WO2018107324A1 - 一种降低了高钙血风险的补钙组合物及其应用 - Google Patents

一种降低了高钙血风险的补钙组合物及其应用 Download PDF

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WO2018107324A1
WO2018107324A1 PCT/CN2016/109473 CN2016109473W WO2018107324A1 WO 2018107324 A1 WO2018107324 A1 WO 2018107324A1 CN 2016109473 W CN2016109473 W CN 2016109473W WO 2018107324 A1 WO2018107324 A1 WO 2018107324A1
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extract
composition
calcium
hypercalcemia
eucommia ulmoides
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PCT/CN2016/109473
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English (en)
French (fr)
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孙明杰
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湘北威尔曼制药股份有限公司
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Priority to CN201680090514.8A priority Critical patent/CN109906084B/zh
Priority to PCT/CN2016/109473 priority patent/WO2018107324A1/zh
Publication of WO2018107324A1 publication Critical patent/WO2018107324A1/zh

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    • 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
    • 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
    • A23L33/105—Plant extracts, their artificial duplicates or their derivatives
    • 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
    • A23L33/16—Inorganic salts, minerals or trace elements
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7008—Compounds having an amino group directly attached to a carbon atom of the saccharide radical, e.g. D-galactosamine, ranimustine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
    • A61K33/10—Carbonates; Bicarbonates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/48—Fabaceae or Leguminosae (Pea or Legume family); Caesalpiniaceae; Mimosaceae; Papilionaceae
    • A61K36/488—Pueraria (kudzu)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis

Definitions

  • the present invention relates to a composition, and more particularly to a composition which reduces calcium and simultaneously reduces adverse reactions.
  • Osteoporosis is a systemic bone disease in which the bone mass is reduced, the microstructure of the bone tissue is degraded, the trabecular bone is thinned, the short lobes are reduced, the number is reduced, and the cortex becomes characteristic, resulting in increased fragility of the bone and prone to fracture. It has been reported that in osteoporotic fractures, vertebral fractures, hip fractures and wrist fractures account for about 3/4. In fractures of postmenopausal women in the United States, vertebral fractures account for 25%, up to 35% by the age of 75. According to some statistics, in China's osteoporotic fractures, hip fractures accounted for 21.41%; about 20% of the fracture patients died within one year due to bedridden complications. Among the diseases with high incidence of common females, including myocardial infarction, stroke, breast cancer, etc., the incidence of osteoporotic fractures ranked first.
  • Bone mineral density is an important indicator of bone quality and an important basis for reflecting the degree of osteoporosis and predicting the risk of fracture. Increasing bone density and effectively treating osteoporosis have become an important topic of widespread concern.
  • Calcium supplementation can effectively prevent or treat osteoporosis.
  • Most of the products currently available for calcium supplementation and joint protection contain glucosamine and calcium carbonate.
  • Glucosamine can promote the synthesis of mucopolysaccharide in the human body, improve the viscosity of joint synovial fluid, and improve the metabolism of articular cartilage.
  • calcium carbonate can supplement the calcium necessary for human bones and is an effective ingredient for preventing osteoporosis.
  • the inventors unexpectedly discovered that the combination of Pueraria lobata extract and Eucommia ulmoides leaf extract can reduce the adverse reactions of commonly used calcium supplement products.
  • the present invention provides a composition for increasing bone density, wherein the active ingredient comprises glucosamine hydrochloride and calcium carbonate, and the composition further comprises Pueraria lobata extract and Eucommia ulmoides leaf extract.
  • Glucosamine is the main component of the cartilage matrix. Supplementation with glucosamine can increase organic bones The substance content, which inhibits the degradation of bone matrix, can protect articular cartilage and has a good effect on improving joint pain and other symptoms caused by osteoporosis.
  • Glucosamine hydrochloride is a salt form which is commercially available.
  • Calcium carbonate is a commonly used calcium supplement and is commercially available.
  • Pueraria is the dry root of the leguminous plant Puerarialobata (Willd.) Ohwi, which has the effects of improving immunity, relieving heat, protecting the liver, and improving cardiovascular and cerebrovascular diseases.
  • the Pueraria lobata extract is an extract obtained by a conventional method of Pueraria lobata, and is also commercially available.
  • Eucommia ulmoides leaves are dried leaves of Eucommiaulmoides Oliver.
  • the traditional Chinese medicine Eucommia ulmoides is the dried skin of Eucommia. Studies have shown that Eucommia leaves have the effects of tonifying the kidney, strengthening the muscles and strengthening the bones.
