WO2016082098A1 - 含有亚铁氨基酸螯合物的组合物在制备改善糖尿病的药物中的用途 - Google Patents

含有亚铁氨基酸螯合物的组合物在制备改善糖尿病的药物中的用途 Download PDF

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WO2016082098A1
WO2016082098A1 PCT/CN2014/092146 CN2014092146W WO2016082098A1 WO 2016082098 A1 WO2016082098 A1 WO 2016082098A1 CN 2014092146 W CN2014092146 W CN 2014092146W WO 2016082098 A1 WO2016082098 A1 WO 2016082098A1
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amino acid
ferrous
composition containing
use according
composition
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PCT/CN2014/092146
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English (en)
French (fr)
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林村源
詹勋锦
傅嘉慧
陈沧泽
陈木桂
李宏谟
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普惠德生技股份有限公司
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Priority to CA2968446A priority Critical patent/CA2968446C/en
Priority to JP2017527915A priority patent/JP6364129B2/ja
Priority to EP14906760.5A priority patent/EP3132797A4/en
Priority to US15/121,013 priority patent/US20170007568A1/en
Priority to AU2014412540A priority patent/AU2014412540B2/en
Priority to CN201480083596.4A priority patent/CN106999514B/zh
Priority to PCT/CN2014/092146 priority patent/WO2016082098A1/zh
Publication of WO2016082098A1 publication Critical patent/WO2016082098A1/zh

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    • 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
    • A61K31/28—Compounds containing heavy metals
    • A61K31/295—Iron group metal compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • 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
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/26—Iron; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • 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

Definitions

  • This invention relates to the use of compositions containing ferrous amino acid chelates, and more particularly to their use in the preparation of a medicament for improving diabetes.
  • Metabolic syndrome is a civilized disease born in response to modern lifestyles (Lupatini et al., 2008) and eating habits (Esposito et al., 2007), as defined by the World Health Organization in 1998.
  • Glucose intolerance or insulin resistance, plus hypertension, obesity, dyslipidemia or microalbuminuria can be called metabolic syndrome; in Taiwan, as long as three of the following are met: 1) Male waist circumference is greater than or equal to 90 cm, female waist circumference is greater than or equal to 80 cm; (2) triglyceride is greater than 150 mg/dl; (3) male high-density lipoprotein (HDL) is less than 40 mg /dl, women's high-density lipoprotein is less than 50mg / dl; (4) systolic blood pressure greater than 130 mm Hg, diastolic blood pressure greater than 85 mm Hg; (5) fasting blood glucose greater than 110 mg / dl; that constitutes metabolic syndrome.
  • HDL
  • Glucose can be divided into two types: (1) Type 1 diabetes accounts for about 5%, often occurs in young people or children. The main cause is that the pancreas cannot produce insulin by itself, and patients need insulin therapy for life; (2) Type 2 Diabetes accounts for about 95%. The main cause is that the patient's insulin transmission is poor, which makes the cells unable to obtain glucose. Therefore, patients will suffer from hyperglycemia due to hunger and ingestion. High concentrations of glucose in the blood stimulate the islet cells to continuously secrete insulin. It causes hyperinsulinism, and finally insulin resistance occurs, and the pancreas is thus depleted. These patients occur in patients over the age of 40, and some patients need medication or insulin treatment.
  • diabetes If diabetes is not adequately controlled, it can cause acute complications such as cardiovascular disease (Vlassara, 1996), chronic renal failure (Monnier et al., 1992), retinopathy (Yamagishi et al., 2002), neuropathy And microvascular disease. Among them, microvascular disease may lead to gangrene in the lower limbs, which in turn leads to amputation of the patient.
  • Vlassara 1996)
  • chronic renal failure Monnier et al., 1992
  • retinopathy Yamagishi et al., 2002
  • neuropathy And microvascular disease may lead to gangrene in the lower limbs, which in turn leads to amputation of the patient.
  • type 2 diabetes is mainly based on the use of drugs and diet control.
  • Common drugs include thiazolidinedione (TZD) and metformin.
