WO2018148922A1 - 含有亚铁氨基酸螯合物的组合物用于制造治疗肝功能异常的医药品的用途 - Google Patents

含有亚铁氨基酸螯合物的组合物用于制造治疗肝功能异常的医药品的用途 Download PDF

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WO2018148922A1
WO2018148922A1 PCT/CN2017/073865 CN2017073865W WO2018148922A1 WO 2018148922 A1 WO2018148922 A1 WO 2018148922A1 CN 2017073865 W CN2017073865 W CN 2017073865W WO 2018148922 A1 WO2018148922 A1 WO 2018148922A1
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amino acid
ferrous
composition
composition containing
liver
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PCT/CN2017/073865
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French (fr)
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王开鼎
林村源
陈木桂
詹勋锦
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普惠德生技股份有限公司
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Priority to US16/485,604 priority Critical patent/US20190365697A1/en
Priority to CN201780084029.4A priority patent/CN110198709A/zh
Priority to PCT/CN2017/073865 priority patent/WO2018148922A1/zh
Publication of WO2018148922A1 publication Critical patent/WO2018148922A1/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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • 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
    • A61K9/08—Solutions
    • 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
    • A61K9/10—Dispersions; Emulsions
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate

Definitions

  • the present invention relates to the use of a composition comprising a ferrous amino acid chelate, in particular for the treatment of abnormal liver function.
  • Liver function tests are one of the most frequently used tests in the clinic, and blood tests are one of the important methods for determining whether there is liver disease. There are quite a number of liver function test programs. The main purpose of clinical liver function tests are as follows: (1) the presence of liver disease; (2) diagnosis of liver disease and discussion of possible diseases; (3) assessment of the severity of liver disease; (4) Tracking and speculation of treatment and prognosis.
  • Glutamic oxaloacetic transaminase GAT, also known as aspartate aminotransferase, AST
  • GGT glutamic-pyruvic transaminase
  • ALT Alanine transaminase
  • GTT Glutamic oxaloacetic transaminase
  • GPT glutamic-pyruvic transaminase
  • ALT Alanine transaminase
  • ALT is very important for detecting hepatocyte injury. Once liver cells are damaged or necrotic, AST and ALT will enter the bloodstream and their values will increase. ALT should mainly come from the liver, and AST should be seen in many extrahepatic tissues such as the heart, skeletal muscles and kidneys. Under normal circumstances, serum AST and ALT values increase or decrease at the same time, and the higher one depends on the cause and course of disease.
  • the serum contains alkaline phosphatase (ALKP) from various organs, including liver, bone, small intestine and placenta.
  • ALKP alkaline phosphatase
  • alkaline phosphatase is caused by the increase of hepatocyte and bile duct epithelial synthetase, generally mild to moderate increase (1 to 2 times higher than normal) can be seen in hepatitis, cirrhosis metastasis or invasive liver Patients with disease (such as leukemia, etc.), a significant increase (three to ten times higher than normal) can be seen in extrahepatic bile duct obstruction or intrahepatic cholestasis (such as drugs or primary biliary cirrhosis).
  • Cholesterol (cholesterol, CHOL) is widely found in animals, especially in the brain and nerve tissues. It is also abundant in kidney, spleen, skin, liver and bile. It is an indispensable substance in tissue cells and is not only involved in the formation of cell membranes. And it is a raw material for the synthesis of bile acids, vitamin D and steroid hormones. Elevated serum cholesterol can be seen in diabetes, simple obstructive jaundice, obesity, high-fat diet, hypothyroidism, Cushing's syndrome, nephrotic syndrome and other diseases. Lower serum cholesterol can be seen in severe malnutrition, malignant tumors, severe damage to liver cells, and protein-losing enteropathy. When there is liver and kidney disease, or an endocrine abnormality, the cholesterol value will rise. And the dog's hypothyroidism will be 70% The chances are that the cholesterol value has risen.
  • Total bilirubin is the sum of direct bilirubin and indirect bilirubin.
  • the bilirubin in normal serum is derived from the hemoglobin produced by the rupture of aging red blood cells.
  • bilirubin can not be converted into bile or due to hepatocyte swelling, resulting in intrahepatic cholestasis caused by direct bilirubin and indirect bilirubin at the same time causing hepatic jaundice.
