CN110934883A - A group of naringin preparations for improving osteoporosis in men and preventing fractures - Google Patents

A group of naringin preparations for improving osteoporosis in men and preventing fractures Download PDF

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CN110934883A
CN110934883A CN201911286740.5A CN201911286740A CN110934883A CN 110934883 A CN110934883 A CN 110934883A CN 201911286740 A CN201911286740 A CN 201911286740A CN 110934883 A CN110934883 A CN 110934883A
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naringin
fructose
osteoporosis
bone
group
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吴铁
崔燎
王可欣
陈彩玲
吴怡
林振波
吕思敏
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ZHANJIANG GUANGYI MEDICAL TECHNOLOGY DEVELOPMENT Co Ltd
Guangdong Medical University
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ZHANJIANG GUANGYI MEDICAL TECHNOLOGY DEVELOPMENT Co Ltd
Guangdong Medical University
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Abstract

With the increase of age, the testosterone level of middle-aged and elderly men is gradually reduced, the biomechanical performance of bones is reduced, and the fracture and the osteoporosis are easy to occur; the research discovers that a preparation consisting of naringin and fructose can replace testosterone and be used for preventing male osteoporosis and people with reduced bone biomechanical properties, the naringin is a natural flavanone glycoside, the fructose is a special energy supplement, the naringin and the fructose are combined into oral liquid, capsules, tablets, granules, oral liquid and beverages according to the ratio of 1: 3-4, and the preparation can be used for preventing and treating people with reduced bone biomechanical properties caused by various reasons and male osteoporosis patients. The invention also discloses a formula and a production process of the naringin fructose oral liquid, the naringin fructose vitamin D calcium preparation granules, the naringin fructose estrogen tablets and the naringin fructose aspirin tablets, and the products have good effects on preventing male osteoporosis and people with low bone biomechanical function; has better curative effect on female osteoporosis patients.

Description

Naringin preparation for improving male osteoporosis and preventing fracture
Technical Field
The invention belongs to the technical field of production of health-care food and medicines, and particularly relates to a naringin preparation for improving male osteoporosis and preventing fracture.
Background
The research shows that the general morbidity of osteoporosis of male population over 50 years old is 22.5%, the incidence rate of bone fracture is 13%, the incidence rate of bone fracture is higher than that of prostatic cancer, the morbidity of osteoporosis in different areas and age stages is different, but the general trend of the development of the general trend of osteoporosis is increased, the medical cost caused by osteoporosis fracture reaches 1.8 trillion (Lin X, etc., Clin Interv Aging, 2015) is expected to reach 2.12 billion, the risk factors of osteoporosis fracture in China are mainly age increase, low body weight, physical activity reduction, smoking, using corticosteroid hormone or androgen ablation therapy, the prevention and treatment of osteoporosis in men are not fully focused on the reduction of bone mass per man and the destruction of bone tissue microstructure of the osteoporosis in men, and the biological performance of the osteoporosis is reduced, the increase, the development of osteoporosis and the related androgen metabolism, the growth, osteoporosis, bone loss, osteoporosis, bone loss, osteoporosis, bone loss, osteoporosis, bone loss, osteoporosis, bone loss, osteoporosis, and other conditions, osteoporosis, bone loss, osteoporosis, bone loss, osteoporosis, and other conditions, Aging, osteoporosis, bone loss, osteoporosis, Aging, osteoporosis, bone loss, osteoporosis, bone loss, Aging, osteoporosis, Aging, osteoporosis, Aging, bone loss, Aging, bone loss, Aging, bone loss, weight.
