starch, sorbitol, crystalline cellulose, etc.
- binders include methylcellulose, ethylcellulose , gum arabic, gelatin, hydroxypropyl cellulose, polyvinyl pyrrolidone, etc.
- lubricants include talc, magnesium stearate, polyethylene glycol, hydrogenated vegetable oil, etc.
- disintegrants include starch, sodium alginate, gelatin , calcium carbonate, calcium citrate, dextrin, magnesium carbonate, etc.
- surfactants include sodium lauryl sulfate, soybean soft phospholipids, sucrose fatty acid esters, polysorbates, etc.
- glidants include light anhydrous Silicic acid, dried aluminum hydroxide gel, synthetic aluminum silicate, magnesium silicate, etc.
- additives include honey, syrup, petrolatum, glycerin,
- the E-10-hydroxy-2-decenoic acid is used for preparing a medicine or a health care product for preventing and treating osteoporosis, and the medicine or the health care product alone can have a significant therapeutic effect on osteoporosis, but does not exclude other
- the nutritional supplement is used in combination; the nutritional supplement is vitamin D and/or phytosterol ketone.
- the present invention discloses for the first time a new use of E-10-hydroxy-2-decenoic acid, and it has been experimentally proved that E-10-hydroxy-2-decenoic acid has a remarkable control effect on osteoporosis, and therefore It can be used in the preparation of medicines or health care products for preventing and treating osteoporosis, and the E-10-hydroxy-2-decene acid is stable, the preparation method is simple, the cost is low, the food and medicine are homologous, and it is applied to the preparation.
- the medicines or health care products for preventing and treating osteoporosis have the advantages of low cost, good control effect, low dosage, long-term use and no toxic side effects, and have broad application prospects in the fields of prevention and treatment of osteoporosis medicine and health care.
- the E-10-hydroxy-2-decenoic acid provided by the invention is prepared into a medicine or a health care product for preventing and treating osteoporosis, and the recommended effective dose is: an effective dose of 10 to 2500 mg per kilogram of body weight per day for an adult. /kg, preferably the recommended dose is 50 to 500 mg/kg, and most preferably the recommended dose is 60 to 200 mg/kg.
- mice 48 female Wistar rats of 6 months old weighing from 180-250g were selected, SPF grade, and the feeding standard was controlled at room temperature 18-22 ° C, humidity 45%-65%. They were randomly divided into 6 groups: sham operation group, 3 experimental groups with different doses of drugs, positive control group and model group, 8 rats in each group; anesthetized animals were injected intraperitoneally with a mass ratio of 0.25% pentobarbital sodium 25 mg/kg. The dorsal incision was used to cut the skin and subcutaneous tissue under aseptic conditions. The experimental group, the positive control group and the model group were used to remove the ovaries. The sham operation group only removed a small amount of adipose tissue around the ovary and sutured layer by layer. After 3 days of intramuscular injection of penicillin for 3 days. The injections are given to ordinary feeds and eat freely.
- E-10-hydroxy-2-decenoic acid was synthetic.
- doses of 30 mg/kg is E-10-hydroxy-2-decenoic acid low dose group
- dose of 60mg/kg is E-10-hydroxy-2-decenoic acid medium dose group
- the dose of 120 mg/kg was high dose of E-10-hydroxy-2-decenoic acid
- the positive control group was injected subcutaneously with 6.6 ⁇ g/kg of calcitonin
- the model group was administered with normal saline.
- the sham operation group had no special treatment.
- the left femur bone density was measured repeatedly at 1 week and 12 weeks after surgery.
- the site of bone density scan included the whole femur and the upper end of the tibia.
- the hydrated chloral hydrate was injected intraperitoneally before scanning. After anesthesia, the rats were placed in the prone position, the hind limbs were maintained in the external rotation position, and the femur and tibia were at an angle of 45°. The scan was repeated 3 times, and the rats were reset each time.
- the scan results are shown in Table 1, and the results are the average of three scans.
- E-10-hydroxy-2-decenoic acid is obtained by oxidation, condensation and hydrolysis of 1,8-octanediol, and the content is ⁇ 99%.
- Table 1 Comparison with sham group, # P ⁇ 0.05; compared with model group, ⁇ P ⁇ 0.05.
- the royal jelly acid is the extract of royal jelly (the mass percentage of royal jelly acid is 90%, calculated in half), and the dosage is 100 mg/kg;
- the drug of the experimental group of Comparative Example 1 is repeatedly prepared according to the technical content disclosed in ZL201210063350.3.
- Example 2 preparation of the experimental drug in the experimental group was repeated by the technical contents disclosed ZL201210063350.3 Calcium calcium citrate, administered at a dose of 100 mg/kg.
- the rats in the experimental group after ovariectomy were randomly divided into 4 groups: diethylstilbestrol group (12), royal acid group (12), and vitamin K2+ calcium sulphuric acid group (12). King calcium sulphate group (12). Subsequently, the diethylstilbestrol group was given to rats with diethylstilbestrol 2 mg/kg, the royal jelly group, the vitamin K2+ calcium sulphate group and the royal calcium sulphate group were respectively dosed with the corresponding drugs, and each administration group was given once a day for 6 consecutive days. One day, continuous administration was 6 and weighed once a week. The normal control group and the sham operation group were given the same volume of distilled water by the same method.
- the drug was administered at the end of 12 weeks and sacrificed.
- the body weight was injected intraperitoneally with tetracycline hydrochloride 30 mg/kg body weight 16 days before and 3 days before sacrifice to fluorescently label the bone.
- the proximal tibia of the rat was taken 1/3, and the non-decalcified bone section was prepared to detect the histomorphometry of the bone tissue.
- Detection of bone mass expressed as percentage of trabecular bone volume (TBV%), which is the percentage of trabecular bone volume to the total volume of the bone marrow cavity being measured. , it is the main indicator to measure the bone level; 2.
- Mineralization rate of trabecular bone (MAR) the average distance of the fluorescent double-marked band on the trabecular bone surface divided by the number of days separated by 2 marks;
- Mineralization rate of cortical bone (mAR) The average distance between the fluorescent double-labeled bands on the inner surface of the cortex divided by the number of days between the two markers. The test results are shown in Table 2.
- the tibia TBV% of the rats in the royal pulp acid group, the vitamin K2+ king calcium sulphate group, the calcium sulphate group and the diethylstilbestrol group were significantly lower than the sham operation group, while the vitamin K2+ king calcium sulphate group and the royal calcium sulphate group.
- the tibia TBV% value of the rats in the group was significantly lower than that in the royal pulp group; the sacral MAR and mAR of the rats in the royal pulp group, the vitamin K2+ king calcium sulphate group, the calcium sulphate group and the diethylstilbestrol group were significantly higher than the sham operation group, but the royal jelly acid.
- the group was closer to the normal control group than the vitamin K2+ calcium sulphate group and the calcium sulphate group. It can be concluded that the effect of royal jelly acid on the prevention and treatment of middle-aged and elderly people with osteoporosis is significantly better than vitamin K2+ king calcium sulphate mixture and calcium sulphuric acid calcium.
- E-10-hydroxy-2-decenoic acid low dose group E-10-hydroxy-2-decenoic acid medium dose group
- E-10-hydroxy-2-quinone High-dose oleic acid group control group and vitamin K2+ king calcium sulphate group and calcium sulphate group
- 8 rats in each group were induced by bilateral ovariectomy and prednisolone acetate for 8 weeks. All white rabbits were at 0 and 8.
- the DXA bone densitometer was used for femoral BMD testing.
- White rabbit ear vein blood was collected using BGP kit to detect white rabbit BGP.
