WO2015106467A1 - 一种药物组合物及其制备方法和用途 - Google Patents
一种药物组合物及其制备方法和用途 Download PDFInfo
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- WO2015106467A1 WO2015106467A1 PCT/CN2014/071593 CN2014071593W WO2015106467A1 WO 2015106467 A1 WO2015106467 A1 WO 2015106467A1 CN 2014071593 W CN2014071593 W CN 2014071593W WO 2015106467 A1 WO2015106467 A1 WO 2015106467A1
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- Prior art keywords
- dendrobium
- fenugreek
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- pharmaceutical composition
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- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 30
- 238000002360 preparation method Methods 0.000 title claims abstract description 27
- 241001523681 Dendrobium Species 0.000 claims abstract description 43
- 206010012601 diabetes mellitus Diseases 0.000 claims abstract description 32
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 18
- 239000002994 raw material Substances 0.000 claims abstract description 10
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims abstract description 10
- 239000000546 pharmaceutical excipient Substances 0.000 claims abstract description 4
- 239000003960 organic solvent Substances 0.000 claims abstract description 3
- 244000250129 Trigonella foenum graecum Species 0.000 claims description 86
- 235000001484 Trigonella foenum graecum Nutrition 0.000 claims description 86
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- 238000000034 method Methods 0.000 claims description 14
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/48—Fabaceae or Leguminosae (Pea or Legume family); Caesalpiniaceae; Mimosaceae; Papilionaceae
-
- 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)
- A61K36/88—Liliopsida (monocotyledons)
- A61K36/898—Orchidaceae (Orchid family)
- A61K36/8984—Dendrobium
-
- 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
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
Definitions
- the invention relates to the field of medicine, in particular to a pharmaceutical composition for treating diabetes.
- Diabetes are caused by genetic factors, immune dysfunction, microbial infections and their toxins, free radical toxins, mental factors and other pathogenic factors that cause the islet dysfunction, insulin resistance, etc. caused by sugar, protein,
- a series of metabolic disorders such as fat, water and electrolytes, clinically characterized by hyperglycemia, typical cases can appear polyuria, polydipsia, polyphagia, weight loss, etc., gp "three more than one less" symptoms, diabetes ( Blood sugar) Once it is not well controlled, it can cause complications, leading to depletion of kidneys, eyes, feet, etc., and it cannot be cured.
- Chinese medicine believes that diabetes is caused by lack of righteousness, emotional injury, poisonous evils, blood stasis, turbidity and so on.
- Dendrobium extract has the effects of nourishing yin and clearing heat, Shengjinyiwei, moistening lung and relieving cough, and improving eyesight. It can exert hypoglycemic effect by regulating the hormone levels secreted by islet ⁇ and ⁇ cells, and has pancreatic and pancreatic The mechanism of action of lowering blood sugar. 4-hydroxyisoleucine and saponin in fenugreek also have good hypoglycemic effect.
- the present invention provides a novel hypoglycemic pharmaceutical composition, a preparation method and use thereof.
- the pharmaceutical composition of the present invention is a preparation prepared from the following raw materials by weight ratio:
- the composition is a preparation prepared from the following raw materials by weight ratio: 10 parts of Dendrobium and 3 parts of Fenugreek.
- the sarcophagus is Dendrobium nobile Lindl., Dendrobium aurantiacum Rchb. f. var. expeanum ⁇ Dendrobium
- composition is based on the original medicinal material of sarcophagus, fenugreek, water extract or organic solvent extract.
- the formulation is an oral formulation.
- the preparation is a powder, a paste, a granule, a tablet, a capsule, an oral solution or a dropping pill.
- the method of the present invention for preparing the aforementioned pharmaceutical composition comprises the following steps:
- the fenugreek extract obtained in the step (2) is mixed with the aqueous extract of the sarcophagus of the step (3), and a pharmaceutically acceptable adjuvant or auxiliary component is added to prepare a pharmaceutically acceptable preparation.
- the concentration of ethanol is 75%
- the amount of ethanol is 11 times that of the fenugreek meal
- the number of times of reflux extraction is 3 times
- the time of each extraction is 120 minutes.
- the amount of water is 11 times that of the stone meal, and the number of times of reflux extraction is 3 times, and the time for each extraction is 120 minutes.
- the present invention finally provides the use of the aforementioned pharmaceutical composition for the preparation of a medicament for the treatment of diabetes.
- the diabetes is type II diabetes.
- the pharmaceutical composition of the invention can effectively treat diabetes, has the advantages of formula, less medicinal taste, less toxic and side effects, simple preparation method and convenient use, and provides a new choice for clinical treatment of diabetes, and the effect of the combination of the two at the same dose Significantly superior to the two drugs alone, indicating that they play a synergistic role.
- the sarcophagus is pulverized into a coarse powder, added with 11 times of water, refluxed for 3 times, 120 min/time, filtered through a filter paper, and the filtrate is combined, and concentrated under reduced pressure to 50 g of the original drug per 100 ml, refrigerated in a refrigerator for 12 hours, and freeze-dried. Stone water extract.
- the fenugreek was pulverized into a coarse powder, 11 times of 75% ethanol was added, and refluxed for 3 times, 120 min/time, filtered through a filter paper, and the filtrate was combined, and concentrated under reduced pressure to 50 g per 100 ml of the original drug, and the refrigerator was chilled for 12 hours. Freeze-dried to obtain a fenugreek extract.
- the aqueous extract of Dendrobium candidum is mixed with the extract of fenugreek and then prepared into a medicament of the desired dosage form, such as granules, tablets, hard capsules, oral liquids, soft capsules, dropping pills or sugar syrups.
- the sarcophagus is a stem of Dendrobium nobile Lindl.