  • cholecystitis and total bile duct obstruction occur, bile is discharged into the duodenal disorder to cause obstructive jaundice. Both direct bilirubin and indirect bilirubin are elevated in hepatic jaundice.
  • hepatic jaundice When hepatic jaundice is suspected, a diagnosis should be made in combination with ALT, AST, ALKP indicators and various clinical symptoms.
  • the level of total bilirubin in hepatic jaundice is proportional to the severity of liver disease to a certain extent. When the total bilirubin value is shown as severe jaundice, if the ALT and AST values are not increased, it is called bile. Enzyme separation.
  • ALT and AST Values can be used as a warning for severe liver damage, advanced cirrhosis, and liver failure.
  • Obstructive jaundice refers to the fact that hepatocytes combine indirect bilirubin into direct bilirubin and produce bile, but obstruction of bile discharge leads to elevated direct bilirubin and indirect or blunt bilirubin. .
  • the main cause of obstructive jaundice is bile duct obstruction and compression caused by gallstones, parasites, liver tumors, gallbladder tumors, and pancreatic tumors.
  • the ALT value is generally slightly elevated
  • the AST value is slightly elevated or normal
  • the ALKP value is significantly increased.
  • SAMe S-adenosylmethionine
  • compositions comprising a ferrous amino acid chelate compound for use in the manufacture of a medicament for treating liver dysfunction, comprising a ferrous amino acid chelate
  • the composition of the composition has the effect of regulating liver function.
  • the technical means adopted by the present invention is to provide a composition containing a ferrous amino acid chelate compound for the manufacture of a medicament for treating liver dysfunction, wherein the medicament contains an effective dose of ferrous amino acid.
  • 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 ferrous metal chelate compound in the composition containing the ferrous amino acid chelate has a chelating ratio of ferrous iron to amino acid of between 1:1 and 1:4.
  • the ferrous metal chelate compound of the ferrous metal chelate-containing composition has a chelating ratio of ferrous iron to amino acid of between 1:1.5 and 1:2.5.
  • the effective dosage of the ferrous amino acid chelate-containing composition is from 0.5 mg (mg/kg/day) to 4 mg/kg/day per kilogram per day.
  • the above dosages are calculated according to the Estimating the maximum safe starting dose in initial clinical trials for therapeutics in adult healthy volunteers.
  • the effective dose of the ferrous metal chelate-containing composition is between 5 mg/kg/day and 20 mg/kg/day in mice.
  • the effective dosage of the ferrous amino acid chelate-containing composition is between 2 mg/kg/day and 5 mg/kg/day in dogs.
  • the ferrous metal chelate-containing composition is a combination of ferrous metal-containing chelates prepared by mixing inorganic iron with amino acids and heating at 60 ° C to 90 ° C for 8 hours to 48 hours.
  • the weight ratio of inorganic iron to amino acid is between 1:1.2 and 1:1.5.
  • the inorganic iron is ferrous sulfate, ferrous chloride, ferrous pyrophosphate or a combination thereof; the amino acid is glycine.
  • the composition containing the ferrous amino acid chelate compound is a ferrous glycine chelate compound containing 95% to 100% by weight; more preferably, the weight percentage is 98% to 99.9%.
  • Iron glycine chelate is a ferrous glycine chelate compound containing 95% to 100% by weight; more preferably, the weight percentage is 98% to 99.9%.
  • the composition containing the ferrous amino acid chelate compound includes a reducing agent, and the reducing agent includes, but not limited to, ascorbic acid, citric acid, acetic acid, and c. Propionic acid, butyric acid, lactic acid, malic acid, sulfonic acid, succinic acid or a combination thereof.
  • the "effective dose” as used in the present invention means an amount effective to achieve a liver biochemical value associated with a reduction in liver function at a dose and for a desired period of time; according to the present invention, it is meant by administering a specific range
  • the amount of the composition containing the ferrous amino acid chelate can lower the liver biochemical values ALT, AST and ALKP of the liver function, or to the normal range; according to the present invention, it can also improve the liver function of aging.
  • liver function refers to the level of serum biochemical values such as ALT and AST in blood.
  • ALKP is also used as an auxiliary judgment basis; the ALT reference standard value is 10 U/L to 100 U/L, and the AST reference standard value is 0 U/L to 50 U/L.