- E-10-hydroxy-2-decenoic acid low dose group was administered 30 mg/kg
- E-10-hydroxy-2-decene daily was administered 30 mg/kg
- the medium-dose group was administered with 60 mg/kg per day
- the high dose group of E-10-hydroxy-2-decenoic acid was administered daily at 120 mg/kg
- the vitamin K2+ calcium sulphuric acid group was administered daily with vitamin K2+ calcium sulphate.
- Table 3 Comparison with control group, # P ⁇ 0.05, ## P ⁇ 0.01; compared with calcium Vitamin K2 + royal jelly group, ⁇ P ⁇ 0.05, ⁇ P ⁇ 0.01; compared with calcium royal jelly group, * P ⁇ 0.05.
- Table 4 Comparison with control group, # P ⁇ 0.05, ## P ⁇ 0.01; compared with calcium Vitamin K2 + royal jelly group, ⁇ P ⁇ 0.05, ⁇ P ⁇ 0.01.
- the 12-month-old rabbits were already aged rabbits and were successfully modeled by castration and hormone induction for 8 weeks.
- the BMD and serum BGP of white rabbits were changed under the influence of different drugs by grouping them into different drug treatments. From the experimental results in Table 3 and Table 4, it can be seen that the administration of E-10-hydroxyl- The doses of 2-decenoic acid can make the BMD and serum BGP values of white rabbits closer to normal values, while the administration of vitamin K + calcium sulphuric acid and calcium sulphuric acid alone can improve the BMD and serum BGP of white rabbit tibia. The effect, but the direct use of E-10-hydroxy-2-decenoic acid ( royal jelly acid) is more effective in the prevention and treatment of osteoporosis in middle-aged and elderly people.
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Abstract
Disclosed in the present invention is a use of E-10-hydroxyl-2-decylenic acid in preparation of medicine or a health care product for preventing and treating osteoporosis. Active ingredient in the medicine or the health care product is only E-10-hydroxyl-2-decylenic acid, wherein the E-10-hydroxyl-2-decylenic acid is artificially synthesized or extracted from royal jelly. In the present invention, a novel use of E-10-hydroxyl-2-decylenic acid is disclosed for the first time. Experiment results prove that E-10-hydroxyl-2-decylenic acid has the obvious prevention and treatment effect on the osteoporosis, so that E-10-hydroxyl-2-decylenic acid can be used to the preparation of medicine or the health care product for preventing and treating osteoporosis. In addition, E-10-hydroxyl-2-decylenic acid is stable; can be simply prepared with low cost, and has homology of medicine and food. When E-10-hydroxyl-2-decylenic acid is used to prepare the medicine or the health care product for preventing and treating osteoporosis, it has the advantages of low cost, good prevention and treatment effect, low consumption, no toxic and side effects after long-time administration and the like. Moreover, wide application prospects are expected in the field of medicine or the health care product.
Description
本发明涉及一种防治骨质疏松症的药品或保健品技术领域，具体地说是一种E-10-羟基-2-癸烯酸在制备防治骨质疏松症的药品或保健品中的应用。The invention relates to the technical field of medicines or health care products for preventing and treating osteoporosis, in particular to the application of E-10-hydroxy-2-decenoic acid in preparing medicines or health care products for preventing and treating osteoporosis .
骨质疏松症(Osteoporosis，OP)是一种以骨量低下、骨微结构破坏、骨脆性增加、易发生骨折为特征的全身性骨病。第三次美国健康及营养调查数据(National Healthand Nutrition Examination Survey Ⅲ，NHANES Ⅲ)显示，超过990万美国人患骨质疏松症，约有4310万美国人患骨量减少症。每2位白人女性中就有1位一生中发生过骨质疏松性骨折，男性为每5人中有1位患骨质疏松性骨折。随着人类寿命延长和老龄化社会的到来，骨质疏松症已成为全球健康问题，中国也不例外。研究表明，在中国，每年患骨质疏松症的人群以20％的速度逐年增加，且患病人群从老年人扩大到了青少年。北京等地区基于影像学的流行病学调查显示，50岁以上妇女脊柱骨折的患病率为15％，相当于每7位50岁以上妇女中就有1位发生过脊柱骨折。骨质疏松性骨折会导致病残率和死亡率的增加。如发生髋部骨折后1年内死亡率超过未发生髋部骨折的8.4％～36％。虽然椎体骨折的死亡率较低，但也会给患者带来疼痛、残疾、畸形等负担。治疗骨质疏松性骨折需要投入巨大的人力和财力，造成沉重的家庭、社会、经济和精神负担。随着中国老龄化社会的推进，骨质疏松已经成为中国重要的公共卫生问题之一，预防和治疗骨质疏松症已成为中国公共卫生的迫切任务之一。研究显示，尽早预防可以避免骨质疏松性骨折，即使发生过骨折，当采取治疗后也可以有效降低再次骨折的风险。因此，提高对骨质疏松症的认识，尤其做到早期诊断、及时预测骨折风险并采取规范的防治措施变得尤为重要。Osteoporosis (OP) is a systemic bone disease characterized by low bone mass, bone microstructural destruction, increased bone fragility, and prone to fracture. According to the National Health and Nutrition Examination Survey III (NHANES III), more than 9.9 million Americans suffer from osteoporosis, and approximately 43.1 million Americans suffer from osteopenia. One in every two white women had an osteoporotic fracture in one lifetime, and one in every five men had an osteoporotic fracture. With the extension of human life and the advent of an aging society, osteoporosis has become a global health problem, and China is no exception. Studies have shown that in China, the number of people suffering from osteoporosis increases year by year at a rate of 20%, and the number of patients has expanded from the elderly to adolescents. Epidemiological surveys based on imaging in Beijing and other regions show that the prevalence of spinal fractures in women over 50 years old is 15%, which is equivalent to one in every 7 women over 50 years old who have had spinal fractures. Osteoporotic fractures lead to an increase in morbidity and mortality. If the hip fracture occurred within 1 year, the mortality rate exceeded 8.4% to 36% of the hip fracture. Although the mortality rate of vertebral fractures is low, it also brings pain, disability, deformity and other burdens to patients. Treating osteoporotic fractures requires enormous human and financial resources, resulting in a heavy family, social, economic and spiritual burden. With the advancement of China's aging society, osteoporosis has become one of the important public health problems in China. Prevention and treatment of osteoporosis has become one of the urgent tasks of public health in China. Studies have shown that early prevention can prevent osteoporotic fractures, even if fractures occur, can also effectively reduce the risk of re-fracture after treatment. Therefore, it is particularly important to improve the understanding of osteoporosis, especially in early diagnosis, timely prediction of fracture risk and adopting standardized prevention and treatment measures.