- the aqueous extract of Dendrobium candidum is mixed with the extract of fenugreek to prepare a drug of the desired dosage form, such as: granules, tablets, hard capsules, oral liquids, soft capsules, dropping pills or sugar canes.
- the sarcophagus is a Dendrobium aurantiacum Rchb. f. var. implementeanum of the genus Dendrobium aurantiacum R.
- the aqueous extract of Dendrobium candidum is mixed with the extract of fenugreek to prepare a drug of the desired dosage form, such as: granules, tablets, hard capsules, oral liquids, soft capsules, dropping pills or sugar canes.
- a drug of the desired dosage form such as: granules, tablets, hard capsules, oral liquids, soft capsules, dropping pills or sugar canes.
- the sarcophagus is Dendrobium officinale Kimura et Migo of the genus Dendrobium officinale.
- the aqueous extract of Dendrobium candidum is mixed with the extract of fenugreek to prepare a drug of the desired dosage form, such as: granules, tablets, hard capsules, oral liquids, soft capsules, dropping pills or sugar canes.
- a drug of the desired dosage form such as: granules, tablets, hard capsules, oral liquids, soft capsules, dropping pills or sugar canes.
- the sarcophagus is Dendrobium chrysotoxum Lindl of the genus Dendrobium chrysotoxum Lindl.
- the aqueous extract of Dendrobium candidum is mixed with the extract of fenugreek to prepare a drug of the desired dosage form, such as: granules, tablets, hard capsules, oral liquids, soft capsules, dropping pills or sugar canes.
- a drug of the desired dosage form such as: granules, tablets, hard capsules, oral liquids, soft capsules, dropping pills or sugar canes.
- the sarcophagus is a genus of the genus Dendrobium fimbriatum Hook.
- Test Example 1 Verification of hypoglycemic effect of the pharmaceutical composition of the present invention
- the pharmaceutical composition of the present invention is prepared from fenugreek 3g and Dendrobium 10g as main raw materials, wherein the Dendrobium is a stem of Dendrobium nobile Lindl., and the preparation method is as follows: Fenugreek: The coarse powder of the reed, added 11 times of 75% ethanol, and refluxed for 3 times. 120 min / time, filter paper filtration, the filtrate was combined, concentrated under reduced pressure to 50 g per 100 ml of the original drug, refrigerator for 12 hours, freeze-dried, the extract yield was 15%;
- Dendrobium Take the coarse powder of Dendrobium, add 11 times of water, reflux for 3 times, 120 min / time, filter paper, filter the filtrate, concentrate under reduced pressure to 50 g per 100 ml of the original drug, refrigerator for 12 hours, freeze-dry, The extract yield was 9%;
- the above-mentioned fenugreek extract and the aqueous extract of Dendrobium can be obtained by mixing.
- Gemlaczide (Gleclazide, 1), produced by the French Servier Pharmaceuticals and Tianjin Huajin Pharmaceutical Factory.
- Aloxan Alloxan
- American Sigma product freshly prepared with physiological saline at a concentration of 1.5% before the experiment.
- the experimental animals were housed in the Pharmacological Laboratory Animal Observation Room of Chengdu University of Traditional Chinese Medicine.
- the environment was adapted to the environment for 3 days before the start of the experiment, and the diet and water were normally administered.
- 90 male rats 180 ⁇ 200g were injected intraperitoneally with Alloxan (alloxan) 150 mg/kg, injected for 4 days, fasted for 8 hours, and blood glucose was detected. (Note, before the animals were tested for blood glucose in the following experiments, the animals were fasted. 811:).
- mice with high blood glucose qualified model blood glucose greater than 10mm O l/L were randomly divided into model group, positive group, fenugreek + Dendrobium high dose group, fenugreek + Dendrobium medium dose group, fenugreek + Dendrobium low dose Group, single-flavored stone group, single-flavored fenugreek group.
- Another 10 batches of unmodeled healthy SD rats were taken as a blank group.
- the rats in the normal control group and the model control group were given an equal volume of 20 ml/kg normal saline for 30 days.
- the other groups were dosed daily as follows:
- Fenugreek 1. 5g/kg. d Observation index: blood was taken from the tail vein at 10d, 20d and 30d respectively. Serum islets were determined by taking blood at 20d and 23d, respectively. The experimental data is represented by x ⁇ S, and the data is processed by statistical SPSS13.0 software, and t-test is used between groups.
- the blood glucose of the positive group was significantly decreased. After 10 days, 20 days, and 30 days of administration, there was a significant difference ( ⁇ .01 or p ⁇ 0.05) compared with the model group, indicating that the Alloxan-induced diabetes model was used to evaluate the blood glucose lowering effect. The effect is feasible.
- the blood glucose levels of the low, medium and high dose groups of the composition of the present invention gradually decreased, wherein the low dose group was significantly different from the model group after 20 days and 30 days of administration, p ⁇ 0.05).
- the high-dose group showed significant difference (p ⁇ 0.01 or p ⁇ 0.05) compared with the model group after administration for 10 days, 20 days, and 30 days, indicating that the composition of the present invention can effectively lower blood sugar.
- the blood glucose level of the composition of the present invention and the high-dose group was lower after administration, wherein the middle-dose group was treated with the single-flavor stone group after 20 days and 30 days of administration.
- the blood glucose level in the high-dose group at 30 days after administration was significantly different from that in the single-flavored group and the single-flavored fenugreek group (p ⁇ 0.05). It is indicated that the present invention combines Dendrobium and Fenugreek, and the two play a synergistic effect.
- Table 3 Serum insulin content (mU/L)
- the serum insulin content of the positive group was significantly decreased. After administration for 10 days, 20 days, and 30 days, there were significant differences compared with the model group ( ⁇ .01 or p ⁇ 0.05), indicating that the drug was evaluated by the Alloxan-induced diabetes model. It is feasible to treat diabetes.