  • the extract of Eucommia ulmoides leaves is an extract obtained by a conventional method of Eucommia ulmoides leaves, and is also commercially available.
  • Hypercalcemia is an abnormal increase in serum ionized calcium concentration, generally higher than 2.75 mmol/L. Many factors such as drugs and diseases can cause hypercalcemia, and high calcium symptoms can cause digestive, motor, neurological, urinary and other multi-system diseases such as anorexia, nausea, vomiting, constipation, fatigue, muscle fatigue, muscle tension. Reduced, annoying, polyuria, lethargy, unconsciousness, and even coma. Hypercalcemia itself is a disorder of calcium metabolism. Calcium supplementation products affect the body's calcium metabolism by increasing the direct intake of external calcium, so there is a risk of high calcium.
  • the ratio of Pueraria lobata extract and Eucommia ulmoides leaf extract is critical to reducing the adverse effects of traditional calcium supplementation products. Adverse reactions of glucosamine hydrochloride and calcium carbonate can be significantly improved when in certain specific ratio ranges.
  • the weight ratio of Pueraria lobata extract and Eucommia ulmoides leaf extract is from 4:1 to 1.2:1. More preferably, the weight ratio of the two is from 3:1 to 1.5:1.
  • the weight percentage of Pueraria lobata extract and Eucommia ulmoides leaf extract in the composition may be 2-30%.
  • the content of glucosamine hydrochloride and calcium carbonate in the composition can be used in a usual amount.
  • the weight percentage of glucosamine hydrochloride may be 20-50%, and the weight percentage of calcium carbonate may be 20-50%.
  • composition of the present invention may be composed only of four components of Pueraria lobata extract, Eucommia ulmoides leaf extract, glucosamine hydrochloride and calcium carbonate, and may also contain adjuvants, or may be added to other active substances to form a compound composition. .
  • the above composition is selected from the group consisting of pueraria extract, eucommia extract, glucosamine and calcium carbonate.
  • the weight ratio is about 1.09-24:0.4-13.64:20-50:20-50.
  • the present invention provides a combination composition for increasing bone density, the combination composition comprising the composition of the present invention.
  • the combination of the present invention may contain suitable excipients such as diluents, binders, lubricants and the like, such as microcrystalline cellulose, starch, lactose, talc, magnesium stearate and the like.
  • suitable excipients such as diluents, binders, lubricants and the like, such as microcrystalline cellulose, starch, lactose, talc, magnesium stearate and the like.
  • the combination composition of the present invention may contain other active ingredients in addition to the above composition in the present invention.
  • the other active component may be selected from one or more of chondroitin sulfate, epimedium extract or skeletal extract.
  • Chondroitin sulfate is an acid mucopolysaccharide extracted from animal tissues, which can remove a large amount of Na+ in the synovial membrane, promote bone growth, repair damaged joints, and enhance the absorption of nutrients by articular cartilage.
  • the chondrocytes have enough water to absorb shock and lubrication.
  • the weight percentage of chondroitin sulfate in the combination composition of the present invention may be 8-30%.
  • Epimediumbrevicornu Maxim belongs to the genus Epimedium. It has the function of inhibiting bone cells, especially increasing the formation of calcified bone, and has the function of “reinforcing bone”.
  • the weight percentage of Epimedium extract in the combination composition of the present invention may be 2-15%.
  • Davalliamariesii Moore ex Bak. is the dry rhizome of the water dragon skeletal plant fern, which has the effects of healing and relieving pain, strengthening kidney and strengthening bone.
  • the weight fraction of the sclerotium extract in the combination composition of the present invention may be 2-15%.
  • composition or combination composition of the present invention can be prepared into various forms such as capsules, tablets and the like as needed.
  • the present invention also provides the use of a combination of Pueraria lobata extract and Eucommia ulmoides leaf extract for reducing adverse reactions in medicines or health care products.
  • the weight ratio of Pueraria lobata extract and Eucommia ulmoides leaf extract is 4:1 to 1.2:1; further preferably 3:1 to 1.5:1.
  • the above-mentioned adverse reactions include hypercalcemia.
  • the function of the above-mentioned pharmaceutical or health food comprises increasing bone density.
  • the above-mentioned pharmaceutical or health food contains glucosamine hydrochloride and calcium carbonate.