在防治骨质疏松症方面，美国所做的研究和防治的重视程度走在世界前列。早在2014年4月，美国骨质疏松基金会(National Osteoporosis Foundation，NOF)发布了新版预防和治疗骨质疏松症临床指南，适用人群为美国绝经后女性及中老年男性(≥50岁)。包括：(1)、基础防护措施，如摄入足够的钙、摄入足够的维生素D、推荐规律的负重及肌肉强化运动、避免吸烟和过量饮酒等；(2)、诊断，推荐临床医生进行详细的病史采集以及体格检查，结合骨密度(bone mineral density，BMD)评估及椎体影像学检查以诊断骨质疏松症；(3)、药物治疗：抗骨质疏松药物有多种，目前美国国家食品药品监督管理局(Food and Drug Administration，FDA)批准的治疗骨质疏松症的药物有双膦酸盐类药物、降钙素、雌激素受体调节剂(雷洛昔芬)、雌激素、组织选择性雌激素复合物(结合雌激素/巴多昔芬)、PTH 1-34(特立帕肽)以及RANKL单抗。指南除对不同 药物的批准适应证、用法、功效(主要为降低椎体及非椎体骨折风险)作了详细地介绍外，还用最新证据对每类药物安全性问题做了客观阐述。如双膦酸盐类药物是FDA批准的适应证为治疗绝经后妇女和中老年男性的骨质疏松症以及糖皮质激素导致的骨质疏松症，但是所有双膦酸盐类药物的不良反应相似，包括胃肠道反应(口服途径)、影响肾功能、颌骨坏死以及不典型骨折、静脉类药物给药后一过性的类流感样症状，其中颌骨坏死及不典型骨折罕见，用药5年以上的患者风险增加。雷洛昔芬是FDA批准用于预防及治疗绝经后妇女骨质疏松症。该药总体安全性良好，会增加潮热的发生，此外还轻度增加深静脉血栓风险，故有静脉血栓史以及有血栓倾向者(如长期卧床和久坐期间)禁用；等等。上述药物治疗虽然有较好的防治功效，但是长期服用会存在诸多副作用，所以这些药物主要作为阶段性的治疗药物使用，而对于需要长期服用、用于防治骨质疏松日常保健的人们来说，仍然会选择无毒副作用的各种常规钙制剂，如《原发性骨质疏松症诊疗指南》(中国全科医学杂志,2017.10)中推荐的“碳酸钙、氯化钙、磷酸钙、醋酸钙、乳酸钙、柠檬酸钙、枸橼酸钙、葡萄糖酸钙”等，主要通过充足的钙摄入来获得相对更为理想的骨峰值、减缓骨丢失、改善骨矿化，达到维护骨骼健康的目的。在这些钙制剂中，碳酸钙的钙含量相对最高(40％)、其次是磷酸钙(38.76％)和醋酸钙(36％)，而乳酸钙和葡萄酸中的钙含量分别为18.37％和9.30％，属于钙制剂中钙含量较低的类型。人们在摄入钙制剂时，其选择的关键因素不仅考察其钙含量，更多会考察其钙吸收率的问题。研究表明，碳酸钙、磷酸钙、氯化钙等无机钙水溶性小、离子化程度小、吸收相对较差，而乳酸钙、醋酸钙、葡萄酸钙等有机酸钙水溶性好、离子化程度大、吸收率要比无机钙相对更高。但是，有机酸钙由于钙量低，必须服用大量制剂才能达到补钙要求，但是大剂量服用成本较高、同时也会带来一些副作用。为克服这些弊端，近些年行业内的技术人员在一直不断地研发各种有机酸钙，如申请号为201611131011.9公开了一种酪蛋白酸钙的制备方法，是以曲拉干酪素为原料，与可溶性钙盐溶解后的溶液挤压膨化转化制得酪蛋白酸钙溶液后，自然冷却干燥，经粉碎制得酪蛋白酸钙粉末，再添加菊粉即得。其具有无需添加维生素D，易于人体吸收利用、吸收效果好，补钙效果比传统产品较佳。又如申请号201510030019.5公开了一种左旋肉碱富马酸钙的制备方法及其用途，将左旋肉碱内盐、富马酸、氢氧化钙按比例进行配比，加入到乙醇中，水域加热回流，回收乙醇、静置、过滤、干燥即得，该制剂适用于口服、注射药物制剂的应用，其化学性质稳定，流动性好、易溶于水，便于人体的吸收，生物利用度高，临床上可用于补钙、降低胆固醇、预防脑动脉硬化药物中的应用。此外，行业内也有报道王浆酸钙的开发及应用的相关技术，如ZL200610057359.8公开了一种蜂王浆酸钙及其制备方法，其具体是在蜂王浆冻干粉中加入钙剂(乳酸钙或碳酸钙、葡萄糖酸钙)、酸奶冻干粉、甘露醇、葡萄糖、糊精和硬脂酸镁等组分混合制得蜂王浆酸钙；报道了该制剂不仅可以提高人体免疫力，延缓衰老，对抗人体对高温等，特别是通过王浆酸与钙的有机结合，促进钙在体内的吸收和利用， 并在协同作用下可以治疗老年骨质疏松。又如ZL201210063350.3公开了王浆酸钙及与维生素K2制成的抗动脉粥样硬化和骨质疏松症保健品，具体是通过将王浆酸钙和维生素K2按特定比例混合制备了对中老年人群具有良好抗动脉粥样硬化与骨质疏松症双重功能的保健品；该专利文件中记载了制备的保健品具有的防治骨质疏松症的功效主要是因为维生素K2可以显著增加γ-羧化骨钙素和基质γ-羧基谷氨酸蛋白的合成，从源头上解决动脉粥样硬化及骨质疏松症的共同致病因素－钙代谢紊乱，同时王浆酸钙中钙离子在骨骼定向沉积而达到了防治骨质疏松的目的。由此可见，目前行业内所研发的无机钙和有机酸钙制剂均是通过促使钙离子沉积和吸收于人体内，进而达到防治骨质疏松症的目的的。但是，这些防治骨质疏松症的钙制剂保健品均存在效果相对较差、长期服用副作用较大的问题，因此，研发无副作用、可长期服用、对预防和治疗骨质疏松症有显著疗效的药物和保健品仍是行业内技术人员的研究热点。In the prevention and treatment of osteoporosis, the importance of research and prevention in the United States is at the forefront of the world. As early as April 2014, the National Osteoporosis Foundation (NOF) released a new clinical guideline for the prevention and treatment of osteoporosis. The applicable population is postmenopausal women and middle-aged men (≥50 years old). Including: (1), basic protective measures, such as adequate intake of calcium, adequate intake of vitamin D, recommended regular weight-bearing and muscle strengthening exercise, avoiding smoking and excessive drinking; (2), diagnosis, recommended clinician Detailed medical history collection and physical examination, combined with bone mineral density (BMD) assessment and vertebral imaging to diagnose osteoporosis; (3), drug treatment: anti-osteoporosis drugs are available, currently the United States The drugs approved by the Food and Drug Administration (FDA) for the treatment of osteoporosis include bisphosphonates, calcitonin, estrogen receptor modulators (raloxifene), and estrogen. , tissue selective estrogen complex (binding estrogen / bazedoxifene), PTH 1-34 (teriparatide) and RANKL mAb. In addition to a detailed introduction to the indications, usage, and efficacy of different drugs (mainly to reduce the risk of vertebral and non-vertebral fractures), the guidelines also provide an objective explanation of the safety of each type of drug with the latest evidence. For example, bisphosphonates are FDA-approved indications for the treatment of osteoporosis in postmenopausal women and middle-aged men, as well as glucocorticoid-induced osteoporosis, but all bisphosphonates have similar adverse effects. Including gastrointestinal reactions (oral route), affecting renal function, osteonecrosis of the jaws, and atypical fractures, transient flu-like symptoms after intravenous drug administration, in which jaw osteonecrosis and atypical fractures are rare, medication 5 Patients over the age are at increased risk. Raloxifene is approved by the FDA for the prevention and treatment of osteoporosis in postmenopausal women. The overall safety of the drug is good, it will increase the incidence of hot flashes, in addition to slightly increase the risk of deep vein thrombosis, so there is a history of venous thrombosis and thrombosis (such as long-term bed rest and sedentary period); Although the above-mentioned drug treatment has a good control effect, there are many side effects in long-term use, so these drugs are mainly used as a phased therapeutic drug, and for those who need long-term use for the prevention and treatment of osteoporosis, Various conventional calcium preparations with no toxic side effects will still be selected, such as "calcium carbonate, calcium chloride, calcium phosphate, calcium acetate recommended in "Guidelines for the diagnosis and treatment of primary osteoporosis" (Chinese Journal of General Medicine, 2017.10). Calcium lactate, calcium citrate, calcium citrate, calcium gluconate, etc., mainly through sufficient calcium intake to obtain relatively better bone peaks, slow bone loss, improve bone mineralization, and maintain bone health. purpose. Among these calcium preparations, calcium carbonate has the highest calcium content (40%), followed by calcium phosphate (38.76%) and calcium acetate (36%), while calcium lactate and gluconic acid have calcium contents of 18.37% and 9.30, respectively. %, which is a type of calcium with a low calcium content. When people take calcium preparations, the key factors for their selection are not only to investigate their calcium content, but also to investigate the problem of calcium absorption rate. Studies have shown that inorganic calcium such as calcium carbonate, calcium phosphate, calcium chloride and the like has low water solubility, small degree of ionization, and relatively poor