- the serum insulin levels in the low, medium and high dose groups of the composition of the present invention decreased significantly, and after 10 days, 20 days, and 30 days, there were significant differences compared with the model group ( ⁇ .01 or p ⁇ 0.05). ).
- the low, medium and high dose groups of the composition of the present invention have lower serum insulin content after administration than the single-flavored group of sarcophagus and the single-flavored fenugreek group, wherein the low-dose group is administered for 20 days, 30 days, and There was a significant difference in serum insulin levels between the groups of the fenugreek group (p ⁇ 0.05). The serum insulin levels were significantly different between the middle and high dose groups after administration for 20 days and 30 days, and the single-flavored group and the single-feathered fenugreek group.
- the present invention uses the combination of Dendrobium and Fenugreek, both of which play a synergistic effect. From the above results, it can be seen that the drug composition of the present invention can lower blood sugar and serum insulin levels in various dose groups, and can effectively treat diabetes. Meanwhile, at the same dose, the hypoglycemic effect of the pharmaceutical composition of the present invention and the effect of lowering serum insulin were significantly superior to those of Dendrobium and Fenugreek alone (p ⁇ 0.01 or p ⁇ 0.05), indicating the components of the drug of the present invention. Played a synergy role.
- Test Example 2 Verification of hypoglycemic effect of the pharmaceutical composition of the present invention
- the pharmaceutical composition of the present invention is prepared from fenugreek 3g and Dendrobium 10g as main raw materials, wherein the Dendrobium is a stem of Dendmbium nobile Lindl., and the preparation method is as follows: Fenugreek: The crude powder of ruba is added with 11 times of 75% ethanol, refluxed for 3 times, 120 min/time, filtered with filter paper, and the filtrate is combined. The concentration is reduced to 100 g per 100 ml of the original drug, and the refrigerator is chilled for 12 hours. , the yield of extract is 15% ;
- Dendrobium Take the coarse powder of Dendrobium, add 11 times of water, reflux for 3 times, 120 min / time, filter paper, filter the filtrate, concentrate under reduced pressure to 50 g per 100 ml of the original drug, refrigerator for 12 hours, freeze-dry, The extract yield was 9%;
- the above-mentioned fenugreek extract and the aqueous extract of Dendrobium can be obtained by mixing.
- rats with successful model selection were randomly divided into model group, metformin group, fenugreek + Dendrobium low-dose group, fenugreek + Dendrobium meridian group, fenugreek + Dendrobium high-dose group, and single-flavored Dendrobium group.
- the middle and low dose groups were given to fenugreek + Dendrobium 1500, 1000, 500 mg/(kg-d); the rats of the single-flavored Dendrobium group and the single-flavored fenugreek group were respectively given sarcophagus and fenugreek 1500 mg/(kg'd:>.
- the group continued to feed high-calorie feed.
- Fenugreek 1. 5g/kg. d At the 11th week, the rats in each group were fasted for 12 hours, and then anesthetized with 2% pentobarbital sodium physiological saline solution 40 mg/kg. Blood samples were taken from the tail vein to determine blood glucose, serum insulin and C-peptide content.
- the data was processed using SPSS 13.0 statistical software. All data of technical data were expressed by x ⁇ s; the mean comparison between groups was tested by one-way ANOVA, P ⁇ 0.05 or PO.01 was statistically significant.
- the blood glucose level of the animal was increased, and there was a significant difference compared with the blank group (P ⁇ 0.01), indicating that the streptozotocin-induced diabetes model was successfully established.
- the blood glucose level of the positive group was significantly decreased (p ⁇ 0.05), indicating that it is feasible to evaluate the hypoglycemic effect of the drug using the urea-supplement-induced diabetes model.
- the blood glucose level of the low, medium and high dose groups of the present invention was significantly decreased, and there was a significant difference (p ⁇ 0.05) compared with the model group, indicating that the pharmaceutical composition of the present invention can effectively lower serum insulin levels.
- the blood glucose level of the low, medium and high dose groups of the composition of the present invention was significantly lower (p ⁇ 0.05) than that of the single-flavored group of sarcophagus and the single-flavored fenugreek group, indicating that the present invention combines sarcophagus with fenugreek. Both play a synergistic role.
- the serum insulin levels in the low, medium and high dose groups of the present invention were significantly decreased, and there was a significant difference (p ⁇ 0.05) compared with the model group, indicating that the pharmaceutical composition of the present invention can effectively lower serum insulin. Level, can treat diabetes.
- the serum insulin content of the low, medium and high dose groups of the composition of the present invention was significantly lower (p ⁇ 0.05) than that of the single-flavored group of sarcophagus and the single-flavored fenugreek group, indicating that the present invention combined the use of sarcophagus with fenugreek. , the two played a synergistic role.
- the serum C-peptide level of the positive group was significantly decreased, and there was a significant difference compared with the model group ( ⁇ 0.01), indicating that it is feasible to evaluate the effect of the drug on diabetes treatment by the urea-mycin-induced diabetes model.
- the serum C-peptide levels of the low, medium and high dose groups of the composition of the present invention decreased significantly, and there were significant differences compared with the model group ( ⁇ 0.05).
- the serum C-peptide content of the low, medium and high dose groups of the composition of the present invention is lower than that of the monosodium sarcophagus group and the single-flavored fenugreek group, wherein the medium and high dose groups and the single-flavored fenugreek group, single
- the present invention selects fenugreek and Dendrobium in combination for the treatment of diabetes, the curative effect is exact, the formula is fine, the medicinal taste is small, the toxic and side effects are small, the preparation method is simple, the use is convenient, and at the same dose, the combination of the two is used.
- the effect is significantly better than the two drugs alone, indicating that they play a synergistic role.