  • compositions and the compound composition of the invention have the effects of traditional calcium supplement products, such as effectively improving bone metabolism, increasing bone density, strengthening bone and joint, and obviously solving problems such as osteoporosis and bone and joint damage. More important
  • compositions and combination compositions of the present invention significantly reduce the risk of hypercalcemia and do not produce new adverse effects. This is especially true for middle-aged and elderly people who need long-term calcium supplementation and poor physical function.
  • Eucommia ulmoides leaf extract 1.2:1 composition of the invention. 929 g of calcium carbonate, 756 g of glucosamine hydrochloride, 19.6 g of Eucommia ulmoides leaf extract, 23.6 g of puerarin extract, 421 g of microcrystalline cellulose, and 10.8 g of magnesium stearate were weighed. According to the preparation method of the tablet, soft materials, granulation, and tableting were carried out to obtain 6,000 tablets.
  • Eucommia ulmoides leaf extract 4:1 composition of the invention. 518.4 g of calcium carbonate, 993.6 g of glucosamine hydrochloride, 129.6 g of Eucommia ulmoides leaf extract and 518.4 g of Pueraria lobata extract were weighed, respectively. According to the preparation method of Example 1, 6000 capsules were prepared.
  • Eucommia leaf extract 3:1 composition of the invention. 1080 g of calcium carbonate, 626.4 g of glucosamine hydrochloride, 113.4 g of Eucommia ulmoides leaf extract and 340.2 g of Pueraria lobata extract were weighed separately. According to the preparation method of Example 1, 6000 capsules were prepared.
  • Eucommia leaf extract 1:1 composition. 1080 g of calcium carbonate, 626 g of glucosamine hydrochloride, 227 g of Eucommia ulmoides leaf extract and 227 g of Pueraria lobata extract were weighed separately. According to the preparation method of Example 1, 6000 capsules were prepared.
  • the active composition of the present invention is prepared by adding an active substance such as chondroitin sulfate, epimedium extract, and sclerotium extract to the composition of the present invention.
  • an active substance such as chondroitin sulfate, epimedium extract, and sclerotium extract
  • 1080 g of calcium carbonate, 626 g of glucosamine hydrochloride, 113 g of eucommia leaf extract, 340 g of puerarin extract, 1080 g of chondroitin sulfate, 72 g of epimedium extract and 289 g of sclerotium extract were weighed. According to the preparation method of Example 1, 6000 capsules were prepared.
  • the combination composition of the present invention is prepared.
  • Magnesium citrate was prepared into a capsule of 6000 granules according to the preparation method of Example 1.
  • the combination composition of the present invention is prepared. Weigh 1080g calcium carbonate, 626g glucosamine hydrochloride, 113g eucommia leaf extract, 340g pueraria extract, 685.7g chondroitin sulfate, 515.3g extract of Epimedium and 69g of sclerotium extract, according to Example 1. The preparation method is prepared into 6000 capsules.
  • the combination composition of the present invention is prepared. Weigh 1080g calcium carbonate, 626g glucosamine hydrochloride, 113g eucommia leaf extract, 340g pueraria extract, 515.3g chondroitin sulfate, 240g epimedium extract and 514.3g of bone granule extract, according to Example 1.
  • the preparation method is prepared into 6000 capsules.
  • the model control group and the group 1-9, the anesthesia method was the same as above, under the strict aseptic operation, the double incision of the lumbar vertebrae was taken into the dorsal side of the abdomen, and after the bilateral ovaries were completely removed, the incision was sutured by careful hemostasis.
  • Example 1 Three days after surgery, the sham operation group and the model control group were orally administered with distilled water.
  • the composition of Example 1 was given 28.4 mg/kg.bw of the composition of Example 1, and the groups of Examples 2-8 were respectively given 36 mg/kg.bw of the composition of Example 2-8, Example 9
  • the composition of Example 9 was given 60 mg/kg.bw. All animals were given 10 ml/kg.bw per day, once a day for 90 days.
  • the animals were sacrificed and the bilateral femurs were removed.
  • the right femur was placed in an oven at 105 ° C, roasted to constant weight, and the bone weight was weighed.
  • the bone density of the left femur was measured by a small animal automatic high-resolution X-ray machine. The effects of each group on bone density are shown in Table 1.
  • the body weight of each group increased significantly after the experiment.
  • the weight gain of the model group was particularly significant (P ⁇ 0.01), and the bone density decreased significantly (P ⁇ 0.01), indicating successful modeling.
  • the femur weight and bone density of the groups of Examples 1-9 were improved, even if the group 1 contained only calcium carbonate and glucosamine hydrochloride, the bone weight and bone density of the rats after the experiment were made.