absorption, while organic calcium acid such as calcium lactate, calcium acetate and calcium gluconate has good water solubility and degree of ionization. Large, absorption rate is relatively higher than inorganic calcium. However, due to the low calcium content, calcium organic acid must take a large amount of preparation to meet the calcium requirement, but the high dose is costly and has some side effects. In order to overcome these drawbacks, in recent years, technicians in the industry have been continuously researching and developing various organic calcium salts. For example, the application method is 201611131011.9, which discloses a method for preparing calcium caseinate, which is based on traserine. After the solution of the dissolved calcium salt is squeezed and transformed to obtain a calcium caseinate solution, it is naturally cooled and dried, and the calcium caseinate powder is obtained by pulverization, and then the inulin is added. It has no need to add vitamin D, is easy to be absorbed and utilized by the human body, and has good absorption effect, and the calcium supplementing effect is better than the traditional products. Further, as disclosed in Application No. 201510030019.5, a method for preparing L-carnitine calcium fumarate and a use thereof are disclosed, wherein L-carnitine inner salt, fumaric acid and calcium hydroxide are proportioned, added to ethanol, and heated in water. It is refluxed, recovered by ethanol, left to stand, filtered and dried. The preparation is suitable for oral and injectable pharmaceutical preparations. It is chemically stable, has good fluidity, is easily soluble in water, is easy for human body to absorb, and has high bioavailability. It can be used clinically for calcium supplementation, cholesterol lowering, and prevention of cerebral arteriosclerosis. In addition, the industry has also reported the development and application of calcium sulphuric acid. For example, ZL200610057359.8 discloses a royal jelly calcium and a preparation method thereof, which specifically adds a calcium agent (calcium lactate or carbonic acid) to the lyophilized powder of royal jelly. Calcium, calcium gluconate), yogurt lyophilized powder, mannitol, glucose, dextrin and magnesium stearate are mixed to prepare royal jelly calcium; it is reported that the preparation can not only improve human immunity, delay aging, and fight human body For high temperature, etc., especially through the organic combination of royal jelly acid and calcium, promote the absorption and utilization of calcium in the body, and can treat senile osteoporosis under the synergistic effect. Another example is ZL201210063350.3, which discloses calcium sulphuric acid and anti-atherosclerosis and osteoporosis health supplements made with vitamin K2, specifically by mixing calcium sulphuric acid calcium and vitamin K2 in a certain proportion to prepare middle-aged and elderly people. A health care product having good dual functions against atherosclerosis and osteoporosis; the patent document describes that the prepared health care product has the effect of preventing and treating osteoporosis mainly because vitamin K2 can significantly increase γ-carboxylated bone Calcium and the synthesis of matrix γ-carboxyglutamic acid protein, from the source to solve the common pathogenic factors of atherosclerosis and osteoporosis - calcium metabolism disorder, while the calcium ion in calcium sulphuric acid is deposited in the bone orientation The purpose of prevention and treatment of osteoporosis. It can be seen that the inorganic calcium and organic calcium acid preparations developed in the industry are aimed at preventing and treating osteoporosis by promoting the deposition and absorption of calcium ions in the human body. However, these calcium preparations for preventing and treating osteoporosis have relatively poor effects and long-term side effects. Therefore, research and development have no side effects, can be taken for a long time, and have significant effects on prevention and treatment of osteoporosis. Drugs and health products are still a research hotspot for technicians in the industry.
发明内容Summary of the invention
本发明的目的就是提供一种E-10-羟基-2-癸烯酸在制备防治骨质疏松症的药品或保健品中的应用，以解决目前防治骨质疏松症的药物和保健品存在长期服用副作用较大、对预防和治疗骨质疏松症疗效较差的问题。The object of the present invention is to provide an application of E-10-hydroxy-2-decenoic acid in the preparation of medicines or health care products for preventing and treating osteoporosis, so as to solve the long-term existence of drugs and health care products for preventing and treating osteoporosis. Taking more side effects and having a poorer effect on preventing and treating osteoporosis.
本发明的目的是这样实现的：一种E-10-羟基-2-癸烯酸在制备防治骨质疏松症的药品或保健品中的应用。The object of the present invention is achieved by the use of an E-10-hydroxy-2-decenoic acid for the preparation of a medicament or a health care product for preventing and treating osteoporosis.
所述药物或保健品中的有效成分仅为E-10-羟基-2-癸烯酸，E-10-羟基-2-癸烯酸是一种中链不饱和脂肪酸，其分子式为C
10H
18O
3，简称10-HAD，其化学结构式为：
The active ingredient in the drug or health care product is only E-10-hydroxy-2-decenoic acid, and E-10-hydroxy-2-decenoic acid is a medium chain unsaturated fatty acid having a molecular formula of C 10 H 18 O 3 , abbreviated as 10-HAD, its chemical structure is:
所述E-10-羟基-2-癸烯酸来源于人工合成或从蜂王浆中提取；该化合物是蜂王浆的重要成分之一，故也称之为王浆酸，一般合格的蜂王浆中含有王浆酸(优级品含量≥1.8％，合格品含量≥1.4％)，属于药食同源的蜂产品，安全，适于长期服用。The E-10-hydroxy-2-decenoic acid is derived from artificial synthesis or extracted from royal jelly; the compound is one of the important components of royal jelly, so it is also called royal jelly acid, and the generally qualified royal jelly contains royal jelly acid ( The quality of the superior grade is ≥1.8%, and the content of qualified products is ≥1.4%. It is a bee product with the same medicine and food, safe and suitable for long-term use.
本发明提供的E-10-羟基-2-癸烯酸对骨质疏松症中的绝经后骨质疏松症Ⅰ型和老年性骨质疏松症Ⅱ型效果显著。The E-10-hydroxy-2-decenoic acid provided by the present invention has a remarkable effect on postmenopausal osteoporosis type I and senile osteoporosis type II in osteoporosis.