  • the "pharmaceutically acceptable carrier” as used in the present invention includes, but is not limited to, a solvent, an emulsifier, a suspending agent, a decomposer, a binding agent. , excipient, stabilizing agent, chelating agent, diluent, gelling agent, preservative, lubricant, surface activity Surfactant, and other carriers similar or suitable for use in the present invention.
  • the "pharmaceutical” of the present invention may exist in various forms including, but not limited to, liquid, semi-solid, and solid pharmaceutical forms such as solutions, emulsions, suspensions, powders ( Powder), tablet, pill, lozenge, troche, chewing gum, slurry, liposomes, suppositories, and the like
  • the dosage form of the invention may exist in various forms including, but not limited to, liquid, semi-solid, and solid pharmaceutical forms such as solutions, emulsions, suspensions, powders ( Powder), tablet, pill, lozenge, troche, chewing gum, slurry, liposomes, suppositories, and the like.
  • the pharmaceutical product is an enteral or parenteral dosage form.
  • the enteral dosage form is an oral dosage form
  • the oral dosage form is a solution, an emulsion, a suspension, a powder, a lozenge, a pill, a buccal tablet, a tablet, a chewing gum or a capsule.
  • the invention has the advantages that the composition containing the ferrous amino acid chelate compound of the invention can effectively reduce the serum biochemical values ALT, AST and ALKP related to liver function; for the animal which can not improve liver function by taking SAMe for a long time, the invention is applied to the invention
  • the composition containing the ferrous amino acid chelate can be effectively improved; further, the composition containing the ferrous amino acid chelate of the present invention can improve the liver function of aging.
  • Figure 1 is a line drawing of the ALT of the A1 composition of the present invention continuously administered to a severe group and a light group of dogs.
  • Figure 2 is a line graph of the AST of a dog of the present invention in which the A1 composition is continuously administered to a light group.
  • Fig. 3 is a bar graph showing the ALT of the dog in the A1 composition of the present invention stopped from being administered.
  • Fig. 4 is a bar graph of the AST of the A1 composition of the present invention in which the administration of the dog is stopped.
  • Figure 5 is a bar graph of AST administered to aged mice of the A1 composition of the present invention.
  • This example is a composition for preparing a ferrous amino acid chelate compound which is prepared in the following manner. First, ferrous sulfate and glycine (purity of 98% or more) are mixed at a weight ratio of 1:1.3 and heated at 60 ° C to 90 ° C for 8 hours to 48 hours to obtain the composition containing the ferrous amino acid chelate compound, wherein The ferrous metal chelate compound has a ferrous and amino acid sequestration ratio of between 1:1 and 1:4 and is referred to as A1 for the composition.
  • A1 composition was administered with 27 mg (2.7 mg/kg) per 10 kg per day, which was not regularly tracked to 160 days.
  • Blood tests were performed for liver function-related serum biochemical values ALT, AST. And ALKP; wherein the ALT reference standard value is 10 U/L to 100 U/L, and the AST reference standard value is 0 U/L to 50 U/L.
  • ALT reference standard value is 10 U/L to 100 U/L
  • AST reference standard value is 0 U/L to 50 U/L.
  • 3 dogs were classified into the severe group before the A1 composition was administered with an ALT value exceeding 500 U/L, and the other 8 dogs were assigned ALT values before the A1 composition was administered. Between 100U/L and 200U/L is classified as a light group.
  • the ALT decreased significantly from an average of 545 U/L to 245 U/L, with a drop of up to 300 U/L; one of the dogs in the severe group was even given 1 day. That is, the drop is about 200U/L.
  • the average value has dropped to the normal range of 92 U/L, and the normal range can be maintained for three months to more than five months, indicating that the administration of the A1 composition can effectively improve.
  • the light group was used on day 0 as data prior to administration of the A1 composition, with AST values ranging from 70 U/L to 200 U/L.
  • the average value has dropped to the normal range of 50 U/L, and the normal range can be maintained for more than three months. It shows that the administration of the A1 composition can effectively improve the abnormal AST of the dog. The situation.
  • the ALKP value decreased from more than 2000 U/L to 705 U/L, and the decrease was as high as 1300 U/L; the other dog continued to administer the A1 composition.
  • the ALKP value decreased from greater than 1834 U/L to 1035 U/L, with a drop of up to about 800 U/L, indicating that administration of the A1 composition can effectively improve the abnormality of the ALKP in dogs.
  • the administration of the dog A1 composition was stopped in the middle and then continued.