  • the increase indicates that the bone weight and bone density of the rats with bilateral ovaries removed after administration of the composition of the present invention are increased.
  • the composition of the present invention is effective in preventing and improving osteoporosis.
  • Example 6 2.50 ⁇ 0.09
  • Example 7 2.47 ⁇ 0.05
  • Example 8 3.00 ⁇ 0.11
  • Example 9 group 2.44 ⁇ 0.07
  • the normal blood calcium level was 2.25-2.75 mmol/L.
  • some animals showed elevated blood calcium, and some of them were as high as 3 mmol/L, suggesting mild to moderate hypercalcemia.
  • serum calcium in the sham operation group and the model control group suggesting that the modeling process was not the cause of hypercalcemia.
  • the effect of the composition of the invention on blood calcium in the test animals can be seen from a comparison of the various sets of examples.
  • the group of Example 1 was a composition containing no extract of Eucommia ulmoides Oliv. and Pueraria lobata extract, and Examples 2 to 9 contained both of the above extracts.
  • the data in Table 2 shows that the average blood calcium levels of the rats in the first, second and eighth groups were significantly higher than those in the sham operation group and the model control group, indicating that the calcium supplement combination of the first, second and eighth groups was taken.
  • the rat developed hypercalcemia.
  • the mean blood calcium levels of the rats of Examples 3 to 7 and Example 9 were comparable to those of the sham operation group and the model control group, and were significantly lower than those of the group 1, group 2, and group 8 (P ⁇ 0.01).
  • the above results indicate that the addition of Eucommia ulmoides leaf extract and Pueraria lobata extract can effectively prevent the calcium-reducing composition from causing hypercalcemia adverse reactions, and can produce a significant positive effect when the two are within a specific ratio range.
  • the toxicology experiment was carried out using the composition prepared in Example 3 of the present invention, and the results showed that in the acute toxicity test, the acute oral MTD of SD rats was greater than 15 g/kg.bw, which was non-toxic according to the acute toxicity classification.