Naringin is a natural flavanone glycoside, exists in Chinese herbal medicines and citrus fruits, has a definite chemical structure, has been reported to have pharmacological actions of reducing blood fat, calming, resisting inflammation, resisting oxidation, resisting tumors, resisting fungi, resisting atherosclerosis, relieving spasm, easing pain, regulating blood sugar and the like, has an antiallergic action, has an inhibitory action on mutagenicity of heterocyclic amines and the like, has a prevention and treatment effect on gastric ulcer, has an inhibitory action on staphylococcus aureus, salmonella, shigella, escherichia coli and certain fungi, has an antagonistic action on certain poisons, has an effect of improving microcirculation and cartilage histiocyte functions, has effects of reducing capillary permeability and osteoarthropathy rate and the like, and recently, scholars at home and abroad find that naringin has important influence on in-vitro culture of mesenchymal stem cells between mouse bone marrow, osteogenic differentiation of fibroblasts of human periodontal ligament, generation inhibition of osteoclasts and the like, research shows that naringin can increase the expression of osteoblast marker protein (such as osteocalcin, osteopontin, osteoprotegerin and bone morphogenetic protein-2 (BMP-2)), and inhibit the NF-kB and ERK signal transmission activity induced by RANKL (stimulator of nuclear factor-kappa B (NF-kB) ligand (RANKL)) and the protein expression of osteoclast gene, thereby causing osteoclast not to be normally formed, thus playing a role in delaying osteoporosis and promoting the proliferation and differentiation of osteoblast. Bone loss induced in the denervation is associated with the inactivation of Wnt/b catenin, the upregulation of periostin and sclerostin downstream of it. Naringin can up-regulate periostin expression and prevent the decrease of bone density (BMD) induced by nerve excision, and finally the microstructure and mechanical characteristics of bones can not be deteriorated. In addition, naringin can inhibit the differentiation and bone resorption function of osteoclast; inhibit the proliferation activity of osteoclast, and make the expression of RANK, TRAP, MMP-9 and NFATc1 mRNA in the differentiation process of osteoclast down-regulated and the expression of C-fosmRNA up-regulated. This also suggests that naringin may inhibit osteoclast differentiation, proliferation and bone resorption function, and its mechanism may be achieved by inhibiting specific gene expression during osteoclast differentiation. Research on the relationship between naringin and blood vessels in osteoporosis shows that neovascularization is positively correlated with the intake amount and frequency of naringin, hematoxylin-eosin staining shows that the blood vessels are increased and become thick, and VEGF and VEGFR-2 activities are increased in osteoporotic fracture callus, so that naringin is inferred to stimulate the regeneration of blood vessels by regulating a VEGF/VEGFR-2 signal channel of an osteoporosis mouse, and further promote rehabilitation. Further studies have shown that naringin can promote the expression of Vascular Endothelial Growth Factor (VEGF) and Brain Derived Neurotrophic Factor (BDNF) following spinal injury. The naringin is integrated into the nano-stent for repairing osteoporosis, so that the hydrophilicity, the thinness and the fiber uniformity of the stent are improved, the rapid degradation of the stent can be promoted, and the effect of the stent can be better exerted. The study has fixed naringin on chitosan substrate to promote the expression of osteogenic proteins in bone repair, such as type I collagen, bone sialoprotein and osteocalcin. Naringin immobilized on ozonated chitosan substrate, according to Smad1 and Smad6 phosphorylation, is able to activate osteogenic protein Smad signaling by activating Smad receptors and suppressing their inhibitory factors. The scholars also find that the Bmi1 gene of human periodontal ligament stem cells is closely related to the immortality of the human periodontal ligament stem cells, and the over-expression of the Bmi1 gene changes the cell cycle, the cell reproduction and the functionality. Naringin can increase Bmi1 gene expression of human periodontal ligament stem cell, increase activity of alkaline phosphatase, human run-related transcription factor 2 (Runx 2) and osteocalcin, and promote formation of mineral nodule. In addition, naringin also activates and regulates extracellular protein kinase 1/2[ (ERK) 1/2 ]. These results indicate that naringin promotes the role of periodontal ligament stem cell Bmi1 gene in odontogenesis at least through ERK 1/2 cell signaling pathway (jinyuanbao et al, china modern medicine journal 2018). Naringin has also been reported in the literature to inhibit OVX-induced increases in urinary calcium excretion and loss of bone mass and strength in Ovariectomized (OVX) mice, and to improve bone mass in the distal femur, proximal tibia and lumbar spine. Naringin and DF flavonoid components mimic estrogen and inhibit osteoclastogenesis in young retinoic acid-induced osteoporotic rats, probably by modulating OPG and RANKL expression in osteoblasts, naringin has been shown to significantly increase plasma insulin-like