  • A1 composition was administered with 27 mg (2.7 mg/kg) per 10 kg per day until blood tests for liver function-related serum biochemical values ALT, AST, and ALKP were significantly reduced.
  • the A1 composition was administered; the A1 composition was continued to be administered after the subsequent liver function-related serum biochemical values ALT, AST, and ALKP were greatly increased.
  • dogs with abnormal liver function continue to administer the A1 composition for an average of about 20 days to observe ALT.
  • the value decreased by about 73 U/L; however, the blood test was again performed about 20 days after the A1 composition was stopped, and the ALT value was found to increase by about 92 U/L, so that the A1 composition was administered again; about 30 days after the continuous administration of the A1 composition. It can be found that the ALT value drops by about 163 U/L.
  • dogs with abnormal liver function continued to administer the A1 composition for an average of about 20 days, and the AST value decreased by about 8 U/L.
  • the blood test was performed again about 20 days later.
  • the AST value was found to increase by about 12 U/L, so the A1 composition was again administered; after about 30 days from the continued application of the A1 composition, the AST value was decreased by about 26 U/L.
  • Example 3 was first applied to the dog A1 composition after using SAMe.
  • the ALT value decreased by about 45 U/L and the AST value decreased by about 50 U/L to reach the standard range.
  • No. 2 dog was changed to the A1 composition. After the last 20 days, the ALT value decreased by about 50 U/L; 2 days after the No. 3 dog was changed to the A1 composition, the ALT value decreased by about 35 U/L. Therefore, the administration of the A1 composition to dogs that have not taken SAMe for a long time will effectively reduce the liver function related values of the dog.
  • mice 12-month-old mice (C57BL/6J) were used as experimental animals in the aging mode, and the dose of 200 ⁇ g ( ⁇ g) per mouse per day was administered (1) for 4 months and (2) 6 months, and then determined. Serum biochemical values ALT and AST related to liver function in the control group and the A1 composition group.
  • liver function ALT and AST values
  • the ALT value will rise sharply when the liver is acutely inflammatory, and the AST value will continue to rise when the liver is chronic inflammation, it can be seen from Table 1 that the liver of aging mice may be aging and chronically inflamed. In the absence of acute inflammation of the liver, the ALT value is within the normal range, while the AST value is as high as 302 U/L. After application After 4 months of A1 composition, it was found that the ALT value remained unchanged in the normal range in terms of liver function, but the AST decreased significantly, from 302U/L to 162U/L, a total of 46%, so A1 The composition contributes to the repair of liver function.