  • the results of Ames test, mouse bone marrow polychromatic erythrocyte micronucleus test and mouse sperm abnormality test were all negative.
  • the highest dose was 100 times recommended by the human body, which did not cause abnormal changes in the overall health status, physiological and biochemical functions, and organ histomorphology of the rats.
  • the above results show that the composition of the present invention does not produce new toxicity and is safe.
  • the present invention relates to a calcium supplement composition which reduces the risk of hypercalcemia and its use.
  • the composition of the present invention can be used alone or in combination with other calcium supplements.
  • the compositions and combination compositions of the invention are effective Improve bone metabolism, increase bone density, and significantly solve problems such as osteoporosis and bone and joint damage. More importantly, the risk of hypercalcemia is reduced, and no new adverse reactions are produced. It is especially suitable for middle-aged and elderly people who have degraded body functions and need long-term calcium supplementation.
  • the invention has broad application prospects and good industrial applicability in the field of medical technology.

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Abstract

一种降低高钙血风险的补钙组合物及其应用，该组合物除含有氨基葡萄糖盐酸盐和碳酸钙之外，还包括葛根提取物和杜仲叶提取物，两种提取物的重量比为4:1-1.2:1，所述组合物可有效改善骨代谢，增加骨密度，降低高钙血风险。

Description

一种降低了高钙血风险的补钙组合物及其应用 技术领域
本发明涉及一种组合物，特别是涉及一种在补钙的同时降低了不良反应的组合物。
背景技术
骨质疏松症是以骨量减少，骨组织微观结构退化，骨小梁变细、短裂、数量减少、皮质变为特征，以致骨的脆性增加，容易发生骨折的一种全身性骨骼疾病。据报道，在骨质疏松性骨折中，椎体骨折、髋部骨折和腕部骨折约占3/4。美国的绝经期后妇女的骨折病人中，椎体骨折占25％，而到75岁时高达35％。有人统计，我国的骨质疏松性骨折中，髋部骨折占21.41％；其中约有20％的骨折患者一年内因卧床不起引起并发症而死亡。而在几种女性常见发生率高的疾病中，包括心肌梗死、脑卒中、乳腺癌等，其中骨质疏松性骨折发生率位列榜首。
骨密度是骨质量的一个重要标志，是反映骨质疏松程度，预测骨折危险性的重要依据。增加骨密度、有效治疗骨质疏松已经成为人们广泛关注的重要课题。
补钙可有效预防或治疗骨质疏松。现有上市的补钙和保护关节的产品中大多含有氨基葡萄糖和碳酸钙。氨基葡萄糖能促进人体粘多糖的合成，提高关节滑液的粘性，改善关节软骨的代谢。碳酸钙作为钙源，能补充人体骨骼必须的钙质，是预防骨质疏松的有效成分。