- the invention selects the combination of fenugreek and sarcophagus for the treatment of diabetes, has the advantages of precise formula, less medicinal taste, less toxic and side effects, simple preparation method and convenient use, and at the same dose, the combination effect of the two is excellent. It is suitable for industrial application in the two drugs alone.
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Abstract
一种药物组合物,是由下述重量配比的原料制备而成的制剂:石斛7-13份、葫芦巴2-4份。其制备方法为采用水或者有机溶剂提取,加入药学上可接受的辅料制备而成。用于治疗糖尿病,特别是II型糖尿病,能降低机体血糖水平、血清胰岛素含量和血清C肽含量。
Description
说 明 书
一种药物组合物及其制备方法和用途 技术领域
本发明涉及药物领域, 具体涉及一种治疗糖尿病的药物组合物。
背景技术
糖尿病(diabetes )是由遗传因素、免疫功能紊乱、微生物感染及其毒素、 自由基毒素、 精神因素等等各种致病因子作用于机体导致胰岛功能减退、 胰 岛素抵抗等而引发的糖、 蛋白质、 脂肪、 水和电解质等一系列代谢紊乱综合 征, 临床上以高血糖为主要特点, 典型病例可出现多尿、 多饮、 多食、 消瘦 等表现, gp"三多一少"症状, 糖尿病 (血糖) 一旦控制不好会引发并发症, 导致肾、 眼、 足等部位的衰竭病变, 且无法治愈。 中医认为糖尿病是由于正 气不足, 情志所伤, 毒邪致病, 瘀血为患, 痰浊蕴结等引起的。 在糖尿病的 治疗方面, 西医主要采用注射胰岛素或单纯的运用降糖药物, 长期注射胰岛 素会导致胰岛功能退化这是饮鸩止渴的方法。 随着医学的进步和人们对糖尿 病认识的深入, 发现糖尿病, 尤其是 II型糖尿病及其慢性并发症的发生、 发 展有多种机制参与。 中药治疗疾病往往是中药复方通过多环节、 多途径、 多 靶点, 作用于全身多个脏器、 系统, 通过多种机制发挥作用, 正好与 II型糖 尿病及糖尿病慢性并发症的多机制参与发病的病理机制吻合。 因此, II型糖 尿病及糖尿病慢性并发症的防治应是中药的优势所在。
现代研究表明, 石斛提取物具有滋阴清热、 生津益胃、 润肺止咳、 明目 强身等功效, 能通过调节胰岛 α、 β细胞分泌的激素水平发挥降血糖作用, 并具有胰内和胰外降血糖的作用机制。 葫芦巴中 4-羟基异亮氨酸、 皂苷也有 较好的降血糖作用。
现未见将石斛、 葫芦巴配合用于治疗糖尿病的报道。
发明内容
本发明提供了一种的新的降糖药物组合物及其制备方法和用途。
本发明药物组合物, 它是由下述重量配比的原料制备而成的制剂: 石斛
7~13份、 葫芦巴 2~4份。
优选地, 所述组合物是由下述重量配比的原料制备而成的制剂: 石斛 10 份、 葫芦巴 3份。
所述的石斛为兰科石斛属植物金钗石斛 Dendrobium nobile Lindl.、叠鞘石 角斗 Dendrobium aurantiacum Rchb . f . var. denneanum ^ 鼓植 Dendrobium
chrysotoxum Lindl或流苏 Dendrobium fimbriatum Hook.的 。
所述组合物是以石斛、 葫芦巴的原药材、 水提物或有机溶剂提取物为有
效成分, 加上药学上可接受的辅料制备而成的制剂。
所述制剂为口服制剂。
所述制剂为散剂、 膏剂、 颗粒剂、 片剂、 胶囊剂、 口服液或者滴丸。 本发明制备前述药物组合物的方法, 它包含如下步骤:
( 1 ) 按照前述配比, 称取原料药石斛、 葫芦巴;
(2 ) 将葫芦巴粉碎为粗粉, 加 30-95%的乙醇回流提取, 过滤, 将滤液 浓缩干燥, 得葫芦巴醇提物;
(3 )将石斛粉碎为粗粉, 加水回流提取, 过滤, 将滤液浓缩干燥, 得石 斛水提取;
(4) 将步骤 (2 ) 得到的葫芦巴醇提物与步骤 (3 ) 的石斛水提物混合, 加上药学上可接受的辅料或辅助性成分制备成药学上常用的制剂。
步骤 (2 ) 中, 乙醇的浓度为 75%, 乙醇的用量为葫芦巴粗粉的 11倍, 回流提取次数为 3次, 每次提取的时间为 120min。
步骤 (3 ) 中, 水的用量为石斛粗粉的 11倍, 回流提取次数为 3次, 每 次提取的时间为 120min。
本发明最后提供了前述药物组合物在制备治疗糖尿病的药物中的用途。 优选地, 所述糖尿病是 II型糖尿病。
本发明药物组合物能有效治疗糖尿病, 配方精当, 药味少, 毒副作用小, 制备方法简单, 使用方便, 为临床治疗糖尿病提供了一种新的选择, 在相同 剂量下, 二者组合使用的效果显著优于两种药物单独使用, 说明它们发挥了 协同增效的作用。