growth factor 1 levels, femoral BMD and intensity, BMD in the fifth lumbar and bone calcium concentrations in the femurs and lumbar. Naringin (200 mg/kg oral gavage) has been shown to cause upregulation of BMD, bone volume, trabecular thickness and maximal load in OVX rats. In male rats with intact gonads, naringin has the effect of statins, and can reduce lipid and stimulate the relation between BMP and bone fat. However, the influence of naringin on an animal model with testis removal is not observed at present, whether the naringin can help middle-aged and old-aged osteoporosis patients with male testicular hypofunction is not shown, a method for removing testis is used for establishing an animal model with osteoporosis caused by androgen deficiency for a male, the influence of testosterone and naringin on the reduction of the biomechanical performance of a mouse bone and the osteoporosis caused by androgen deficiency is observed, meanwhile, a series of control medicines which are combined with the naringin and other medicines are designed for observation, and the result shows that the naringin is administrated by gastric irrigation according to 300mg/kg and 600mg/kg solutions for 8 weeks continuously, the bone biomechanical performance of a mouse with testis removal is obviously improved, the osteoporosis is also benefited to a certain extent, and the difference has statistical significance. In the observation of the combination group, we found that the administration of a solution of naringin 300mg/kg + fructose 1200mg/kg through gastric lavage showed better therapeutic effects than naringin alone on various relevant indexes of biomechanical properties of the bone of the testicular-free mice and bone mass loss (see example 1)
The action of the composition is equivalent to that of high-dose naringin, and the fructose is considered to be a special energy supplement, plays an important energy supplement role in the process of replacing androgen by the naringin to prevent bone loss and promote bone formation, enhances the formation of collagen by the naringin, improves the biomechanical property of the bone, and shows that the composition can effectively prevent the occurrence of fracture caused by osteoporosis and is a good medicine for preventing and treating osteoporosis fracture.
Disclosure of Invention
According to the discovery that the preparation consisting of naringin and fructose can prevent osteoporosis caused by sex hormone deficiency after testicle removal, the method for preparing the pharmaceutical preparation or the health food for treating male osteoporosis by using the naringin and the fructose is provided. The combination has a good ratio of 1-2: 3-8 of naringin, and researches prove that the optimal ratio is 1: 4; the medicine preparation consists of 1 part of naringin and 4 parts of fructose, and can be added with a certain excipient to be prepared into clinically applicable oral buccal tablets, oral tablets, capsules, granules, oral liquid and beverages. When the beverage is prepared from naringin fructose, each 1000ml of the beverage contains 1-3 g of naringin and 60-100 g of fructose, and the optimal proportion is that the ratio of naringin to fructose is 1: 2-4.
We also find that calcium carbonate and vitamin D3 can be added into the preparation consisting of naringin and fructose to form a group of health-care food suitable for all kinds of osteoporosis people, and the calcium supplement is an essential precondition in any osteoporosis treatment, can correct negative calcium balance in the bone absorption and bone formation process, and is a material basis for improving bone mass. At present, the recommended value of the element calcium taken by middle-aged and elderly people every day is 1000-1500 mg. The calcium agent mainly applied at present comprises calcium carbonate, calcium lactate, calcium citrate, calcium gluconate, active calcium, amino acid chelated calcium and the like. Vitamin D can promote intestinal calcium absorption and urinary calcium reabsorption, and is prepared from Ginseng radixRegulating with calcium and phosphorus, and promoting calcium precipitation in bone matrix. Vitamin D may also regulate nerve-muscle tissue coordination. The vitamin D3 and the calcium agent are added into the preparation consisting of the naringin and the fructose, so that the anti-osteoporosis activity of the preparation consisting of the naringin and the fructose can be further improved, the biomechanical property of bones can be better improved, and the health food is suitable for various people to take and is used for protecting bones and preventing osteoporosis. The calcium agent provided by the invention is calcium carbonate, calcium lactate, calcium citrate, calcium gluconate, active calcium and amino acid chelated calcium; the vitamin D provided by the invention is vitamin D2, vitamin D3Calcitriol and alfacalcidol. The best product provided by the invention is prepared from naringin, fructose, calcium carbonate and vitamin D3Adding certain excipient, and making into clinically applicable buccal tablet, capsule, tablet, granule, oral liquid and beverage, wherein when the preparation is granule, each tablet contains 30-50 mg of naringin, 100-250 mg of fructose and vitamin D30.1-0.5 ug, 0.3-0.5 g calcium carbonate.