  • Metformin is a biguanide oral hypoglycemic agent. The mechanism is unknown, but it is known to reduce liver gluconeogenesis and increase muscle glucose uptake, effectively lower blood sugar, and is widely used in the treatment of type 2 diabetes (Granberry and Fonseca, 2005). There are side effects such as diarrhea and nausea.
  • compositions comprising a ferrous amino acid chelate for the preparation of a medicament for improving diabetes, comprising a ferrous amino acid chelate
  • the composition has an effect of improving diabetes.
  • the present invention provides a use of a composition containing a ferrous amino acid chelate compound for the preparation of a medicament for improving diabetes, wherein the medicament comprises an effective dose of a composition containing a ferrous amino acid chelate compound for improving diabetes. And its pharmaceutically acceptable carrier.
  • the "composition containing a ferrous amino acid chelate” is a composition containing a ferrous amino acid chelate prepared by mixing inorganic iron with an amino acid.
  • the inorganic iron includes, but is not limited to, ferrous sulfate, ferrous chloride and ferrous pyrophosphate; preferably, the amino acid is glycine.
  • the ferrous metal chelate-containing composition is 95% to 100% by weight of a ferrous glycine chelate; more preferably, it is 98% to 99.9% by weight.
  • Iron glycine chelate is 95% to 100% by weight of a ferrous glycine chelate; more preferably, it is 98% to 99.9% by weight.
  • the composition of the ferrous amino acid chelate is obtained by heating ferrous sulfate and glycine at 60 ° C to 90 ° C for 8 hours to 48 hours, wherein the weight of ferrous sulfate and glycine is The ratio is between 1:1.2 and 1:1.5.
  • the composition containing the ferrous amino acid chelate compound is a chelate compound containing at least one ferrous metal, and the chelating ratio of the ferrous iron to the amino acid of the ferrous amino acid chelate is 1: Between 1 and 1:4; more preferably, the ferrous and amino acid chelating ratio of the ferrous amino acid chelate is between 1:1.5 and 1:2.5.
  • the composition containing the ferrous amino acid chelate compound comprises a reducing agent which maintains the oxidation state of the ferrous iron of the composition containing the ferrous amino acid chelate compound, and also enhances the ferrous phase.
  • the composition of the amino acid chelate is in the intestinal absorption rate of the receptor, wherein the reducing agent includes, but is not limited to, ascorbic acid, citric acid, acetic acid, propionic acid, Butyric acid, lactic acid, malic acid, sulfonic acid, and succinic acid.
  • "improving diabetes” means effectively treating or soothing diabetes, as exemplified by the present invention, conditions for ameliorating diabetes include, but are not limited to, lowering blood glucose, improving glucose tolerance, and increasing sensitivity to insulin.
  • an effective dose means an amount effective to achieve the desired improvement in diabetes on a dose and for a desired period of time; as exemplified by the present invention, a dose effective to improve diabetes can be administered through A specific range of compositions containing ferrous amino acid chelate compounds and measuring changes in blood glucose, fasting blood glucose, and insulin over a specific time frame.
  • the effective dose of the composition containing the ferrous amino acid chelate is 0.1 mg. /kg/day (mg/kg/day) to 15 mg/kg/day; more preferably, the effective dose is between 0.16 mg/kg/day and 12 mg/kg/day.
  • pharmaceutically acceptable carrier includes any and all solvents, dispersion media, clothing, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like which are physiologically compatible.
  • pharmaceutically acceptable carriers include one or more of water, saline, phosphate buffered solution (PBS), dextrose, glycerol, ethanol, and the like, and combinations thereof.
  • preferred compositions include isotonic agents, such as sugars, polyols such as mannitol, sorbitol, or sodium chloride.
  • the pharmaceutically acceptable carrier can further comprise minor amounts of auxiliary substances such as wetting or emulsifying agents, preservatives or buffers.
  • the medicaments of the invention may exist in a variety of forms. Such forms include, but are not limited to, liquid, semi-solid, and solid dosage forms, including, but not limited to, dispersions or suspensions; semi-solids and solids including, but not limited to, tablets, pills, powders, liposomes, and Suppository.