显然,根据本发明的上述内容,按照本领域的普通技术知识和惯用手段, 在不脱离本发明上述基本技术思想前提下,还可以做出其它多种形式的修改、 替换或变更。
以下通过实施例形式的具体实施方式, 对本发明的上述内容再作进一步 的详细说明。 但不应将此理解为本发明上述主题的范围仅限于以下的实例。 凡基于本发明上述内容所实现的技术均属于本发明的范围。
具体实施方式
实施例 1 本发明药物组合物的制备
称取石斛 10g、 葫芦巴 3g。将石斛粉碎成粗粉, 加入 11倍的水, 回流提 取 3次, 120 min/次, 滤纸过滤, 合并滤液, 减压浓缩至每 100ml相当于原 生药 50g, 冰箱冷藏 12小时, 冷冻干燥, 得石斛水提物。 将葫芦巴粉碎成粗 粉, 加入 11倍的 75%乙醇, 回流提取 3次, 120 min/次, 滤纸过滤, 合并滤 液, 减压浓缩至每 100 ml相当于原生药 50g, 冰箱冷藏 12小时, 冷冻干燥, 得葫芦巴醇提物。
将石斛水提物与葫芦巴醇提物混合, 再制成所需剂型的药物, 如: 颗粒 剂、 片剂、 硬胶囊、 口服液、 软胶囊、 滴丸或糖桨。 其中, 所述的石斛为兰 科石斛属植物金钗石斛 Dendrobium nobile Lindl.的茎。
实施例 2 本发明药物组合物的制备
取石斛 7g、葫芦巴 2g。按照实施例 1的方法制备石斛水提物与葫芦巴醇 提物。
将石斛水提物与葫芦巴醇提物混合, 再制成所需剂型的药物, 如: 颗粒 剂、 片剂、 硬胶囊、 口服液、 软胶囊、 滴丸或糖桨。 其中, 所述的石斛为兰 禾斗石角斗属叠鞘石角斗 Dendrobium aurantiacum Rchb. f. var. denneanum的 。
实施例 3 本发明药物组合物的制备
取石斛 13g、 葫芦巴 4g。 按照实施例 1的方法制备石斛水提物与葫芦巴 醇提物。
将石斛水提物与葫芦巴醇提物混合, 再制成所需剂型的药物, 如: 颗粒 剂、 片剂、 硬胶囊、 口服液、 软胶囊、 滴丸或糖桨。 其中, 所述的石斛为兰 禾斗石角斗属铁皮石角斗 Dendrobium officinale Kimura et Migo的 。
实施例 4 本发明药物组合物的制备
取石斛 10g、 葫芦巴 3g。 按照实施例 1的方法制备石斛水提物与葫芦巴 醇提物。
将石斛水提物与葫芦巴醇提物混合, 再制成所需剂型的药物, 如: 颗粒 剂、 片剂、 硬胶囊、 口服液、 软胶囊、 滴丸或糖桨。 其中, 所述的石斛为兰 禾斗石角斗属植物鼓槌 Dendrobium chrysotoxum Lindl的 。
实施例 5 本发明药物组合物的制备
取石斛 8g、 葫芦巴 2.5g。按照实施例 1的方法制备石斛水提物与葫芦巴 醇提物。
将石斛水提物与葫芦巴醇提物混合, 再制成所需剂型的药物, 如: 颗粒 剂、 片剂、 硬胶囊、 口服液、 软胶囊、 滴丸或糖桨。 其中, 所述的石斛为兰 禾斗石角斗属流苏 Dendrobium fimbriatum Hook.的 。 以下通过具体药效学实验证明本发明的有益效果:
试验例 1 本发明药物组合物降糖作用的验证
1 实验材料
1.1 实验药物
本发明药物组合物, 由葫芦巴 3g, 石斛 10g为主要原料制成, 其中, 所 述石斛为兰科石斛属金钗石斛 Dendrobium nobile Lindl.的茎, 制备方法如下: 葫芦巴: 取炒制胡芦巴的粗粉, 加入 11倍的 75%乙醇, 回流提取 3次,
120 min/次, 滤纸过滤, 合并滤液, 减压浓缩至每 100 ml相当于原生药 50g, 冰箱冷藏 12小时, 冷冻干燥, 浸膏得率为 15%;
石斛: 取石斛的粗粉, 加入 11倍的水, 回流提取 3次, 120 min/次, 滤 纸过滤, 合并滤液, 减压浓缩至每 100ml相当于原生药 50g, 冰箱冷藏 12小 时, 冷冻干燥, 浸膏得率为 9%;
将上述葫芦巴醇提物和石斛水提物混合即得。
1.2 实验动物
SD大鼠 ( , 180〜200g, 清洁级, 购自于成都达硕生物有限公司)。 1.3 实验试剂
达美康 (gliclazide, 格列齐特片 1), 法国施维雅药厂、 天津华津制药厂合 作生产。 Aloxan (四氧嘧啶), 美国 Sig— ma产品, 实验前用生理盐水新鲜配 制浓度为 1.5 %。
2 实验方法
本实验动物饲养于成都中医药大学药理实验动物观察室, 于实验开始前 适应环境 3天, 正常给予饮食和水。 取雄性 (180〜200g) SD大鼠 90只, 腹腔注射 Alloxan (四氧嘧啶) 150 mg/kg, 注射 4d, 禁食 8h, 检测血糖 (注, 以下实验中测定动物血糖前, 动物均禁食 811:)。
选取高血糖合格模型大鼠 (血糖大于 10mmOl/L)50只进行随机分为模型 组、 阳性组、 葫芦巴 +石斛高剂量组、 葫芦巴 +石斛中剂量组、 葫芦巴 +石斛 低剂量组、 单味石斛组、 单味葫芦巴组。 另取 10只同批次的未造模的健康 SD大鼠为空白组。 连续灌胃给药 30d, 正常对照组、 模型对照组动物给予等 容积 20 ml/kg生理盐水。 其余组每天给药剂量如下:
表 1动物分组与给药剂量 组名 给予药液剂量
空白组 等体积蒸馏水
模型组 等体积蒸馏水
阳性组 达美康 (30mg/kg. d)
葫芦巴 +石斛低 0. 5g/kg. d