但是研究发现，氨基葡萄糖和碳酸钙在长期服用后可产生一些不良反应。如何更好地发挥传统补钙产品的作用，同时能降低不良反应是值得深入研究的问题。
发明内容
在进行研究中，发明人意外发现：葛根提取物和杜仲叶提取物的组合，可以降低常用补钙产品的不良反应。
第一方面，本发明提供了一种增加骨密度的组合物，其活性成分包括氨基葡萄糖盐酸盐和碳酸钙，该组合物中还包括葛根提取物和杜仲叶提取物。
氨基葡萄糖是软骨基质的主要成分。补充氨基葡萄糖可以增加骨骼中的有机 物质含量，抑制骨基质降解破坏，可保护关节软骨，对改善骨质疏松引起的关节疼痛等症状有良好的作用。氨基葡萄糖盐酸盐是其一种盐形式，可通过市购获得。
碳酸钙是补钙的常用药，可通过市购获得。
葛根是豆科植物野葛(Puerarialobata(Willd.)Ohwi)的干燥根，具有提高免疫、解热、护肝、改善心脑血管疾病等功效。葛根提取物为葛根经常规方法提取得到的提取物，也可以通过市售获得。
杜仲叶是杜仲科植物杜仲(EucommiaulmoidesOliver)的干燥叶。传统中药杜仲则是杜仲的干燥皮。有研究表明，杜仲叶有补肾、强筋健骨等功效。杜仲叶提取物为杜仲叶经常规方法提取得到的提取物，也可以通过市售获得。
通过研究发现，长期服用葡萄糖盐酸盐和碳酸钙之后可能导致一些不良反应，例如高钙血风险增加。高钙血症表现为血清离子钙浓度的异常升高，一般高于2.75mmol/L。药物、疾病等多种因素均可引起高钙血，而高钙血症状又可引起消化、运动、神经、泌尿等多系统疾病，例如厌食、恶心、呕吐、便秘，乏力、肌肉疲劳、肌张力减低、烦喝、多尿，嗜睡、神志不清，甚至昏迷等。高钙血本身属于钙代谢的紊乱，补钙产品通过增加外界钙的直接摄取，影响了人体钙代谢，故存在高钙血的风险。
而意外地发现，葛根提取物和和杜仲叶提取物的组合可降低这种不良反应。
葛根提取物和杜仲叶提取物的比例对于降低传统补钙产品的不良反应非常关键。当在某些特定的比例范围内时，氨基葡萄糖盐酸盐和碳酸钙的不良反应可得到显著的改善。在本发明中，优选地，葛根提取物和杜仲叶提取物的重量比为4:1～1.2:1。更优选地，二者的重量比为3:1～1.5:1。
组合物中葛根提取物和杜仲叶提取物的重量百分含量可以是2-30％。
组合物中的氨基葡萄糖盐酸盐和碳酸钙的含量可以采用常用量。例如，氨基葡萄糖盐酸盐的重量百分含量可以是20-50％，碳酸钙的重量百分含量可以是20-50％。
本发明的上述组合物可以仅由葛根提取物、杜仲叶提取物、氨基葡萄糖盐酸盐和碳酸钙四种组分组成，也可以含有辅料，另外也可以添加到其他活性物质中形成复方组合物。
优选地，上述组合物中葛根提取物、杜仲提取物、氨基葡萄糖、碳酸钙四者 的重量比例约为1.09-24：0.4-13.64：20-50：20-50。
第二方面，本发明提供了一种增加骨密度的复方组合物，该复方组合物含有本发明中的组合物。
优选地，本发明的复方组合物可以含有适用的辅料，例如稀释剂、黏合剂、润滑剂等，具体如微晶纤维素、淀粉、乳糖、滑石粉、硬脂酸镁等。
优选地，本发明的复方组合物除含有本发明中的上述组合物之外，还可以含有其他活性组分。进一步优选地，所述的其他活性组分可选自硫酸软骨素、淫羊藿提取物或骨碎补提取物中的一种或多种。
硫酸软骨素是从动物组织中提取制备的酸性粘多糖，其可去除大量吸收滑膜中的Na+，促进骨质增长，修复受损的关节，其可增强关节软骨对营养的吸收，也可使软骨细胞有足够的水分，从而能达到缓冲震动及润滑的作用。在本发明的复方组合物中硫酸软骨素的重量百分含量可以是8-30％。
淫羊藿(Epimediumbrevicornu Maxim.)属于小檗科淫羊藿属。具有抑制骨细胞功能，特别是使钙化骨形成增加，具有“补骨”作用。在本发明的复方组合物中淫羊藿提取物的重量百分含量可以是2-15％。
骨碎补(Davalliamariesii Moore ex Bak.)为水龙骨科植物槲蕨的干燥根茎，具有疗伤止痛、补肾强骨等功效。在本发明的复方组合物中骨碎补提取物的重量百分含量可以是2-15％。
本发明的上述组合物或者复方组合物，可以根据需要制备成不同的形式，如胶囊、片剂等。
第三方面，本发明还提供了葛根提取物和杜仲叶提取物的组合在减轻药品或保健品的不良反应中的应用。
优选地，葛根提取物和杜仲叶提取物的重量比为4:1～1.2:1；进一步优选为3:1～1.5:1。
优选地，上述的不良反应包括高钙血症。
优选地，上述的药品或保健食品的功能包括增加骨密度。
优选地，上述的药品或保健食品中含有氨基葡萄糖盐酸盐和碳酸钙。
本发明的组合物和复方组合物具有传统补钙产品的功效，如可有效改善骨代谢，增加骨密度，加强骨关节，明显解决骨质疏松及骨关节受损等问题。更重要 的是，本发明的组合物和复方组合物可显著降低高钙血风险，并且不产生新的不良反应。这对于需要长期补钙而身体机能较差的中老年人群特别适用。
具体实施方式
以下参照具体的实施例来说明本发明。本领域技术人员能够理解，这些实施例仅用于说明本发明，其不以任何方式限制本发明的范围。
下述实施例中的实验方法，如无特殊说明，均为常规方法。所用的原辅料、试剂材料等，如无特殊说明，均为市售购买产品。