  • forms include, but are not limited to, liquid, semi-solid, and solid dosage forms, including, but not limited to, dispersions or suspensions; semi-solids and solids including, but not limited to, tablets, pills, powders, liposomes, and Suppository.
  • the preferred form depends on the intended mode of administration and therapeutic application.
  • the medicament of the present invention is in the form of an orally or infusible solution, and the preferred mode of administration is enteral mode, such as oral administration.
  • a drug comprising a composition of a ferrous amino acid chelate compound which is effective for improving the dose of diabetes and obesity is administered orally.
  • the medicament further comprises an excipient to render the medicament suitable for enteral or parenteral dosage forms.
  • the enteral dosage form is an oral dosage form including, but not limited to, solutions, suspensions, lozenges, and capsules.
  • the composition containing the ferrous amino acid chelate of the present invention has an effect of improving diabetes more than the commercially available Metformin for treating diabetes, and the ferrous metal-containing chelate compound of the present invention
  • the ferrous phase can be maintained in a chelated state and passed through the stomach, and the composition containing the ferrous amino acid chelate compound can be effectively reduced in blood glucose and the insulin sensitivity can be improved by the present invention.
  • Figure 1 is a bar graph of fasting blood glucose in obese mice induced by a high fat diet of the present invention.
  • composition A1 of the present invention for diabetic rats, in which Met is a metformin group.
  • Figure 3 is a bar graph of the area under the curve of the oral glucose tolerance test of Figure 2 in accordance with Figure 2, wherein Met is the metformin group.
  • This example is a composition for preparing a ferrous amino acid chelate compound which is prepared in the following manner.
  • ferrous sulfate and glycine purity of 98% or more
  • ferrous sulfate and glycine purity of 98% or more
  • the ratio of ferrous iron to amino acid chelate of the ferrous amino acid chelate is between 1:1 and 1:4; the obtained composition containing the ferrous amino acid chelate is further adjusted to a concentration of 0.16 per ml.
  • Micrograms i.e., 0.16 ⁇ g/ml
  • 0.4 ⁇ g/ml 1.2 ⁇ g/ml
  • 4 ⁇ g/ml 4 ⁇ g/ml
  • 12 ⁇ g/ml the composition is referred to as A1.
  • mice 50 g (purchased from the National Animal Center) were housed in a 12-hour light-dark cycle with any water supply.
  • the above mice were grouped as shown in Table 1, wherein the control group was given the general feed, the control group, the experimental group 1 and the experimental group 2 were respectively given the high fat diet, and the experimental group 1 and the experimental group 2 were fed orally 0.16 mg/ Composition A1 at kg/day or 0.4 mg/kg/day was continuously fed for 3 months, and the body weight of the mice was measured every 3 days, and blood glucose measurement was performed every 4 weeks after the administration of the composition A1.
  • mice with fasting blood glucose higher than 140 mg/dl and glucose intolerance i.e., blood glucose could not return to the normal range after two hours of glucose injection
  • mice with fasting blood glucose higher than 140 mg/dl and glucose intolerance i.e., blood glucose could not return to the normal range after two hours of glucose injection
  • mice were divided into a control group (administered with phosphate solution), a metformin group (Metformin, Met), a low dose group of composition A1 (4 mg/kg/day), and a high dose group of composition A1 (12 mg/kg/day), after which The body weight of the mice was measured every 3 days, and blood glucose, oral glucose tolerance test (OGTT), glycated hemoglobin (HbA1c), and insulin change were measured every 4 weeks.
  • a control group administered with phosphate solution
  • Met metformin group
  • a low dose group of composition A1 4 mg/kg/day
  • a high dose group of composition A1 (12 mg/kg/day
  • blood glucose (Glucose, Glu) was detected by a chemical analyzer (purchased by Hitachi, Japan); whole blood HbA1c was detected by Glycohemoglobin Analyzer (available from Tosoh); insulin The amount of change was detected by an enzyme-linked immunosorbent assay (ELISA) (purchased from Mercodia).