所述的E-10-羟基-2-癸烯酸制备防治骨质疏松症的药品或保健品时，可以添加药理上可接受辅料制备而成，如通常使用的赋形剂、结合剂、润滑剂、崩解剂、表面活性剂、助流剂等；赋形剂包括乳糖、果糖、葡萄糖、玉米淀粉、山梨糖醇、结晶纤维素等等；粘合剂包括甲基纤维素、 乙基纤维素、阿拉伯树胶、明胶、羟丙基纤维素、聚乙烯基吡咯烷酮等；润滑剂包括滑石粉、硬脂酸镁、聚乙二醇、氢化植物油等；崩解剂包括淀粉、藻酸钠、明胶、碳酸钙、柠檬酸钙、糊精、碳酸镁等；表面活性剂包括十二烷基硫酸钠、大豆软磷脂、蔗糖脂肪酸酯、聚山梨酸酯等等；助流剂包括轻质无水硅酸、干燥氢氧化铝凝胶、合成硅酸铝、硅酸镁等；添加剂包括蜂蜜、糖浆、凡士林、甘油、乙醇、丙二醇、柠檬酸、氯化钠、磷酸钠等；进而制备成、颗粒剂、散剂、丸剂、胶囊剂或口服液等药剂学中常见的剂型。When the E-10-hydroxy-2-decenoic acid is used for preparing a medicine or a health care product for preventing osteoporosis, it may be prepared by adding a pharmaceutically acceptable auxiliary material, such as an excipient, a binder, and a lubricant which are generally used. Agents, disintegrants, surfactants, glidants, etc.; excipients include lactose, fructose, glucose, corn starch, sorbitol, crystalline cellulose, etc.; binders include methylcellulose, ethylcellulose , gum arabic, gelatin, hydroxypropyl cellulose, polyvinyl pyrrolidone, etc.; lubricants include talc, magnesium stearate, polyethylene glycol, hydrogenated vegetable oil, etc.; disintegrants include starch, sodium alginate, gelatin , calcium carbonate, calcium citrate, dextrin, magnesium carbonate, etc.; surfactants include sodium lauryl sulfate, soybean soft phospholipids, sucrose fatty acid esters, polysorbates, etc.; glidants include light anhydrous Silicic acid, dried aluminum hydroxide gel, synthetic aluminum silicate, magnesium silicate, etc.; additives include honey, syrup, petrolatum, glycerin, ethanol, propylene glycol, citric acid, sodium chloride, sodium phosphate, etc.; Agent, powder, pills , Pharmaceutics common dosage forms like capsules or oral solution.
所述的E-10-羟基-2-癸烯酸制备防治骨质疏松症的药品或保健品，该药品或保健品单独服用可以起到骨质疏松显著的治疗效果，但也不排斥与其他营养补充剂联合使用；其营养补充剂为维生素D和/或植物固醇酮类物质等。The E-10-hydroxy-2-decenoic acid is used for preparing a medicine or a health care product for preventing and treating osteoporosis, and the medicine or the health care product alone can have a significant therapeutic effect on osteoporosis, but does not exclude other The nutritional supplement is used in combination; the nutritional supplement is vitamin D and/or phytosterol ketone.
本发明首次公开了E-10-羟基-2-癸烯酸的一种新用途，通过实验证明，E-10-羟基-2-癸烯酸对骨质疏松症具有显著的防治效果，因此其可在制备防治骨质疏松症的药品或保健品中得到应用，而且E-10-羟基-2-癸烯酸质稳定、制备方法简单、成本低廉、食药同源，将其应用于制成防治骨质疏松症的药品或保健品具有成本低、防治效果好、用量少、长期服用无毒副作用等优势，在防治骨质疏松症医药和保健等领域具有广阔的应用前景。The present invention discloses for the first time a new use of E-10-hydroxy-2-decenoic acid, and it has been experimentally proved that E-10-hydroxy-2-decenoic acid has a remarkable control effect on osteoporosis, and therefore It can be used in the preparation of medicines or health care products for preventing and treating osteoporosis, and the E-10-hydroxy-2-decene acid is stable, the preparation method is simple, the cost is low, the food and medicine are homologous, and it is applied to the preparation. The medicines or health care products for preventing and treating osteoporosis have the advantages of low cost, good control effect, low dosage, long-term use and no toxic side effects, and have broad application prospects in the fields of prevention and treatment of osteoporosis medicine and health care.
本发明提供的E-10-羟基-2-癸烯酸在制备成防治骨质疏松症的药品或保健品，其建议使用有效剂量为：成人每日每千克体重服用的有效剂量为10～2500mg/kg，优选推荐的剂量是50～500mg/kg，最优选推荐的剂量是60～200mg/kg。The E-10-hydroxy-2-decenoic acid provided by the invention is prepared into a medicine or a health care product for preventing and treating osteoporosis, and the recommended effective dose is: an effective dose of 10 to 2500 mg per kilogram of body weight per day for an adult. /kg, preferably the recommended dose is 50 to 500 mg/kg, and most preferably the recommended dose is 60 to 200 mg/kg.
下面实施例用于进一步详细说明本发明，但不以任何形式限制本发明。The following examples are intended to illustrate the invention in further detail but are not intended to limit the invention in any way.
实施例1Example 1
选取体重180-250g的6月龄雌性Wistar大鼠48只，SPF级，饲养标准控制在室温18-22℃、湿度45％-65％。随机分为6组：假手术组、3个不同剂量药物作用的实验组、阳性对照组、模型组，每组8只；质量比浓度0.25％戊巴比妥钠25mg/kg腹腔注射麻醉动物，采用背侧切口，无菌条件下切开皮肤、皮下组织，实验组、阳性对照组、模型组切除卵巢；假手术组只切除卵巢周围少量脂肪组织，逐层缝合；术后连续3d肌注青霉素注射液，均给普通饲料，自由饮食。48 female Wistar rats of 6 months old weighing from 180-250g were selected, SPF grade, and the feeding standard was controlled at room temperature 18-22 ° C, humidity 45%-65%. They were randomly divided into 6 groups: sham operation group, 3 experimental groups with different doses of drugs, positive control group and model group, 8 rats in each group; anesthetized animals were injected intraperitoneally with a mass ratio of 0.25% pentobarbital sodium 25 mg/kg. The dorsal incision was used to cut the skin and subcutaneous tissue under aseptic conditions. The experimental group, the positive control group and the model group were used to remove the ovaries. The sham operation group only removed a small amount of adipose tissue around the ovary and sutured layer by layer. After 3 days of intramuscular injection of penicillin for 3 days. The injections are given to ordinary feeds and eat freely.
手术后1周给药，3个实验组分别用给药剂量为30mg/kg、60mg/kg、90mg/kg的E-10-羟基-2-癸烯酸进行灌胃(E-10-羟基-2-癸烯酸为人工合成)。且给药剂量为30mg/kg的是E-10-羟基-2-癸烯酸低剂量组、给药剂量为60mg/kg的是E-10-羟基-2-癸烯酸中剂量组、给药剂量为120mg/kg的是E-10-羟基-2-癸烯酸高剂量组、阳性对照组采用6.6μg/kg的降钙素皮下注射，模型组采用生理盐水灌胃，连续给药12周，假手术组无特殊处理。于手术后1周、12周重复测量大鼠左侧股骨骨密度。骨密度扫描的部位包括全股骨和胫骨上端，扫描前水合氯醛腹腔注射，麻醉后使大鼠处 于俯卧位，后肢维持在外旋位，股骨与胫骨呈45°角。扫描重复3次，每次重置大鼠，扫描结果如表1所示，其结果为三次扫描的平均值。Three weeks after the operation, the three experimental groups were intragastrically administered with E-10-hydroxy-2-decenoic acid at doses of 30 mg/kg, 60 mg/kg, and 90 mg/kg, respectively (E-10-hydroxyl- 2-decenoic acid is synthetic). And the dose of 30mg/kg is E-10-hydroxy-2-decenoic acid low dose group, the dose of 60mg/kg is E-10-hydroxy-2-decenoic acid medium dose group, given The dose of 120 mg/kg was high dose of E-10-hydroxy-2-decenoic acid, the positive control group was injected subcutaneously with 6.6 μg/kg of calcitonin, and the model group was administered with normal saline. Week, the sham operation group had no special treatment. The left femur bone density was measured repeatedly at 1 week and 12 weeks after surgery. The site of bone density scan included the whole femur and the upper end of the tibia. The hydrated chloral hydrate was injected intraperitoneally before scanning. After anesthesia, the rats were placed in the prone position, the hind limbs were maintained in the external rotation position, and the femur and tibia were at an angle of 45°. The scan was repeated 3 times, and the rats were reset each time. The scan results are shown in Table 1, and the results are the average of three scans.