We also find that the preparation consisting of naringin and fructose can also form a new anti-osteoporosis compound with estrogen drugs, and the compound preparations can be used for preventing and treating osteoporosis patients after female menopause; estrogen deficiency is the leading factor in osteoporosis in postmenopausal women, and therefore, estrogen supplementation can be used to treat osteoporosis. Estrogens natural estrogens and synthetic estrogens. The natural estrogen mainly comprises estradiol and estrone. The artificial synthetic estrogen-like substance comprises diethylstilbestrol, ethinyl estradiol, nilestriol and the like. Estrogens bind to osteoblast receptors to promote bone synthesis and remodeling by promoting the release of various cytokines from osteoblasts, and furthermore, estrogens can directly inhibit the bone resorption action of osteoclasts. However, the side effects of estrogen are related to the dosage used, and the lowest dosage recommended to prevent bone mass loss is not suitable for long-term use. Because estrogen is dangerous to induce coronary heart disease, cerebral apoplexy, breast cancer, thromboembolism and other diseases, FDA only applies it as a preventive drug. NIH also advises the cessation of estrogen therapy for osteoporosis, which is considered more disadvantageous. According to the characteristics of the influence of the peony seed oil on the bone biomechanics and the bone quality, the invention provides that the peony seed oil is combined with low-dose estrogen, so that the side effect generated by the estrogen can be reduced while the osteoporosis is prevented. The medicine composition is especially suitable for preventing bone loss of female postmenopausal osteoporosis patients, and has good prevention and treatment effects on climacteric syndromes accompanied by the patients. The estrogen mentioned in the invention refers to estradiol, estrone, diethylstilbestrol, ethinyl estradiol, nilestriol, tibolone (livee) and primimaline (double meili). The combination of the compound of naringin and fructose and low-dose estrogen provided by the invention means that the dose of the estrogen contained in each soft capsule is one third to one half of the dose of the existing estrogen preparation. The best product provided by the invention is an oral tablet prepared from 30-50 mg of naringin and fructose and 0.05-0.01 mg of diethylstilbestrol according to the production process of the tablet, wherein each tablet contains 100-250 mg of the fructose composed of the naringin and the fructose and 0.05-0.01 mg of the diethylstilbestrol.
We also found that the preparation of naringin and fructose can be combined with anti-inflammatory drug aspirin to form a new compound for preventing and treating osteoporosis and bone pain caused by osteoporosis. Our previous studies have demonstrated that aspirin, a cyclooxygenase inhibitor commonly used in the first-class prevention of cardiovascular diseases and cancer, is useful for the first-class prevention of cardiovascular diseases and cancer, and inhibits the synthesis of prostaglandin E2 essential for bone remodeling, has a preventive and therapeutic effect on osteoporosis, and particularly has a superior analgesic effect on pain caused by osteoporosis. This suggests that it may affect the bone health of the user. In vitro studies have shown that aspirin can enhance the survival of bone marrow mesenchymal stem cells (progenitors of osteoblasts) and stimulate differentiation of osteoblasts. Aspirin also inhibits the nuclear factor κ B (NF κ B) pathway and reduces NF receptor activation of expressed κ B ligand, thereby inhibiting osteoclast formation, aspirin may prevent bone loss in an animal model of osteoporosis. Despite the positive impact on bone mineral density, limited human epidemiological studies have shown that aspirin does not reduce the fracture risk. There was a study even mentioning that aspirin increases fracture risk. The current view is that aspirin increases bone mineral density, but its role in fracture prevention is not yet known, and more data is needed to determine the impact of aspirin and bone health on humans. According to the research result of the influence of the peony seed oil on bones, the peony seed oil and aspirin form a compound preparation which can increase bone density, increase ossein, improve the mechanical properties of bones of patients with osteoporosis and prevent fractures. The optimum product of the compound aspirin tablet, which is provided by the invention, can be prepared into tablets for clinical application by adding pharmaceutical auxiliary materials according to the production process of common tablets, wherein each tablet contains 30-50 mg of naringin, 100-250 mg of fructose and 100-500 mg of aspirin.