  • ELISA enzyme-linked immunosorbent assay
  • Example 1 Detection of blood glucose, glucose tolerance, and islets of a given composition A1 for diabetic rats
  • the blood glucose of the mice was measured by the method described in Preparation Example 2. The results are shown in Fig. 1. After 3 months of feeding the drug, although both the experimental group 1 and the experimental group 2 were administered a high-fat diet, the experimental group 1 (administered 0.16 mg/kg/day of the composition A1) or the experimental group The fasting blood glucose values of 2 (administered 0.4 mg/kg/day composition A1) were lower than those of the control group (no drug was administered), and experimental group 2 (administered 0.4 mg/kg/day composition) The fasting blood glucose level of A1) is even lower than that of the control group (administration of general feed, that is, no high-fat diet induces obesity), and as a result, it can be seen that the administration of the composition A1 has a blood sugar lowering effect on the high fat diet-induced obese mice. .
  • the blood glucose of the mice was measured by the method described in Preparation Example 3. The results are shown in Figure 2. Both the metformin group and the composition A1 group had improved glucose tolerance, and the area under the calculated curve (Fig. 3) showed that the composition A1 only required a low dose, ie, a higher dose. The metformin group has a better effect.
  • HbA1C Glycated hemoglobin (HbA1C) insulin
  • Control group 4.00 ⁇ 0.16 18.34 ⁇ 6.68 Metformin group 3.57 ⁇ 0.04* 11.11 ⁇ 6.47
  • Composition A1 low dose group 3.70 ⁇ 0.03* 6.00 ⁇ 2.22*
  • Glycine 3.71 ⁇ 0.03* 12.47 ⁇ 2.36 Normal value 2.9 ⁇ 0.05