E-10-羟基-2-癸烯酸由1,8-辛二醇经氧化、缩合、水解得到，含量≥99％。E-10-hydroxy-2-decenoic acid is obtained by oxidation, condensation and hydrolysis of 1,8-octanediol, and the content is ≥99%.
表1 E-10-羟基-2-癸烯酸对去势骨质疏松大鼠骨密度的影响(mg/cm
2)
Table 1 Effect of E-10-hydroxy-2-decenoic acid on bone mineral density in ovariectomized osteoporosis rats (mg/cm 2 )
| 组别Group | 1周末1 weekend | 12周末12 weekends |
| 假手术组(n＝8)Sham operation group (n=8) | 149.4±0.713149.4±0.713 | 145.55±0.701145.55±0.701 |
| 模型组(n＝8)Model group (n=8) | 148.9±0.921148.9±0.921 | 121.13±0.805 # 121.13±0.805 # |
| E-10-羟基-2-癸烯酸低剂量组(n＝8)Low dose group of E-10-hydroxy-2-decenoic acid (n=8) | 149.0±0.707149.0±0.707 | 129.2±0.712 #△ 129.2±0.712 #△ |
| E-10-羟基-2-癸烯酸中剂量组(n＝8)E-10-hydroxy-2-decenoic acid middle dose group (n=8) | 149.1±0.811149.1±0.811 | 135.2±0.834 #△ 135.2±0.834 #△ |
| E-10-羟基-2-癸烯酸高剂量组(n＝8)High dose group of E-10-hydroxy-2-decenoic acid (n=8) | 149.6±0.627149.6±0.627 | 141.34±0.602 #△ 141.34±0.602 #△ |
| 阳性对照组(n＝8)Positive control group (n=8) | 148.8±0.758148.8±0.758 | 139.45±0.692 #△ 139.45±0.692 #△ |
表1中：与假手术组比较，
#P＜0.05；与模型组比较，
△P＜0.05。
Table 1: Comparison with sham group, # P <0.05; compared with model group, △ P <0.05.
从以上结果可以看出实验鼠在用药之前各组骨密度基线总体无差异，用药12周后检测器各组实验鼠的差异比较显著，其中模型组的骨密度低于假手术组，而采用E-10-羟基-2-癸烯酸给药后其骨密度指标较模型组大鼠骨密度指标下降显著减缓，说明E-10-羟基-2-癸烯酸具有促进骨形成、抑制骨吸收，降低骨代谢率的作用。From the above results, it can be seen that there was no difference in the baseline of bone mineral density between the groups before the administration of the drug. After 12 weeks of treatment, the difference between the experimental groups was significant. The bone density of the model group was lower than that of the sham operation group, and E was used. The bone mineral density index of -10-hydroxy-2-decenoic acid was significantly slower than that of the model group, indicating that E-10-hydroxy-2-decenoic acid promoted bone formation and inhibited bone resorption. Reduce the role of bone metabolic rate.
实施例2Example 2
将本发明提供的王浆酸与ZL201210063350.3公开的王浆酸钙与维生素K2混合物以及ZL201210063350.3公开的方法制备的王浆酸钙在防治骨质疏松症方面的效果进行实验对比。The effect of the royal jelly acid provided by the present invention and the calcium alginate and vitamin K2 mixture disclosed in ZL201210063350.3 and the calcium alginate prepared by the method disclosed in ZL201210063350.3 in experimental prevention and treatment of osteoporosis are experimentally compared.
王浆酸为蜂王浆提取物(王浆酸的质量百分含量为90％，折百计算)，给药剂量为100mg/kg；对比例1实验组的药物按照ZL201210063350.3公开的技术内容重复实验制备王浆酸钙与维生素K
2的混合物，王浆酸钙与维生素K
2的质量比为250:1，给药剂量为100mg/kg；对比例2实验组的药物按照ZL201210063350.3公开的技术内容重复实验制备王浆酸钙，给药剂量100mg/kg。
The royal jelly acid is the extract of royal jelly (the mass percentage of royal jelly acid is 90%, calculated in half), and the dosage is 100 mg/kg; the drug of the experimental group of Comparative Example 1 is repeatedly prepared according to the technical content disclosed in ZL201210063350.3. the mixture of calcium and vitamin K 2, vitamin K, calcium royal jelly mass ratio of 2 to 250: 1, at a dose of 100mg / kg; Example 2 preparation of the experimental drug in the experimental group was repeated by the technical contents disclosed ZL201210063350.3 Calcium calcium citrate, administered at a dose of 100 mg/kg.
选用SPF级健康雌性Wistar大鼠72只，随机分为3组，分别是：正常对照组12只、假手术组12只、给药实验组48只。所有大鼠适应性喂养1周后，将给药实验组和假手术组的大鼠以45mg/kg剂量的戊巴比妥钠腹腔注射麻醉，腹位固定，将给药实验组进行卵巢切除术，假手术组只是切除小块脂肪组织，但不摘除卵巢。手术后10周，将卵巢切除后的给药实验组大鼠随机分为4小组，分别是己烯雌酚组(12只)、王浆酸组(12只)、维生素K2+王浆酸钙组(12只)、王浆酸钙组 (12只)。随后，己烯雌酚组分别给予大鼠罐服己烯雌酚2mg/kg，王浆酸组、维生素K2+王浆酸钙组和王浆酸钙组分别罐服对应药物，各给药组每日1次，连续6天，休息1天，再连续给药6，每周称重1次。正常对照组和假手术组按同法灌服等体积的蒸馏水。给药12周结束，处死。处死前16天和前3天分别腹腔注射盐酸四环素30mg/kg体质量，以对骨进行荧光标记。给药结束后，取大鼠右侧胫骨近端1/3，制作不脱钙骨切片，进行骨组织形态计量学指标的检测。72 SPF healthy female Wistar rats were randomly divided into 3 groups: 12 in the normal control group, 12 in the sham operation group, and 48 in the experimental group. One week after all rats were fed adaptively, rats in the experimental and sham-operated groups were anesthetized with intraperitoneal injection of pentobarbital sodium at a dose of 45 mg/kg, fixed in the abdominal position, and the experimental group was subjected to oophorectomy. The sham operation group only removes small pieces of adipose tissue, but does not remove the ovaries. Ten weeks after the operation, the rats in the experimental group after ovariectomy were randomly divided into 4 groups: diethylstilbestrol group (12), royal acid group (12), and vitamin K2+ calcium sulphuric acid group (12). King calcium sulphate group (12). Subsequently, the diethylstilbestrol group was given to rats with diethylstilbestrol 2 mg/kg, the royal jelly group, the vitamin K2+ calcium sulphate group and the royal calcium sulphate group were respectively dosed with the corresponding drugs, and each administration group was given once a day for 6 consecutive days. One day, continuous administration was 6 and weighed once a week. The normal control group and the sham operation group were given the same volume of distilled water by the same method. The drug was administered at the end of 12 weeks and sacrificed. The body weight was injected intraperitoneally with tetracycline hydrochloride 30 mg/kg body weight 16 days before and 3 days before sacrifice to fluorescently label the bone. After the end of the administration, the proximal tibia of the rat was taken 1/3, and the non-decalcified bone section was prepared to detect the histomorphometry of the bone tissue.