The following are specific embodiments of the present invention and further description of the technical solutions of the present invention, but the scope of the present invention is not limited to these embodiments, and all changes or equivalent substitutions that do not depart from the spirit of the present invention are included in the scope of the present invention.
Example one
Naringin fructose oral liquid: 30-50 mg of naringin and 100-250 mg of fructose are added into 100-150 mg of drinking water, dissolved, prepared into oral liquid for clinical application according to the production process of the oral liquid, and filled.
The invention relates to a naringin fructose oral liquid: and corresponding pharmaceutic adjuvants can be added according to the requirements of clinical application to prepare capsules, tablets, granules or beverages.
The experimental scheme of the naringin fructose oral liquid for protecting the bone biomechanical function decline and osteoporosis of the testicular-removed mice is as follows: 70 SPF-grade 4-week-old male KM mice are purchased from the center of Experimental animals in Guangdong province, and the license number is SCXK (Guangdong) 2018-. Adaptive feeding for 2 weeks, then evenly dividing into 7 groups according to a random block method, carrying out testicular removal operation in the 6 th week, and beginning intragastric administration of different drugs the next day after operation. Grouping experiments: (1) the sham operation group: performing a pseudo-operation without removing the testis, and beginning to perfuse stomach with normal saline two days after the operation; (2) and (3) removing testis: mice were subjected to bilateral testicular extirpation, epididymis was retained, and after the surgery was completed, the wound was disinfected with iodophor every day until the wound was completely healed. The normal saline for gastric lavage is started two days after the operation; (3) destesticle + testosterone undecanoate: the operation method is the same as that of the testicle removal group, and the gastric lavage testosterone solution (soybean oil is used as a solvent) of 10.4mg/kg is started two days after the operation; (4) removing testis and fructose: the operation method is the same as that of the testicle removal group, and the gastric fructose solution with the concentration of 1200mg/kg is infused in two days after the operation; (5) testicular removal + L naringin: the operation method is the same as that of the testicle removing group, and the administration is started two days after the operation. Feeding naringin solution at a ratio of 300 mg/kg; (6) testicular + H naringin removal: the operation method is the same as that of the testicle removing group, and the administration is started two days after the operation. The naringin solution is infused according to the ratio of 600 mg/kg. Taking a proper amount of naringin raw material medicine, and dissolving the naringin raw material medicine by using 0.9 percent physiological saline solution. (7) Testicle-free + fructose + L naringin (naringin fructose oral liquid): the operation method is the same as that of the testicle removal group, administration is started two days after the operation, and the dosage of the administration by intragastric administration is 300mg/kg of naringin and 1200mg/kg of fructose. Naringin in this study was purchased from Sigma, USA, with a purity of 90.0% or more, and a cargo number N1376. The preparation method comprises the following steps: precisely weighing 3.333g naringin powder in a 50ml volumetric flask, adding sterile normal saline to the scale mark, shaking up to obtain suspension, shaking up before each administration, and then intragastrically administering. Each group of mice was dosed once daily for 8 weeks. In the experiment process, changes of the mice in eating, drinking, activity and the like are observed and recorded every day, the weight is weighed for 1 time in 7 days, and the dosage is adjusted according to the weight change. After the experiment is finished, the left femur is taken, the muscles and the tendons around the femur are removed, the biomechanical indexes of the specimen are detected and analyzed by adopting a Lloyd LR5K Plus bone biomechanical detection system, the experiment adopts a three-point bending method, and the steps are as follows: the left femur of a rat is placed on a testing machine, a pressure head with the diameter of 1mm is used, the loading speed is 2mm/min, the span L is 20mm, the femur is pressurized until fracture occurs, the measurement of a yield point and fracture parameters can be provided, the instrument can record the load (F) and radius (d) change value of each time point in time, a load-displacement curve is drawn, then the maximum load, the fracture load and the elastic load are read, and the rigidity (rigidity coefficient) is calculated. The results of the biomechanical property measurements of the femurs of the experimental mice are shown in table 1.