  • glycosylated hemoglobin (HbA1c), insulin secretion and fasting blood glucose of diabetic rats were analyzed. Each group had a significant effect on glycosylated hemoglobin and was secreted in insulin. Among the dose and fasting blood glucose levels, the therapeutic effect was best in the low dose group of composition A1.
  • HOMA-IR index insulin( ⁇ U/ml) ⁇ glucose(mmol/L)/22.5

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Abstract

本发明公开了一种含有亚铁氨基酸螯合物的组合物用于制备改善糖尿病的药物中的用途，其中药物包含有效改善糖尿病剂量的含有亚铁氨基酸螯合物的组合物以及药学上可接受的载剂。

Description

含有亚铁氨基酸螯合物的组合物在制备改善糖尿病的药物中的用途 技术领域
本发明是关于含有亚铁氨基酸螯合物的组合物的用途，尤指其用于制备改善糖尿病药物中的用途。
背景技术
代谢性症候群(metabolic syndrome)是因应现代人的生活型态(Lupatini et al.,2008)及饮食习惯(Esposito et al.,2007)而生的文明病，以世界卫生组织在1998年所定义，有葡萄糖耐受不良或胰岛素抗性，再加上高血压、肥胖、血脂异常或微蛋白尿等其中两项，就可称其有代谢性症候群；而在台湾，只要符合以下其中3项：(1)男性腰围大于或等于90公分，女性腰围大于或等于80公分；(2)三酸甘油脂大于150mg/dl；(3)男性的高密度脂蛋白(high-density lipoprotein，HDL)低于40mg/dl，女性的高密度脂蛋白低于50mg/dl；(4)收缩压大于130毫米汞柱，舒张压大于85毫米汞柱；(5)空腹血糖大于110mg/dl；即构成代谢性症候群。台湾人患有代谢性症候群比率随着年龄增加而逐渐上升，且十大死因中，有许多与代谢性症候群相关的疾病，代谢性症候群患者的平均寿命也较正常人短，原因在于高血压或高血脂所导致的心血管疾病或胰岛素抗性导致高血糖而引发糖尿病，进而引起一些急性并发症。
糖尿糖可分为两型：(1)第一型糖尿病约占5％，常发生于青年或孩童，主要病因乃胰脏无法自行生产胰岛素，病人需终生接受胰岛素治疗；(2)第二型糖尿病约占95％，主要病因为病人体内对胰岛素讯息传递不良，使得细胞无法获得葡萄糖，所以患者会因为饥饿而不停地摄食造成高血糖，血中高浓度葡萄糖会刺激胰岛细胞持续分泌胰岛素，又造成了高胰岛素症，最后就产生胰岛素抗性，胰脏也因此衰竭。这类病人都发生在40岁以上的病人，部分病患需借助药物或胰岛素的治疗。如果糖尿病没有得到足够的控制，会引起一些急性并发症，如心血管疾病(Vlassara,1996)、慢性肾衰竭(Monnier et al.,1992)、视网膜病变(Yamagishi et al.,2002)、神经病变及微血管病变。其中，微血管病变可能导致下肢坏疽，进而导致患者截肢。
目前第二型糖尿病的治疗主要是运用药物配合饮食控制，常见用药有噻唑烷二酮(thiazolidinedione，TZD)以及二甲双胍(Metformin)，二甲双胍是一种双胍类(biguanide)的口服降血糖药物，真正作用机制不明，但已知其可以减少肝脏糖质新生作用及增加肌肉的葡萄糖摄取量，有效的降低血糖，而广泛的用在第二型糖尿病的治疗上(Granberry and Fonseca,2005)，其缺点是会有腹泻、恶心等副作用。
发明内容
鉴于现有技术化学药物治疗糖尿病产生副作用的缺点，本发明的目的在于提供一种含有亚铁氨基酸螯合物的组合物用于制备改善糖尿病的药物的用途，其中含有亚铁氨基酸螯合物的组合物具有可改善糖尿病的功效。
为达到上述目的，本发明提供一种含有亚铁氨基酸螯合物的组合物用于制备改善糖尿病的药物中的用途，其中药物包含改善糖尿病的有效剂量的含有亚铁氨基酸螯合物的组合物以及其医药学上可接受的载剂。