用Leica Qwin图像分析系统进行计量分析：1.骨量的检测：用骨小梁体积百分比(percentage of trabecular bone volume,TBV％)，即骨小梁体积占被测骨髓腔总体积的百分比进行表示，它是衡量骨量水平的主要标志；2.骨小梁矿化率(mineralization rate of trabecular bone,MAR)：骨小梁表面荧光双标记带的平均距离除以2次标记相隔的天数；3.骨皮质矿化率(mineralization rate of cortical bone,mAR)：皮质内表面荧光双标记带的平均距离除以2次标记相隔的天数。其检测结果如表2所示。Metrology analysis using the Leica Qwin image analysis system: 1. Detection of bone mass: expressed as percentage of trabecular bone volume (TBV%), which is the percentage of trabecular bone volume to the total volume of the bone marrow cavity being measured. , it is the main indicator to measure the bone level; 2. Mineralization rate of trabecular bone (MAR): the average distance of the fluorescent double-marked band on the trabecular bone surface divided by the number of days separated by 2 marks; 3 Mineralization rate of cortical bone (mAR): The average distance between the fluorescent double-labeled bands on the inner surface of the cortex divided by the number of days between the two markers. The test results are shown in Table 2.
表2 E-10-羟基-2-癸烯酸对去势骨质疏松大鼠骨形态学影响Table 2 Effect of E-10-hydroxy-2-decenoic acid on bone morphology in ovariectomized osteoporosis rats
| 组别Group | nn | TBV(％)TBV (%) | MAR(％)MAR (%) | mAR(％)mAR (%) |
| 正常对照组Normal control group | 1212 | 35.83±5.4835.83±5.48 | 0.95±0.230.95±0.23 | 1.52±0.311.52±0.31 |
| 假手术组mock surgical group | 1212 | 36.14±4.3236.14±4.32 | 1.03±0.291.03±0.29 | 1.49±0.331.49±0.33 |
| 己烯雌酚组Diethylstilbestrol group | 1212 | 28.73±5.26**28.73±5.26** | 1.14±0.19**1.14±0.19** | 1.64±0.24**1.64±0.24** |
| 王浆酸组Royal pulp group | 1212 | 25.77±5.17**25.77±5.17** | 1.23±0.21**1.23±0.21** | 1.67±0.28**1.67±0.28** |
| 维生素K2+王浆酸钙组Vitamin K2+ calcium sulphate group | 1212 | 17.82±4.21**17.82±4.21** | 1.95±0.23 ## 1.95±0.23 ## | 2.13±0.29* ## 2.13±0.29* ## |
| 王浆酸钙组Royal calcium sulphate group | 1212 | 18.36±5.13**18.36±5.13** | 1.86±0.16 ## 1.86±0.16 ## | 2.06±0.32* ## 2.06±0.32* ## |
注：与假手术组比较，**P<0.01；与王浆酸组比较，##P<0.01。Note: Compared with the sham operation group, **P<0.01; compared with the royal jelly group, ##P<0.01.
从表2可以看出王浆酸组、维生素K2+王浆酸钙组、王浆酸钙组、己烯雌酚组的大鼠胫骨TBV％均显著性低于假手术组，而维生素K2+王浆酸钙组和王浆酸钙组大鼠的胫骨TBV％值明显小于王浆酸组；王浆酸组、维生素K2+王浆酸钙组、王浆酸钙组、己烯雌酚组大鼠胫骨MAR和mAR均显著性高于假手术组，但王浆酸组比维生素K2+王浆酸钙组和王浆酸钙组更为接近正常对照组的值。由此可以得出，王浆酸对于患有骨质疏松症的中老年的预防和治疗效果显著优于维生素K2+王浆酸钙混合物和王浆酸钙。It can be seen from Table 2 that the tibia TBV% of the rats in the royal pulp acid group, the vitamin K2+ king calcium sulphate group, the calcium sulphate group and the diethylstilbestrol group were significantly lower than the sham operation group, while the vitamin K2+ king calcium sulphate group and the royal calcium sulphate group. The tibia TBV% value of the rats in the group was significantly lower than that in the royal pulp group; the sacral MAR and mAR of the rats in the royal pulp group, the vitamin K2+ king calcium sulphate group, the calcium sulphate group and the diethylstilbestrol group were significantly higher than the sham operation group, but the royal jelly acid. The group was closer to the normal control group than the vitamin K2+ calcium sulphate group and the calcium sulphate group. It can be concluded that the effect of royal jelly acid on the prevention and treatment of middle-aged and elderly people with osteoporosis is significantly better than vitamin K2+ king calcium sulphate mixture and calcium sulphuric acid calcium.
实施例3Example 3
选取48只12月龄雌性新西兰白兔，体重3.9-4.6kg，SPF级。实验进行前在相同室内环境单笼喂养2周，室温20℃-25℃。将其随机分为5组，分别为：E-10-羟基-2-癸烯酸低剂量组、E-10-羟基-2-癸烯酸中剂量组、E-10-羟基-2-癸烯酸高剂量组、对照组和维生素K2+王浆酸钙组以及王 浆酸钙组，每组8只，采用双侧卵巢切除和醋酸泼尼松龙诱导8周，所有白兔均在第0、8周使用DXA骨密度仪进行股骨BMD检测，采白兔耳缘静脉血使用BGP试剂盒检测白兔BGP。48 12-month-old female New Zealand white rabbits were selected, weighing 3.9-4.6 kg, SPF. The animals were fed in a single cage for 2 weeks in the same indoor environment before the experiment, and the room temperature was 20 °C - 25 °C. They were randomly divided into 5 groups: E-10-hydroxy-2-decenoic acid low dose group, E-10-hydroxy-2-decenoic acid medium dose group, E-10-hydroxy-2-quinone High-dose oleic acid group, control group and vitamin K2+ king calcium sulphate group and calcium sulphate group, 8 rats in each group were induced by bilateral ovariectomy and prednisolone acetate for 8 weeks. All white rabbits were at 0 and 8. The DXA bone densitometer was used for femoral BMD testing. White rabbit ear vein blood was collected using BGP kit to detect white rabbit BGP.
第8周末建模完成后，按以下设计对白兔进行给药处理：E-10-羟基-2-癸烯酸低剂量组每日给药30mg/kg、E-10-羟基-2-癸烯酸中剂量组每日给药60mg/kg、E-10-羟基-2-癸烯酸高剂量组每日给药120mg/kg、维生素K2+王浆酸钙组每日给药维生素K2+王浆酸钙的混合物100mg/kg(按照ZL201210063350.3公开的技术内容重复实验制备且王浆酸钙与维生素K
2的质量比为600:1)、王浆酸钙组(按照ZL201210063350.3公开的技术内容重复实验制备且王浆酸钙，剂量60mg/kg)、对照组每日降钙素皮下注射6.6μg/kg、生理盐水灌胃，其中E-10-羟基-2-癸烯酸(由蜂王浆提取得到，含量≥90.0％，折百计算)；将磨成粉末状的药物与10g饲料进行搅拌混合，于每日18时给药，再于20时补充普通饲料40g，第24周末检测：在兔耳缘静脉注射30mg/kg戊巴比妥钠溶液麻醉后固定于DXA骨密度仪上，运用小动物骨密度测量软件测量股骨BMD；在24周末当晚给药前于耳缘静脉采血并分离血清，严格按ELISA试剂盒操作步骤测定血清BGP。所得数据采用SPSS 17.0统计软件处理分析。其检测结果见表3和表4。
After modeling at the end of the 8th week, the rabbits were treated as follows: E-10-hydroxy-2-decenoic acid low dose group was administered 30 mg/kg, E-10-hydroxy-2-decene daily. The medium-dose group was administered with 60 mg/kg per day, the high dose group of E-10-hydroxy-2-decenoic acid was administered daily at 120 mg/kg, and the vitamin K2+ calcium sulphuric acid group was administered daily with vitamin K2+ calcium sulphate. Mixture 100 mg/kg (reproduced according to the technical content disclosed in ZL201210063350.3 and the mass ratio of calcium calcium sulphate to vitamin K 2 is 600:1), calcium sulphuric acid group (reproduced according to the technical content disclosed in ZL201210063350.3 and repeated Calcium sulphuric acid calcium, dose 60mg/kg), daily control calcitonin subcutaneous injection of 6.6μg/kg, normal saline, E-10-hydroxy-2-decenoic acid (extracted from royal jelly, content ≥90.0 %, fold 100 calculations; the powdered drug is mixed with 10g of feed, mixed at 18 o'clock every day, and then supplemented with ordinary feed 40g at 20 o'clock, the 24th weekend test: 30mg in the rabbit ear vein /kg pentobarbital sodium solution was anesthetized and fixed on DXA bone densitometer, and the femur bone BMD was measured by small animal bone density measurement software; Blood was collected from the ear vein before the administration on the evening of the 24th week and the serum was separated. Serum BGP was determined strictly according to the ELISA kit procedure. The data obtained were analyzed by SPSS 17.0 statistical software. The test results are shown in Tables 3 and 4.