TABLE 1 Change in bone biomechanical parameters for groups of mice (` C)x±s,n=10）。
Figure 61001DEST_PATH_IMAGE001
As can be seen from the results in Table 1, the maximum load, the elastic load and the rigidity coefficient in the bone biomechanical parameters of the mice in the testicle-removed group are obviously reduced (P is less than 0.05) compared with the mice in the sham operation group; compared with the mouse of the testicle-removing model group, the rigidity coefficient of the testosterone-supplementing group mouse is obviously improved (P is less than 0.01); compared with the testis-removed group, the rigidity coefficient of the fructose group mouse is obviously improved (P is less than 0.05); compared with the mouse with the testis removed group, the L-naringin group mouse has obviously increased breaking load, maximum load, elastic load and rigidity coefficient (P < 0.05). Compared with the testicle-removed group, the elastic load and the rigidity coefficient of the H-naringin group mice are obviously improved (P is less than 0.05); compared with the testis-removed group, the low-dose naringin fructose oral liquid group has the advantages that the breaking load, the maximum load, the elastic load and the rigidity coefficient are obviously increased (P is less than 0.05); the fracture load refers to the plastic strain of bone before fracture, which reflects the plasticity of bone materials, the maximum load reflects the maximum external force which can be borne by bone, the elastic load reflects the maximum deformation length which can be borne by bone in the elastic range, the rigidity coefficient reflects the external hardness of a bone specimen, and the naringin fructose oral liquid group obviously increases the three mechanical properties of the maximum load, the elastic load and the rigidity coefficient of bone, which indicates that the naringin fructose oral liquid group has obvious bone strengthening function, wherein the elastic load of the bone of a mouse treated by the naringin fructose oral liquid group is stronger than that of a mouse treated by testosterone and better than that of the mouse treated by the testosterone alone with high dose, and the naringin fructose oral liquid group is prompted to replace the testosterone to prevent the reduction of the bone mechanical properties caused by androgen reduction.
And (3) carrying out Micro-CT detection on the thighbone of the mouse without the testis by using the naringin fructose oral liquid: muscle and attached tissues of the left femur of the mouse are removed, the mouse is placed into a Micro-CT (Micro-computed tomography) instrument, and the metaphysis of the femur is subjected to X-ray scanning. The viva CT40 selects the scan parameters image matrix 2048X 2048, integration time 200ms, energy/intensity 70kVp, 114 μ A, 8W. Scanning is performed with 0 ° rotation. After the scanning is finished, selecting bone tissues 1.0mm away from the far end of the growth plate and 2.0mm in layer thickness as a cancellous bone interested Region (ROI) for three-dimensional reconstruction, and extracting image information with the lowest threshold value of 150. Quantitative analysis parameters were analyzed using the SCANCOMedical AG software. The parameters are as follows: connection Density (conn.d.), Structural Model Index (SMI), Volume Bone Density (BMD), Bone Volume fraction (Bone Volume/Tissue Volume, BV/TV), Trabecular number (tb.n), Trabecular Thickness (Trabecular thicness, tb.th), Trabecular separation (tb.sp). The results are shown in tables 2 and 3.