实施例1
制备现有的补钙组合物。分别称取1080g碳酸钙和626g氨基葡萄糖盐酸盐，将两种原料过40目筛后，混合均匀，取混合物从漏斗上方慢慢加入，从漏斗底部漏出的供试品在水平面上形成圆锥状堆积体的倾斜角。用直尺精密量出圆锥体的直径和高度，用公式tanθ＝h/r求出倾斜角θ。每种配方三次测定休止角，测定结果休止角均≤40°后，将原料混合后粉末直接填充成胶囊6000粒。
实施例2
在实施例1处方的基础上增加杜仲叶提取物和葛根提取物，制备葛根提取物：杜仲叶提取物＝6:1的组合物。分别称取1080g碳酸钙，626g氨基葡萄糖盐酸盐，66g杜仲叶提取物和388g葛根提取物，按照实施例1的制备方法，制备成胶囊6000粒。
实施例3
制备葛根提取物：杜仲叶提取物＝1.2:1的本发明的组合物。分别称取929g碳酸钙，756g氨基葡萄糖盐酸盐，19.6g杜仲叶提取物，23.6g葛根提取物，421g微晶纤维素，10.8g硬脂酸镁。按照片剂的制备方法，制软材，制粒，压片，得到6000片。
实施例4
制备葛根提取物：杜仲叶提取物＝2:1的本发明的组合物。分别称取820.8g碳酸钙，432g氨基葡萄糖盐酸盐，108g杜仲叶提取物，216g葛根提取物和583.2g微晶纤维素。按照实施例1的制备方法，制备成胶囊6000粒。
实施例5
制备葛根提取物：杜仲叶提取物＝1.5:1的本发明的组合物。分别称取432g 碳酸钙，1080g氨基葡萄糖盐酸盐，51.8g杜仲叶提取物，77.8g葛根提取物和518.4g微晶纤维素。按照实施例1的制备方法，制备成胶囊6000粒。
实施例6
制备葛根提取物：杜仲叶提取物＝4:1的本发明的组合物。分别称取518.4g碳酸钙，993.6g氨基葡萄糖盐酸盐，129.6g杜仲叶提取物和518.4g葛根提取物。按照实施例1的制备方法，制备成胶囊6000粒。
实施例7
制备葛根提取物：杜仲叶提取物＝3:1的本发明的组合物。分别称取1080g碳酸钙，626.4g氨基葡萄糖盐酸盐，113.4g杜仲叶提取物和340.2g葛根提取物。按照实施例1的制备方法，制备成胶囊6000粒。
实施例8
制备葛根提取物：杜仲叶提取物＝1:1的组合物。分别称取1080g碳酸钙，626g氨基葡萄糖盐酸盐，227g杜仲叶提取物和227g葛根提取物。按照实施例1的制备方法，制备成胶囊6000粒。
实施例9
在本发明组合物的基础上增加了硫酸软骨素、淫羊藿提取物、骨碎补提取物等活性物质，制备本发明的复方组合物。分别称取1080g碳酸钙，626g氨基葡萄糖盐酸盐，113g杜仲叶提取物，340g葛根提取物，1080g硫酸软骨素，72g淫羊藿提取物和289g骨碎补提取物。按照实施例1的制备方法，制备成胶囊6000粒。
实施例10
制备本发明的复方组合物。分别称取1080g碳酸钙，626g氨基葡萄糖盐酸盐，113g杜仲叶提取物，340g葛根提取物，243.9g硫酸软骨素，304.2g淫羊藿提取物、304.2g骨碎补提取物和30.6g硬脂酸镁，按照实施例1的制备方法，制备成胶囊6000粒。
实施例11
制备本发明的复方组合物。分别称取1080g碳酸钙，626g氨基葡萄糖盐酸盐，113g杜仲叶提取物，340g葛根提取物，685.7g硫酸软骨素，515.3g淫羊藿提取物和69g骨碎补提取物，按照实施例1的制备方法，制备成胶囊6000粒。
实施例12
制备本发明的复方组合物。分别称取1080g碳酸钙，626g氨基葡萄糖盐酸盐，113g杜仲叶提取物，340g葛根提取物，515.3g硫酸软骨素，240g淫羊藿提取物和514.3g骨碎补提取物，按照实施例1的制备方法，制备成胶囊6000粒。
实施例13
在去卵巢骨质疏松(OP)模型大鼠中观察实施例1～9的各组合物对骨密度和血液学的影响。
1、分组及处理：
取10月龄SD雌性大鼠110只，将大鼠随机分成11组，每组10只，即假手术组、模型对照组、实施例1组、实施例2组、实施例3组、实施例4组、实施例5组、实施例6组、实施例7组、实施例8组、实施例9组。假手术组用3％戊巴比妥钠腹腔麻醉，在严格无菌操作下，取腰椎旁背侧双切口进入腹腔，摘除少许小肠系膜后，仔细止血逐层缝合切口。模型对照组和实施例1-9组，麻醉方法同上，在严格无菌操作下，取腰椎旁背侧双切口，进入腹腔背侧，完整摘除双侧卵巢后，仔细止血逐层缝合切口。
术后三天，假手术组和模型对照组以蒸馏水灌胃。实施例1组给与实施例1中的组合物28.4mg/kg.bw，实施例2-8组分别对应地给与实施例2-8中的组合物36mg/kg.bw，实施例9组给与实施例9中的组合物60mg/kg.bw。所有动物灌胃量均为10ml/kg.bw，每天一次，连续灌胃90天。
2、测定指标：
在实验前、实验中和实验后记录动物的体重。在实验结束后，对所有大鼠尾部取血后，血液滴入1.5mL离心管中，于室温下静置0.5小时之后血清置于冰上，继续静置1小时。取出离心管，以4000～6000rpm在室温下离心3～5分钟，每600μL全血取200～300μL血清。一次性吸取完毕后，将取得的血清分装到已经灭菌的离心管中，进行血钙测定。各组平均血钙值如表2所示。取血完成后安乐处死动物，取出双侧股骨，右侧股骨放置于105℃烘箱中，烤至恒重，称量骨重，采用小动物全自动高分辨率X光机测定左股骨骨密度。各组对骨密度的影响如表1所示。