依据本发明，“含有亚铁氨基酸螯合物的组合物”是由无机铁与氨基酸混合所制得的含有亚铁氨基酸螯合物(ferrous amino acid chelate)的组合物。
较佳的，所述的无机铁包括，但不限于硫酸亚铁、氯化亚铁及焦磷酸亚铁；较佳的，所述的氨基酸是甘氨酸。
更佳的，所述的含有亚铁氨基酸螯合物的组合物是含有重量百分比为95％至100％的亚铁甘氨酸螯合物；又更佳的，重量百分比为98％至99.9％的亚铁甘氨酸螯合物。
较佳的，亚铁氨基酸螯合物的组合物是将硫酸亚铁(ferrous sulfate)与甘氨酸(glycine)经60℃至90℃加热8小时至48小时所获得，其中硫酸亚铁与甘氨酸的重量比例是介于1：1.2至1：1.5之间。
依据本发明，所述的含有亚铁氨基酸螯合物的组合物是包含至少一种亚铁氨基酸螯合物，且亚铁氨基酸螯合物的亚铁与氨基酸的螯合比例是介于1：1至1：4之间；更佳的，亚铁氨基酸螯合物的亚铁与氨基酸的螯合比例是介于1：1.5至1：2.5之间。
较佳的，所述的含有亚铁氨基酸螯合物的组合物中包括还原剂，该还原剂可维持含有亚铁氨基酸螯合物的组合物的亚铁的氧化态，亦可提升含有亚铁氨基酸螯合物的组合物于受体的肠道吸收率，其中还原剂包括，但不限于抗坏血酸(ascorbic acid)、柠檬酸(citric acid)、乙酸(acetic acid)、丙酸(propionic acid)、丁酸(butyric acid)、乳酸(lactic acid)、羟琥珀酸(malic acid)、磺酸(sulfonic acid)及丁二酸(succinic acid)。
依据本发明，“改善糖尿病”是指有效治疗或舒缓糖尿病，其如本发明所例示者，改善糖尿病的病症包括，但不限于降低血糖、改善葡萄糖耐受度以及增加对胰岛素的感受性。
依据本发明，“有效剂量”是指在剂量上及对于所需要的时间段而言对达成所要改善糖尿病结果有效的量；其如本发明所例示者，有效改善糖尿病的剂量可透过施予特定范围量的含有亚铁氨基酸螯合物的组合物，并于特定时间范围内测量血糖、空腹血糖以及胰岛素的变化而得。
较佳的，所述的含有亚铁氨基酸螯合物的组合物的有效剂量是介于0.1毫克 /公斤/天(mg/kg/day)至15mg/kg/day；更佳的，有效剂量是介于0.16mg/kg/day至12mg/kg/day。
依据本发明，“医药学上可接受的载剂”包括生理上相容的任意及所有溶剂、分散介质、衣料、抗菌剂及抗真菌剂、等张剂及吸收延缓剂及其类似物。药学上可接受的载剂的实例包括水、盐水、磷酸盐缓冲生理食盐水(phosphate buffered solution,PBS)、右旋糖、甘油、乙醇及其类似物的一或多种及其组合。在许多情况中，较佳的组合物包括等张剂，例如糖、诸如甘露醇、山梨糖醇的多元醇或氯化钠。药学上可接受的载剂可进一步包含微量辅助物质，诸如湿润剂或乳化剂、防腐剂或缓冲剂。
本发明所述的药物可以多种形式存在。该等形式包括，但不限于液体、半固体及固体药剂形式，其中液体包括，但不限于分散液或悬浮液；半固体及固体包括，但不限于锭剂、丸剂、粉剂、脂质体及栓剂。较佳的形式取决于预期的投药模式及治疗应用。
较佳的，本发明的药物是呈可口服或可输注溶液形式，且较佳的投药模式为经肠模式，诸如口服。在本发明的实施例中，有效改善糖尿病以及肥胖的剂量的包含有亚铁氨基酸螯合物的组合物的药物是藉由口服施予。
较佳的，所述的药物更包括一赋形剂(excipient)，使药物适用于经肠道的或非经肠道的剂型。
较佳的，所述的经肠道的剂型是口服剂型，其包括，但不限于溶液、悬浮液、锭剂及胶囊。
本发明所述的含有亚铁氨基酸螯合物的组合物相较于施予市售的用于治疗糖尿病药物Metformin更具有改善糖尿病的效果，且本发明所述的含有亚铁氨基酸螯合物的组合物中，由于氨基酸分子量小，可与亚铁维持螯合状态通过胃，且经本发明证实施予含有亚铁氨基酸螯合物的组合物可有效降低血糖以及改善胰岛素的感受性。
附图说明
图1是本发明的以高脂饮食诱发肥胖老鼠的空腹血糖柱状图。
图2是本发明的组合物A1对于糖尿病鼠的口服葡萄糖耐量试验的曲线图，其中Met为二甲双胍组。