TABLE 2 Micro-CT quantitative parameter index Change (1) for each group of micex±s,n=10）。
Figure 102775DEST_PATH_IMAGE002
As can be seen from the results in Table 2, the Micro-CT parameters of the mice in the testicular-free model group showed a significant decrease in the femoral junction density and the number of bone integration, and the structural model index showed a significant increase in the number of bone integration in the mice in the Micro-CT model group, as compared with the mice in the sham operation group (see the following table 2)P<0.05); the integral number of bone parts of the testosterone-supplemented mice is obviously increased and the structural model index is obviously reduced compared with the testicular-removed model mice (the structural model index is obviously reduced) ((P<0.05); compared with the oral liquid group without testis, the naringin fructose oral liquid group has obviously increased femur connection density and bone integration number, and the structural model index is obviously reduced (P<0.05). The Structural Model Index (SMI) reflects the extent of trabecular (plate-like) and rod-like (rod-like) bone, with SMIs for trabecular and rod-like trabecular bone being 0 and 3 in order. In the case of osteoporosis, the trabecular bone changes from plate-like to rod-like and the SMI value increases. The SMI of the testicle-removing model group reaches 3.09, which indicates that the trabecula bone is changed from a plate shape to a rod shape, the osteoporosis appears, and the change of the trabecula bone from a plate shape to a rod shape can be improved by supplementing testosterone or naringin and fructose oral liquidThe bone is in a rod-shaped state, so that the loss of trabecular bone is reduced, the connection density (conn.d) represents the connection number between trabecular networks, the connection density is obviously reduced in the testicular removal model group compared with a sham operation group, and the reduction of the connection number between the trabecular networks of the bone after testicular removal can be prevented by supplementing testosterone or naringin fructose oral liquid; the bone volume fraction is an important index for evaluating bone mass, the number of bone parts of the testicle-removed model group is obviously reduced, which indicates that the bone mass is lost in a large amount, and the number of the bone parts of the testicle-removed model group is obviously increased by supplementing testosterone or naringin fructose oral liquid, which indicates that the two medicines can reduce the bone loss but far cannot reach the level of a control group.
TABLE 3 Micro-CT quantitative parameter index Change (2) for each group of micex±s,n=10）。
Figure 882512DEST_PATH_IMAGE003
As can be seen from the results in Table 3, the number of trabeculae of femur was significantly decreased in the Micro-CT parameter and the trabecular bone separation was significantly increased in the mice of the testicular removal model group compared to the mice of the sham operation group: (P<0.01); the number and thickness of trabeculae are obviously increased and the separation degree of trabeculae is obviously reduced in the testosterone supplementing group mice and the testicular removal model group mice (the separation degree of the trabeculae is obviously reduced: (P<0.05); compared with the mice of the testicle-removed model group, the mice of the naringin fructose oral liquid group have obviously increased number of the trabeculae of the femur and obviously reduced separation degree of the trabeculae (P<0.01). Research results show that naringin fructose oral liquid group has the same effect as testosterone, can obviously increase the number and thickness of trabeculae, reduce the separation degree of the trabeculae and obviously resist the bone loss caused by testicle removal, but compared with a control group, the antagonism still can not reach the level of the control group.
Example two
According to the experimental result of the first embodiment, calcium carbonate and vitamin D3 are added into the naringin fructose preparation to form a group which is better in curative effect and suitable for various osteoporosis peopleA health food for group administration. Calcium supplement for naringin fructose preparation can be calcium carbonate, calcium lactate, calcium citrate, calcium gluconate, active calcium, and amino acid chelated calcium; the vitamin D can be vitamin D, vitamin D2Vitamin D3Calcitriol and alfacalcidol. The best product provided by the invention is composed of peony seed oil, calcium carbonate and vitamin D3The components, the formula and the production process are as follows.
Naringin, fructose and vitamin D calcium preparation granules: selecting appropriate amount of naringin, fructose, and vitamin D3Calcium carbonate is prepared into a formula, then a proper amount of stabilizing agent, antioxidant, suspending agent, emulsifier and other ingredients are added, and then the granules are prepared according to the production process of the granules, wherein each granule comprises 30-50 mg of naringin, 100-250 mg of fructose and fructose, and vitamin D30.1-0.5 ug, 0.3-0.5 g calcium carbonate.
EXAMPLE III
According to the experimental result of the first embodiment, a novel anti-osteoporosis compound is formed by adding estrogen medicines into a naringin fructose preparation, and the compound preparation can be used for preventing and treating female postmenopausal osteoporosis patients, is particularly suitable for preventing bone loss of the female postmenopausal osteoporosis patients and has good prevention and treatment effects on climacteric syndromes accompanied by the patients. The estrogen which can be added in the naringin fructose preparation is estradiol, estrone, diethylstilbestrol, ethinyl estradiol, nilestriol, tibolone (livea) and primeverine (bimesol). The content of each grain of the compound preparation prepared by the naringin fructose estrogen and the estrogens is one third to one half of the pharmaceutical preparation dosage of the estrogens. The formula and production process of the optimal product provided by the invention are as follows.