葫芦巴 +石斛中 1. Og/kg. d
葫芦巴 +石斛高 1. 5g/kg. d
石斛 1. 5g/kg. d
葫芦巴 1. 5g/kg. d 观察指标:于给药 10d、 20d、 30d分别尾静脉取血测定血糖。于给药 20d、 23d分别取血测定血清胰岛索。实验数据以 x± S表示,数据用统计 SPSS13. 0 软件处理, 组间用 t检验。
3 实验结果
给药后, 各组血糖水平与胰岛素含量分别如下表 2、 表 3所示。
血糖水平 (mmo
注: 与模型组比较, *Ρ<0.05, **Ρ<0Μ; 与石斛组比较: #Ρ<0.05, # #Ρ<0.01·' 与葫芦巴 组比较: " <0.05, Ύρ<0.01;
如表 2所示, 大鼠注射 Aloxan4d后, 血糖含量升高, 与空白组比较有 显著性差异 (PO.01) 说明 Alloxan致糖尿病模型成功。
给药后, 阳性组大鼠血糖明显下降, 给药 10d、 20d、 30d后, 与模型组 比较均有显著性差异(ρθ.01或 p<0.05), 说明采用 Alloxan致糖尿病模型评 价药物降血糖作用是可行的。
给药后, 单味石斛组、 单味葫芦巴组大鼠血糖均下降, 给药 20d、 30d 后, 与模型组比较均有显著性差异 (p<0.05)。
给药后, 本发明组合物低、 中、 高剂量组大鼠血糖均逐步下降, 其中, 低剂量组在给药 20天、 30天后, 与模型组比较有显著差异 p<0.05), 中、 高 剂量组在给药 10天、 20天、 30天后, 与模型组比较有显著差异 (p<0.01或 p<0.05), 说明本发明组合物可以有效降低血糖。
与单味石斛组、 单味葫芦巴组比较, 本发明组合物中、 高剂量组在给药 后的血糖水平更低, 其中, 中剂量组在给药 20d、 30d后与单味石斛组、 单味 葫芦巴组比较有显著差异 (p<0.01或 p<0.05), 高剂量组在给药后 30d的血 糖水平与单味石斛组、 单味葫芦巴组比较有显著差异(p<0.05), 说明本发明 将石斛与葫芦巴联合使用, 二者发挥了协同增效的作用。 表 3 血清胰岛素含量 (mU/L)
组别 给药前 给药后 10天 给药后 20天 给药后 30天 空白组 9.20±1.09** 9. 18±1.13** 9.21±1.04** 9.22±1.05 模型组 13.94±1.11 13.97±1.15 14.23±1.45 14.94 +1.10
阳性组 14.01士 1.05 11.56±1.52* 10.25士1.7广 9.56±1.71** 组合物低 13.84士1.09 11.03±1.68** 10.73士 1.28**' 10.03±1.68**' 组合物中 13.93士 1.20 11.56±2.09* 10.56士 1.07*** τ 9.75±2.09***τ 组合物高 13.97士1.15 10.71 ±1.08 10.27士 1.2Γ**Τ 9.81±1.08 ίΤ 石斛 14.03士1.14 13.11士 1.06 12.17士 1.38* 11.85±1.12** 葫芦巴 13.88士1.12 13.02士 1.19 12.67士1.14* 12.01 + 1.33* 注: 与模型组比较, *P<0.05, **P<0M; 与石斛组比较: <0.05, # #Ρ<0.01·' 与葫芦巴 组比较: " <0.05, Ύρ<0.01; 如表 3所示,大鼠注射 Aloxan(150mg/kg:)4d后,血清胰岛素含量持续升 高, 与空白组比较有显著性差异 (P<0.01), 说明 Alloxan致 II型糖尿病模型 成功。
给药后, 阳性组大鼠血清胰岛素含量明显下降, 给药 10d、 20d、 30d后, 与模型组比较均有显著性差异(ρθ.01或 p<0.05), 说明采用 Alloxan致糖尿 病模型评价药物治疗糖尿病作用是可行的。
给药后, 单味石斛组、 单味葫芦巴组大鼠血清胰岛素水平均下降, 给药 20d、 30d后, 与模型组比较均有显著性差异 (ρθ.01或 p<0.05)。
给药后, 本发明组合物低、 中、 高剂量组大鼠血清胰岛素水平均明显下 降,给药 10d、 20d、 30d后,与模型组比较均有显著性差异(ρθ.01或 p<0.05 )。
与单味石斛组、 单味葫芦巴组比较, 本发明组合物低、 中、 高剂量组在 给药后的血清胰岛素含量更低, 其中, 低剂量组在给药 20d、 30d后, 与单味 葫芦巴组的血清胰岛素水平有显著差异(p<0.05), 中、高剂量组在给药 20d、 30d后, 与单味石斛组和单味葫芦巴组的血清胰岛素水平均有显著差异
(p<0.05), 说明本发明将石斛与葫芦巴联合使用, 二者发挥了协同增效的作 用。 从上述结果可知, 本发明药物组合物各剂量组均可以降低血糖和血清胰 岛素水平, 能够有效治疗糖尿病。 同时, 相同剂量下, 本发明药物组合物的 降糖作用和降低血清胰岛素的作用, 都显著优于石斛和葫芦巴单独使用 (p<0.01或 p<0.05), 说明本发明药物中各组分发挥了协同增效的作用。
试验例 2 本发明药物组合物降糖作用的验证
1、 实验材料
1.1 实验药物