图3是本发明依据图2的口服葡萄糖耐量试验的曲线下的面积的柱状图，其中Met为二甲双胍组。
具体实施方式
以下配合图式及本发明的较佳实施例，进一步阐述本发明为达成预定发明目的所采取的技术手段。
制备例1制备含有亚铁氨基酸螯合物的组合物
本实施例是用以制备含有亚铁氨基酸螯合物的组合物，其是以下述方式制备。首先，将硫酸亚铁与甘氨酸(纯度98％以上)以重量比1:1.3混合并历经60℃至90℃加热8小时至48小时，以获得该含有亚铁氨基酸螯合物的组合物，其中亚铁氨基酸螯合物的亚铁与氨基酸螯合比例是介于1：1至1：4之间；再将所获得的含有亚铁氨基酸螯合物的组合物调制成浓度为每毫升含有0.16微克(即0.16μg/ml)、0.4μg/ml、1.2μg/ml、4μg/ml及12μg/ml，并以A1代称该组合物。
制备例2高脂饮食诱发肥胖老鼠的动物实验
表1
组别 控制组 对照组 实验组1 实验组2
施予组合物A1 - - 0.16mg/kg 0.4mg/kg
只数 10 5 5 5
饮食 一般 高脂 高脂 高脂
将数只12周大C57BL/6JNR雄鼠(50g)(购自国家动物中心)饲养于12小时光暗循环，任意给水的环境下。将上述老鼠分组如表1所示，其中控制组是给予一般饲料，对照组、实验组1及实验组2皆分别给予高脂饲料，且实验组1及实验组2分别以口服喂食0.16mg/kg/day或0.4mg/kg/day的组合物A1，持续喂食3个月，每3天测量小鼠体重，在喂食组合物A1后每4周进行血糖测量。
制备例3药物诱发糖尿病老鼠的动物实验
将数只6周大C57BL/6J雄鼠(购自于财团法人国家实验研究院国家动物中心)先给予一般饮食适应一周后，利用腹腔注射每公斤240毫克(mg/kg)烟碱酰氨(nicotinamide)，15分钟后再注射100mg/kg链佐霉素(streptozotocin，STZ)；2天后，再以同样的剂量与方式注射一次，接着给予高脂饮食(60％脂肪)；再历经2个月后，挑选出空腹血糖高于140mg/dl及葡萄糖耐受不良(即注射葡萄糖两小时后，血糖无法回到正常范围)的小鼠，以形成第二型糖尿病鼠。
将小鼠分成控制组(给予磷酸盐溶液)、二甲双胍组(Metformin,Met)、组合物A1低剂量组(4mg/kg/day)以及组合物A1高剂量组(12mg/kg/day)，之后每3天测量小鼠体重，并每4周检测血糖、口服葡萄糖耐受试验(oral glucose tolerance test，OGTT)、糖化血色素(glycatedhemoglobin，HbA1c)以及胰岛素变化量。
其中血中葡萄糖(Glucose,Glu)是由化学分析仪(Chemistry Analyzer，购于日本Hitachi公司)进行检测；全血HbA1c则是由糖化血红蛋白分析仪(Glycohemoglobin Analyzer，购于Tosoh公司)进行检测；胰岛素变化量是以酵素连结免疫吸附分析法(enzyme-linked immunosorbent assay,ELISA)进行检测(购自于Mercodia公司)。
实施例1检测施予组合物A1对于糖尿病鼠的血糖、葡萄糖耐受度以及胰岛
素感受性的影响
以制备例2所述的方法检测小鼠血糖。结果如图1所示，喂食药物3个月后，尽管实验组1和实验组2皆是施予高脂饮食，但实验组1(施予0.16mg/kg/day组合物A1)或实验组2(施予0.4mg/kg/day组合物A1)的空腹血糖值皆相较于对照组(未施予任何药物)来的低，且实验组2(施予0.4mg/kg/day组合物A1)的空腹血糖值甚至低于控制组(施予一般饲料，即无高脂饮食诱导肥胖)，因此由此结果可知，施予组合物A1对于高脂饮食诱导肥胖的老鼠具有降低血糖的效果。
以制备例3所述的方法检测小鼠血糖。结果如图2所示，二甲双胍组及组合物A1组皆对于葡萄糖耐受度均有所改善，且经计算曲线下的面积(图3)，显示组合物A1只需要低剂量即比高剂量的二甲双胍组具有更佳的效果。
表1糖尿病鼠的糖化血色素、空腹血糖值以及HOMA-IR值
  糖化血色素(HbA1C) 胰岛素
控制组 4.00±0.16 18.34±6.68
二甲双胍组 3.57±0.04* 11.11±6.47
组合物A1低剂量组 3.70±0.03* 6.00±2.22*