Naringin fructose estrogen tablets: the preparation method comprises the steps of taking naringin, fructose and diethylstilbestrol, adding a proper amount of a stabilizer, an antioxidant, a suspending agent and an emulsifier, and then preparing the oral tablet according to the production process of the tablet, wherein each tablet contains 30-50 mg of naringin, 100-250 mg of fructose and 0.05-0.01 mg of diethylstilbestrol.
Example four
According to the experimental result of the first embodiment, a novel compound is designed by adding anti-inflammatory aspirin in a naringin fructose preparation, and the compound is used for preventing and treating osteoporosis and bone pain caused by osteoporosis. The optimum product formula and production process of the compound preparation consisting of the naringin fructose preparation and the aspirin are as follows.
The naringin fructose preparation aspirin tablet: naringin, fructose and aspirin are selected, pharmaceutical auxiliary materials are added according to a production process of a common tablet, and the tablet is pressed into a tablet for clinical application, wherein each tablet contains 30-50 mg of naringin, 100-250 mg of fructose and 100-500 mg of aspirin.
The products described in the first, second, third and fourth examples can be prepared into clinically applicable capsules, tablets, granules, oral liquid and beverages by adding excipients.

Claims (5)

1.一组改善男性骨质疏松预防骨折的柚皮苷制剂，其特征是该制剂中含有柚皮苷和果糖，两者的比例为1:3～4。1. A group of naringin preparations for improving male osteoporosis and preventing fractures, characterized in that the preparations contain naringin and fructose in a ratio of 1:3 to 4. 2.如权利要求1所述的一组改善男性骨质疏松预防骨折的柚皮苷制剂，其特征是制备为柚皮苷果糖维生素D钙颗粒剂时，可添加适量的稳定剂，抗氧化剂、助悬剂、乳化剂，按照颗粒剂的生产工艺，制成每包含有柚皮苷30～50mg，果糖100～250mg，维生素D3 0.1～0.5ug，碳酸钙0.3～0.5g。2. a group of naringin preparations for improving male osteoporosis and preventing fractures as claimed in claim 1, is characterized in that when being prepared as naringin fructose vitamin D calcium granules, an appropriate amount of stabilizer can be added, antioxidants, Suspending agent and emulsifier are prepared according to the production process of granules, each containing 30-50 mg of naringin, 100-250 mg of fructose, 0.1-0.5 ug of vitamin D 3 and 0.3-0.5 g of calcium carbonate. 3.如权利要求1所述的一组改善男性骨质疏松预防骨折的柚皮苷制剂，其特征是制备柚皮苷果糖雌激素片剂时，可按照片剂的生产工艺制成的口服片剂，该片剂每粒含有柚皮苷30～50mg果糖100～250mg，己烯雌酚0.05mg～0.01mg。3. a group of naringin preparations for improving male osteoporosis and preventing fractures as claimed in claim 1, when it is characterized in that preparing naringin fructose estrogen tablet, the oral tablet that can be made according to the production technology of tablet Each tablet contains 30-50 mg of naringin, 100-250 mg of fructose, and 0.05-0.01 mg of diethylstilbestrol. 4.如权利要求1所述的一组改善男性骨质疏松预防骨折的柚皮苷制剂，其特征是制备柚皮苷果糖阿司匹林片剂时，可按照普通片剂的生产工艺，添加药剂学上的辅料，压制成可供临床应用的片剂，该片剂每粒含有柚皮苷30~50mg，果糖100～250mg，阿司匹林100mg～500mg。4. a group of naringin preparations for improving male osteoporosis and preventing fractures as claimed in claim 1, when it is characterized in that preparing naringin fructose aspirin tablet, can according to the production technology of common tablet, add pharmacy. The excipients are compressed into tablets for clinical application, and each tablet contains 30-50 mg of naringin, 100-250 mg of fructose, and 100-500 mg of aspirin. 5.如权利要求2～4所述的一组改善男性骨质疏松预防骨折的柚皮苷制剂，还可添加赋形剂，制备成临床可应用的胶囊，片剂，颗粒剂，口服液和饮料。5. A group of naringin preparations for improving male osteoporosis and preventing fractures according to claims 2 to 4, can also add excipients to prepare clinically applicable capsules, tablets, granules, oral liquids and drinks.
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