本发明药物组合物, 由葫芦巴 3g, 石斛 10g为主要原料制成, 其中, 所 述石斛为兰科石斛属金钗石斛 Dendmbium nobile Lindl.的茎, 制备方法如下: 葫芦巴: 取炒制胡芦巴的粗粉, 加入 11倍的 75%乙醇, 回流提取 3次, 120 min/次, 滤纸过滤, 合并滤液, 减压浓缩至每 100 ml相当于原生药 50g, 冰箱冷藏 12小时, 冷冻干燥, 浸膏得率为 15% ;
石斛: 取石斛的粗粉, 加入 11倍的水, 回流提取 3次, 120 min/次, 滤 纸过滤, 合并滤液, 减压浓缩至每 100ml相当于原生药 50g, 冰箱冷藏 12小 时, 冷冻干燥, 浸膏得率为 9%;
将上述葫芦巴醇提物和石斛水提物混合即得。
1.2 实验动物
SPF级 Wistar大鼠雄性, 体重为(180-200)g。
1.3 实验试剂
链脲佐菌素 (STZ) , 高热量饲料, 二甲双胍。
2、 实验方法
基础饲料适应性喂养 1周后,在 100只大鼠中,以随机数字表法抽取 10只 为空白组;其余大鼠均喂以高热量饲料 (其中含 10.0%猪油、 20.0%蔗糖、 2.5% 胆固醇、 1.0%胆酸盐、 66.5%常规饲料)。 第 5周以低剂量 (25 mg/kg)STZ (溶 于 0.1 mmol/L柠檬酸缓冲液 ,ρΗ 4.4)—次性左侧下腹部注射,并继续高热量饮 食喂养,正常饮水。 第 7周大鼠禁食 12 h后,按 2 g/kg体重灌喂 20%D-葡萄糖 溶液,凡 0、 120 min血糖分别≥7.8和 (;或)≥11.0 mmol/L的大鼠为造模成功。
选择造模成功的大鼠 50只按体重编号随机分为模型组、二甲双胍组、葫 芦巴 +石斛低剂量组、 葫芦巴 +石斛中剂量组、 葫芦巴 +石斛高剂量组、 单味 石斛组、 单味葫芦巴组大鼠,各 10只; 第 2天开始灌胃,空白组、 模型组予等 体积的生理盐水; 二甲双胍组予二甲双胍 70 mg/(kg'd) ; 葫芦巴 +石斛高、 中、 低剂量组予葫芦巴 +石斛 1500、 1000、 500mg/(kg-d) ; 单味石斛组、 单味葫芦 巴组大鼠分别予石斛、 葫芦巴 1500mg/(kg'd:>。 各组均继续喂以高热量饲料。
表 4. 动物分组与给药剂量
组名 给予药液剂
空白组 等体积蒸馏水
模型组 等体积蒸馏水
阳性组 二甲双胍 (70mg/kg. d)
葫芦巴 +石斛低 0. 5g/kg. d
葫芦巴 +石斛中 1. Og/kg. d
葫芦巴 +石斛高 1. 5g/kg. d
石斛 1. 5g/kg. d
葫芦巴 1. 5g/kg. d
第 11周各组大鼠禁食 12 h后,腹腔注射 2%戊巴比妥钠生理盐水溶液 40 mg/kg麻醉,尾静脉取血测定血糖、 血清胰岛素和 C肽含量。
数据采用 SPSS13.0统计软件处理。技术资料所有数据用 x±s表示; 组间 均数比较采用单因素方差分析检验 ,P<0.05或 PO.01为有统计学意义。
3、 实验结果
( 1 ) 血糖检测结果如表 5所示:
组合物对血糖的影响 (X±s。 mmol/L)
注: 与模型组比较, * Ρ<0.05, ** Ρ<0.01; 与石斛组比较: #Ρ<0.05, # #Ρ<0.01·' 与葫芦巴 组比较: P<0.05, P<0.01。
采用本发明方法造模后, 动物血糖水平升高, 与空白组比较有显著性差 异 (P<0.01), 说明链脲佐菌素致糖尿病模型造模成功。
给药后, 与模型组相比, 阳性组大鼠血糖水平明显下降(p<0.05), 说明 采用脲佐菌素致糖尿病模型评价药物降血糖作用是可行的。
给药后, 单味石斛组、 单味葫芦巴组大鼠血糖水平均下降, 与模型组比 较均有显著性差异 (p<0.05)。
给药后, 本发明组合物低、 中、 高剂量组大鼠血糖水平均明显下降, 与 模型组比较均有显著性差异(p<0.05), 说明本发明药物组合物能够有效降低 血清胰岛素水平, 可以治疗糖尿病。
与单味石斛组、 单味葫芦巴组比较, 本发明组合物低、 中、 高剂量组给 药后的血糖水平明显更低 (p<0.05), 说明本发明将石斛与葫芦巴联合使用, 二者发挥了协同增效的作用。
(2) 血清胰岛素含量检测结果如表 6所示:
表 6 组合物对胰岛素的影响 (X±S。 mU/L))
组别 给药前 给药后 空白组
9.12士1.03** ^οι+ι.οι1" 模型组
13.09士1.08 13.90士1.12 阳性组
14.21士1.14 9.75士 1.23** 组合物低
13.79士1.17 10.13±1.12*T 组合物中
13.83士1.05 9.76士 1.11* # V 组合物高 13.98士1.12 10.52±1.18*V
石斛 13.87士1.16 11. 74士 1.06*
葫芦巴 14.04士1.21 12.86±1.13*
注: 与模型组比较, * P<0.05, ** Ρ<0.01; 与石斛组比较: #Ρ<0.05, # #Ρ<0.01·' 与葫芦巴 组比较: P<0.05, P<0.01。
如表 6所示, 采用本发明方法造模后, 血清胰岛素含量升高, 与空白组 比较有显著性差异 (P<0.01), 说明链脲佐菌素致 II型糖尿病模型造模成功。
给药后, 阳性组大鼠血清胰岛素水平明显下降, 与模型组比较均有显著 性差异(p<0.01), 说明采用脲佐菌素致糖尿病模型评价药物治疗糖尿病作用 是可行的。