表3各实验组白兔股骨近端BMD情况(mg/cm
2，x±s)
Table 3 BMD of proximal femur in rabbits of each experimental group (mg/cm 2 , x ± s)
表3中：与对照组比较，
#P<0.05，
##P<0.01；与维生素K2+王浆酸钙组比较，
△P<0.05,
△△P<0.01；与王浆酸钙组比较，*P<0.05。
Table 3: Comparison with control group, # P <0.05, ## P <0.01; compared with calcium Vitamin K2 + royal jelly group, △ P <0.05, △△ P <0.01; compared with calcium royal jelly group, * P < 0.05.
表4各组动物血清BGP情况(μg/L，x±s,n＝8)Table 4 serum BGP status of each group of animals (μg / L, x ± s, n = 8)
表4中：与对照组比较，
#P<0.05，
##P<0.01；与维生素K2+王浆酸钙组比较，
△P<0.05,
△△P<0.01。
Table 4: Comparison with control group, # P <0.05, ## P <0.01; compared with calcium Vitamin K2 + royal jelly group, △ P <0.05, △△ P <0.01.
12月龄兔已属老龄兔，并且通过去势和激素诱导8周成功建立模型。本实验通过将其分组进行不同的给药处理，得到了白兔胫骨BMD和血清BGP在不同药物影响下的变化，从表3和表4的实验结果可以看到给药E-10-羟基-2-癸烯酸的各个剂量组可以使白兔胫骨BMD和血清BGP的值更加接近正常值，而给药维生素K+王浆酸钙及单独使用王浆酸钙对提高白兔胫骨BMD和血清BGP有一定效果，但直接使用E-10-羟基-2-癸烯酸(王浆酸)对于中老年骨质疏松的防治效果更为显著。The 12-month-old rabbits were already aged rabbits and were successfully modeled by castration and hormone induction for 8 weeks. In this experiment, the BMD and serum BGP of white rabbits were changed under the influence of different drugs by grouping them into different drug treatments. From the experimental results in Table 3 and Table 4, it can be seen that the administration of E-10-hydroxyl- The doses of 2-decenoic acid can make the BMD and serum BGP values of white rabbits closer to normal values, while the administration of vitamin K + calcium sulphuric acid and calcium sulphuric acid alone can improve the BMD and serum BGP of white rabbit tibia. The effect, but the direct use of E-10-hydroxy-2-decenoic acid ( royal jelly acid) is more effective in the prevention and treatment of osteoporosis in middle-aged and elderly people.
上述实施例为本发明较佳的实施方式，但本发明的实施方式并不受所述实施例的限制，其他的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化，均应为等效的置换方式，都包含在本发明的保护范围之内。The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the embodiments, and any other changes, modifications, substitutions, and combinations may be made without departing from the spirit and scope of the present invention. And simplifications, all of which are equivalent replacement means, are included in the scope of protection of the present invention.
Claims (5)
- 一种E-10-羟基-2-癸烯酸在制备防治骨质疏松症的药品或保健品中的应用。The use of E-10-hydroxy-2-decenoic acid in the preparation of medicines or health care products for preventing and treating osteoporosis.
- 根据权利要求1所述的E-10-羟基-2-癸烯酸在制备防治骨质疏松症的药品或保健品中的应用，其特征在于，所述药物或保健品中的有效成分仅为E-10-羟基-2-癸烯酸。The use of E-10-hydroxy-2-decenoic acid according to claim 1 for the preparation of a medicament or a health care product for preventing and treating osteoporosis, characterized in that the active ingredient in the medicament or health care product is only E-10-hydroxy-2-decenoic acid.
- 根据权利要求1或2所述的E-10-羟基-2-癸烯酸在制备防治骨质疏松症的药品或保健品中的应用，其特征在于，所述E-10-羟基-2-癸烯酸来源于人工合成或从蜂王浆中提取。The use of E-10-hydroxy-2-decenoic acid according to claim 1 or 2 for the preparation of a medicament or a health care product for preventing and treating osteoporosis, characterized in that said E-10-hydroxy-2- The decenoic acid is derived from synthetic synthesis or extraction from royal jelly.
- 根据权利要求1所述的E-10-羟基-2-癸烯酸在制备防治骨质疏松症的药品或保健品中的应用，其特征在于，所述骨质疏松症是指绝经后骨质疏松症Ⅰ型和老年性骨质疏松症Ⅱ型。The use of E-10-hydroxy-2-decenoic acid according to claim 1 for the preparation of a medicament or a health care product for preventing and treating osteoporosis, characterized in that the osteoporosis refers to postmenopausal bone quality Osteoporosis type I and senile osteoporosis type II.
- 根据权利要求1、2或4所述的E-10-羟基-2-癸烯酸在制备防治骨质疏松症的药品或保健品中的应用，其特征在于，所述药品或保健品为片剂、颗粒剂、散剂、丸剂、胶囊剂或口服液。The use of E-10-hydroxy-2-decenoic acid according to claim 1, 2 or 4 for the preparation of a medicament or a health care product for preventing and treating osteoporosis, characterized in that the medicine or health care product is a tablet Agent, granule, powder, pill, capsule or oral solution.
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| JP2006062986A (en) * | 2004-08-25 | 2006-03-09 | Api Co Ltd | Estrogenic agent, method for producing the same, prophylactic agent for osteoporosis and food and beverage |
| CN108125941A (en) * | 2018-01-08 | 2018-06-08 | 石家庄康诺生物技术有限公司 | A kind of application of E-10- hydroxyls -2- decylenic acids in the drug or health products for preparing anti-curing osteoporosis |
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| JP2006062986A (en) * | 2004-08-25 | 2006-03-09 | Api Co Ltd | Estrogenic agent, method for producing the same, prophylactic agent for osteoporosis and food and beverage |
| CN108125941A (en) * | 2018-01-08 | 2018-06-08 | 石家庄康诺生物技术有限公司 | A kind of application of E-10- hydroxyls -2- decylenic acids in the drug or health products for preparing anti-curing osteoporosis |
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| Title |
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| MATSUBARA, T. ET AL.: "A Theoretical Insight into the Interaction of Fatty Acids Involved in Royal Jelly with the Human Estrogen Receptor 13", BULL. CHEM. SOC. JPN., vol. 81, no. 10, October 2008 (2008-10-01), pages 1258 - 1266 * |
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