3、实验结果：
表1各组大鼠体重与股骨重及骨密度统计
Figure PCTCN2016109473-appb-000001
根据表中数据，实验后各组体重较实验前明显增加。与假手术组比较，模型组体重增加尤为显著(P<0.01)，骨密度明显降低(P<0.01)，说明造模成功。与模型组比较，实施例1-9组股骨重量和骨密度都得到提高，即使实施例1组中仅含有碳酸钙和氨基葡萄糖盐酸盐，也使得大鼠在实验后的骨重和骨密度有所增大，说明在服用本发明的组合物后，被摘除了双侧卵巢的大鼠骨重和骨密度得到了增加。本发明的组合物能有效预防和改善骨质疏松。
表2各组大鼠的平均血钙值统计结果
组别 平均血钙值(mmol/L)
假手术组 2.48±0.07
模型对照组 2.43±0.08
实施例1组 3.07±0.12
实施例2组 2.97±0.08
实施例3组 2.51±0.06
实施例4组 2.53±0.05
实施例5组 2.46±0.07
实施例6组 2.50±0.09
实施例7组 2.47±0.05
实施例8组 3.00±0.11
实施例9组 2.44±0.07
正常血钙水平为2.25-2.75mmol/L，在试验中观察到部分动物出现血钙升高，有的高达3mmol/L以上，提示出现轻中度的高钙血症。但假手术组和模型对照组均未出现血钙升高，表明造模过程不是导致高钙血症产生的原因。从各个实施例组的对比可以看出本发明组合物对试验动物血钙的影响。实施例1组为不含杜仲叶提取物和葛根提取物的组合物，实施例2～实施例9均含有上述两种提取物。表2数据显示，实施例1组、2组和8组大鼠的平均血钙水平明显高于假手术组和模型对照组，说明经过服用实施例1组、2组和8组的补钙组合物后，大鼠产生了高钙血症的现象。实施例3～实施例7以及实施例9大鼠的平均血钙水平与假手术组和模型对照组相当，并且显著低于实施例1组、2组和8组(P<0.01)。上述结果表明，杜仲叶提取物和葛根提取物的加入能有效预防补钙组合物导致高钙血症的不良反应，并且当二者在特定比例范围内时，能产生显著的积极效果。
实施例14
使用本发明中的实施例3制备的组合物进行毒理学实验，结果显示：急性毒性实验中，SD大鼠急性经口MTD大于15g/kg.bw，根据急性毒性分级，属无毒级。遗传毒性试验中，Ames试验、小鼠骨髓嗜多染红细胞微核试验和小鼠精子畸形试验结果均为阴性。30天喂养试验中，最高剂量为人体推荐摄入量100倍，未引起大鼠整体健康状况、生理生化功能和器官组织形态学等各项重要指标的异常变化。以上结果说明本发明的组合物未产生新的毒性，安全性好。
虽然，上文中已经用一般性说明及具体实施方案对本发明作了详尽的描述，但在本发明基础上，可以对之作一些修改或改进，这对本领域技术人员而言是显而易见的。因此，在不偏离本发明精神的基础上所做的这些修改或改进，均属于本发明要求保护的范围。
工业实用性
本发明涉及一种降低了高钙血风险的补钙组合物及其应用，本发明组合物可以单用，也可以与其他补钙物质一起使用。本发明的组合物和复方组合物可有效 改善骨代谢、增加骨密度、明显解决骨质疏松及骨关节受损等问题。更重要的是使得高钙血风险得以降低，且不产生新的不良反应，特别适用于身体机能退化而又需要长期补钙的中老年人群。本发明在医药技术领域具有广阔的应用前景及良好的工业实用性。

Claims (10)

  1. 一种降低了高钙血风险的补钙组合物，其活性成分包括氨基葡萄糖盐酸盐和碳酸钙，其特征在于，所述组合物中还包括葛根提取物和杜仲叶提取物，所述葛根提取物与杜仲叶提取物的重量比为4:1～1.2:1。
  2. 根据权利要求1所述的组合物，其特征在于，所述葛根提取物与杜仲叶提取物的重量比为3:1～1.5:1。
  3. 根据权利要求1所述的组合物，其特征在于，所述组合物由氨基葡萄糖盐酸盐、碳酸钙、葛根提取物和杜仲叶提取物组成。
  4. 一种降低了高钙血风险的补钙复方组合物，其特征在于，含有权利要求1-3中任一所述的组合物。
  5. 根据权利要求4所述的复方组合物，其特征在于，所述复方组合物中还含有适用的辅料。
  6. 根据权利要求4所述的复方组合物，其特征在于，所述复方组合物中还含有其他活性组分。
  7. 根据权利要求6所述的复方组合物，其特征在于，所述其他活性组分选自硫酸软骨素、淫羊藿提取物或骨碎补提取物中的一种或多种。
  8. 葛根提取物和杜仲叶提取物的组合在减轻药品或保健食品的不良反应中的应用。
  9. 根据权利要求8所述的应用，其特征在于，所述药品或保健食品的功能包括增加骨密度。
  10. 根据权利要求8所述的应用，其特征在于，所述不良反应包括高钙血症。
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