给药后, 单味石斛组、 单味葫芦巴组大鼠血清胰岛素水平均下降, 与模 型组比较均有显著性差异 (p<0.05)。
给药后, 本发明组合物低、 中、 高剂量组大鼠血清胰岛素水平均明显下 降, 与模型组比较均有显著性差异(p<0.05), 说明本发明药物组合物能够有 效降低血清胰岛素水平, 可以治疗糖尿病。
与单味石斛组、 单味葫芦巴组比较, 本发明组合物低、 中、 高剂量组给 药后的血清胰岛素含量明显更低(p<0.05), 说明本发明将石斛与葫芦巴联合 使用, 二者发挥了协同增效的作用。
(3) 血清 C肽含量检测结果如表 7所示:
空白组 341.6士 49.1** 模型组 740.3士 74.2 阳性组 628.4士 86.8** 组合物低 583.3士 69.2* 组合物中 513.6士91.4* # 组合物高 501.2士78.4* # V
石斛 631.6士 68.9*
葫芦巴 657.7士 58.3*
注: 与模型组比较, * Ρ<0.05, ** Ρ<0.01-, 与石斛组比较: #Ρ<0.05, # #Ρ<0.01·' 与葫芦巴 组比较: P<0.05, ΎΡ<0.01;
如图 7所示, 采用本发明方法造模后, 大鼠血清 C肽的含量升高, 与空 白组比较有显著性差异(Ρ<0.01), 说明链脲佐菌素致 II型糖尿病模型造模成 功。
给药后, 阳性组大鼠血清 C肽水平明显下降, 与模型组比较均有显著性 差异(ρ<0.01), 说明采用脲佐菌素致糖尿病模型评价药物治疗糖尿病作用是 可行的。
给药后, 单味石斛组、 单味葫芦巴组大鼠血清 C肽水平均下降, 与模型 组比较均有显著性差异 (ρ<0.05)。
给药后,本发明组合物低、中、高剂量组大鼠血清 C肽水平均明显下降, 与模型组比较均有显著性差异 (ρ<0.05)。
与单味石斛组、 单味葫芦巴组比较, 本发明组合物低、 中、 高剂量组给 药后的血清 C肽含量更低, 其中, 中、 高剂量组与单味葫芦巴组、 单味石斛 组的血清 C肽水平有显著差异(ρ<0.05),说明本发明将石斛与葫芦巴联合使 用, 二者发挥了协同增效的作用。
效的作用。
综上,本发明选取葫芦巴和石斛组合使用,用于治疗糖尿病的疗效确切, 配方精当, 药味少, 毒副作用小, 制备方法简单, 使用方便, 同时, 在相同 剂量下, 二者组合使用的效果显著优于两种药物单独使用, 说明它们发挥了 协同增效的作用。 工业应用性
本发明选取葫芦巴和石斛组合使用, 用于治疗糖尿病的疗效确切, 配方 精当, 药味少, 毒副作用小, 制备方法简单, 使用方便, 同时, 在相同剂量 下,二者组合使用的效果显著优于两种药物单独使用,适合产业上推广应用。
Claims
1、 一种药物组合物, 其特征在于: 它是由下述重量配比的原料药制备而 成的制剂: 石斛 7~13份、 葫芦巴 2~4份。
2、 根据权利要求 1所述的药物组合物, 其特征在于: 它由下述重量配比 的原料药制备而成的制剂: 石斛 10份、 葫芦巴 3份。
3、 根据权利要求 1或 2所述的药物组合物, 其特征在于: 所述的石斛为 兰科石斛属植物金钗石斛 Dendrobium nobile Lindl.、 叠鞘石斛 Dendrobium diWxantiacum Rchb.f. var. denneanum ^鼓植 Dendrobium chrysotoxum Lindl或流苏 Dendrobium fimbriatum Hook.的 ¾。
4、 根据权利要求 1~3任意一项所述的药物组合物, 其特征在于: 所述组 合物是以石斛、 葫芦巴的原药材、 水提物或者有机溶剂提取物为有效成分, 加上药学上可接受的辅料制备而成的制剂。
5、根据权利要求 4所述的药物组合物, 其特征在于: 所述制剂为口服制 剂;
优选地, 所述制剂为散剂、 膏剂、 颗粒剂、 片剂、 胶囊剂、 口服液或者 滴丸。
6、一种制备权利要求 1~5任意一项所述药物组合物的方法,其特征在于: 它包含如下步骤:
( 1 ) 按照权利要求 1~5任意一项所述配比, 称取原料药石斛、 葫芦巴;
(2 ) 将葫芦巴粉碎为粗粉, 加 30-95%的乙醇回流提取, 过滤, 将滤液 浓缩干燥, 得葫芦巴醇提物;
(3 )将石斛粉碎为粗粉, 加水回流提取, 过滤, 将滤液浓缩干燥, 得石 斛水提物;
(4 ) 将步骤 (2 ) 所得葫芦巴醇提物与步骤 (3 ) 所得石斛水提物混合, 加上药学上可接受的辅料或辅助性成分制备成药学上常用的制剂。
7、 根据权利要求 6所述的方法, 其特征在于: 步骤 (2 ) 中, 乙醇的浓 度为 75% , 乙醇的用量为葫芦巴粗粉的 11倍 (v/w), 回流提取次数为 3次, 每次提取的时间为 120min。
8、 根据权利要求 6所述的方法, 其特征在于: 步骤 (3 ) 中, 水的用量 为石斛粗粉的 11倍(v/w),回流提取次数为 3次,每次提取的时间为 120min。
9、权利要求 1~5任意一项药物组合物在制备治疗糖尿病的药物中的用途。
10、 根据权利要求 9所述的用途, 其特征在于: 所述糖尿病是 II型糖尿
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