甘氨酸 3.71±0.03* 12.47±2.36
正常值 2.9±0.05  
表2糖尿病鼠的糖化血色素、空腹血糖值以及HOMA-IR值
  血糖(Glu) HOMA-IR
控制组 203.00±17.43 8.59±2.00
二甲双胍组 169.00±10.77* 4.53±1.42*
组合物A1低剂量组 152.71±4.74* 2.17±0.87*
组合物A1高剂量组 166.13±5.02* 3.85±2.08*
甘氨酸 182.88±11.20 5.23±1.73
正常值 143.5±9.14  
在投药治疗一个月后，如表1及表2所示，分析糖尿病鼠的糖化血色素(HbA1c)、胰岛素分泌量及空腹血糖值，各组对于糖化血色素都有明显降低的效果，且在胰岛素分泌量及空腹血糖值中，以组合物A1低剂量组的治疗效果最佳。
胰岛素抗性(homeostasis model assessment for insulin resistance)，可藉由以下公式算出
HOMA-IR index＝insulin(μU/ml)×glucose(mmol/L)/22.5
结果显示，二甲双胍组及组合物A1低剂量组的胰岛素抗性结果最佳，且组合物A1低剂量组的HOMA-IR值由控制组的8.59降到2.17，甚至比二甲双胍组的4.53更为有效；以上数据显示组合物A1低剂量组在空腹血糖、胰岛素及HOMA-IR的表现都较二甲双胍组更为有效，而且组合物A1所使用的剂量远低于二甲双胍，因此根据以上实验的结果，我们可以合理地推论组合物A1在低剂 量的治疗对于糖尿病病症改善最为有效。
以上所述仅是本发明的较佳实施例而已，并非对本发明做任何形式上的限制，虽然本发明已以较佳实施例揭露如上，然而并非用以限定本发明，任何熟悉本领域的技术人员，在不脱离本发明技术方案的范围内，当可利用上述揭示的技术内容作出些许更动或修饰为等同变化的等效实施例，但凡是未脱离本发明技术方案的内容，依据本发明的技术实质对以上实施例所作的任何简单修改、等同变化与修饰，均仍属于本发明技术方案的范围内。

Claims (10)

  1. 一种含有亚铁氨基酸螯合物的组合物用于制备改善糖尿病的药物中的用途，其中药物含有有效剂量的亚铁氨基酸螯合物的组合物以及其医药学上可接受的载剂。
  2. 根据权利要求1所述的用途，其中含有亚铁氨基酸螯合物的组合物中的亚铁氨基酸螯合物的亚铁与氨基酸的螯合比例是介于1：1至1：4之间。
  3. 根据权利要求1所述的用途，其中含有亚铁氨基酸螯合物的组合物中的亚铁氨基酸螯合物的亚铁与氨基酸的螯合比例是介于1：1.5至1：2.5之间。
  4. 根据权利要求1所述的用途，其中含有亚铁氨基酸螯合物的组合物的有效剂量是介于0.1mg/kg/day至15mg/kg/day。
  5. 根据权利要求1所述的用途，其中含有亚铁氨基酸螯合物的组合物的有效剂量是介于0.16mg/kg/day至12mg/kg/day。
  6. 根据权利要求1至5中任一项所述的用途，其中含有亚铁氨基酸螯合物的组合物是由无机铁与氨基酸混合并历经60℃至90℃加热8小时至48小时所制得的含有亚铁氨基酸螯合物的组合物，其中无机铁与氨基酸的比例是介于1：1.2至1：1.5之间。
  7. 根据权利要求6所述的用途，其中无机铁是硫酸亚铁、氯化亚铁或焦磷酸亚铁；该氨基酸是甘氨酸。
  8. 根据权利要求6所述的用途，其中含有亚铁氨基酸螯合物的组合物中包括还原剂，该还原剂是抗坏血酸(ascorbic acid)、柠檬酸(citric acid)、乙酸(acetic acid)、丙酸(propionic acid)、丁酸(butyric acid)、乳酸(lactic acid)、羟琥珀酸(malic acid)、磺酸(sulfonic acid)或丁二酸(succinic acid)。
  9. 根据权利要求1所述的用途，其中药物是经肠道的或非经肠道的剂型。
  10. 根据权利要求9所述的用途，其中该经肠道的剂型是口服剂型，其口服剂型是溶液、悬浮液、锭剂或胶囊。
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