  • AST had a tendency to decrease in liver function, and thus the A1 composition contributes to the repair of liver function.

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Abstract

本发明提供含有亚铁氨基酸螯合物的组合物用于制造治疗肝功能异常的医药品的用途，其中医药品含有有效剂量的亚铁氨基酸螯合物的组合物以及其药学上可接受的载剂。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肝功能相关血清生化学数值；对于长期服用S-腺苷甲硫氨酸而无法改善肝脏功能的动物，改施予本发明的含有亚铁氨基酸螯合物的组合物能获得有效改善；再者，本发明的含有亚铁氨基酸螯合物的组合物能改善老化的肝脏功能。

Description

含有亚铁氨基酸螯合物的组合物用于制造治疗肝功能异常的医药品的用途 技术领域
本发明涉及一种含有亚铁氨基酸螯合物的组合物的用途，特别是用于治疗肝功能异常的用途。
背景技术
肝功能试验是临床上被使用最频繁的检验之一，而验血则是作为判定是否有肝脏疾病的重要方法之一。肝功能试验项目相当多，临床上肝功能试验目的主要有以下几种：(1)发现肝病的存在；(2)进行肝病的诊断并探讨其可能的病；(3)评估肝病的严重程度；(4)治疗及预后的追踪推测。
麸胺草醋酸转胺酶(glutamic oxaloacetic transaminase，GOT，又称为天冬氨酸氨基转移酶，aspartate aminotransferase，AST)和丙胺酸转胺酶(glutamic-pyruvic transaminase，GPT，又称为丙氨酸转氨酶，alanine transaminase，ALT)对于检测肝细胞损伤而言是相当重要的，肝细胞一旦受损或坏死，AST及ALT便会进入血液中且其数值会升高。ALT主要应来自肝脏，而AST应见于许多肝外组织如心脏、骨骼肌和肾脏等。一般情形下血清AST及ALT数值同时上升或下降，何者较高则视病因及病程而定。
血清中含有来自各器官的碱性磷酸酶(alkaline phosphatase，ALKP)，包括肝脏、骨骼、小肠和胎盘等。血清碱性磷酸酶上升时要排除怀孕、发育中的青少年、罕见的小肠淋巴增生性疾病后，再辨别来源是肝胆系统或骨骼系统。碱性磷酸酶的增高乃源于肝细胞和胆管上皮合成酶增加所致，一般轻度至中度增高(高于正常值的1倍至2倍)可见于肝炎、肝硬化转移或浸润性肝脏疾病(如白血病等)的患者，显著的增高(高于正常值的3倍至10倍)可见于肝外胆管阻塞或肝内胆汁郁积(如药物或原发性胆汁性肝硬化)。
胆固醇(cholesterol，CHOL)广泛存在于动物体内，尤以脑及神经组织中最为丰富，在肾、脾、皮肤、肝和胆汁中含量也高，是组织细胞不可缺少的重要物质，不仅参与形成细胞膜，而且是合成胆汁酸、维生素D以及类固醇激素的原料。血清胆固醇升高可见于糖尿病、单纯的阻塞性黄疸、肥胖、高脂肪饮食、甲状腺机能低下症、库兴氏症候群(Cushing's syndrome)、肾病综合症(nephrotic syndrome)等疾病。血清胆固醇降低可见于严重的营养不良、恶性肿瘤、肝细胞严重受损、蛋白丢失性肠病(protein-losing enteropathy)等情况。当有肝肾疾病，或是内分泌异常时会使胆固醇数值上升。而犬类的甲状腺机能低下症会有70％ 的机率出现胆固醇数值上升。
总胆红素(total bilirubin，TBIL)是直接胆红素和间接胆红素的总和，正常血清中的胆红素基本是来源于衰老的红细胞破碎后产生出来的血红蛋白衍化而成。肝病时，胆红素不能转化为胆汁或因肝细胞肿胀而导致肝内胆汁淤积引起直接胆红素和间接胆红素同时升高造成肝细胞性黄疸。发生胆囊炎、总胆管阻塞时，胆汁排入十二指肠障碍而引起阻塞性黄疸。肝细胞性黄疸时直接胆红素和间接胆红素均会升高。当怀疑发生肝细胞性黄疸时，要结合ALT、AST、ALKP指标及各项临床症状作出诊断。肝细胞性黄疸时总胆红素的高低在一定程度上是与肝病的严重程度成正比的，当总胆红素值显示为重度黄疸时，如果ALT、AST数值升高不多则称为胆酶分离。胆酶分离的原因是肝细胞严重受损时，间接胆红素不能被转化使胆汁大量在肝内淤积，而具有活性的肝细胞数量很少因此释出的酶也相应减少，因此ALT与AST数值可作为极严重的肝损伤、肝硬化中晚期以及肝衰竭的警示。阻塞性黄疸(obstructive jaundice)是指肝细胞将间接胆红素结合为直接胆红素并产生胆汁，但胆汁排出受阻导致直接胆红素升高、间接胆红素正常或轻度升高的症状。阻塞性黄疸主要病因为胆结石、寄生虫、肝脏肿瘤、胆囊肿瘤、胰腺肿瘤造成的胆管阻塞及压迫。此时，ALT数值一般轻度升高，AST数值轻度升高或正常，ALKP数值明显升高。
肝脏受损时，由于S-腺苷甲硫氨酸(S-adenosylmethionine，SAMe)的制造减少导致谷胱甘肽(glutathione)减少而加剧影响肝脏机能，且研究报告中指出多数肝脏问题中，谷胱甘肽含量都有减少的现象。肝脏功能出问题时往往无法找到真正的原因，所以不管何种缘故，平常的维护增进肝脏的功能是非常重要的。现有技术中为了改善的肝功能，狗和猫多利用给予SAMe来增加谷胱甘肽的含量，用以改善肝脏功能。然而，近来实务亦有发现针对肝脏功能受损的动物给予SAMe，仍无法改善肝脏功能。
有鉴于此，如何发展出改善肝脏功能的组合物，现有技术实有待改善的必要。
发明内容
有鉴于现有技术的药物产生副作用的缺点，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造治疗肝功能异常的医药品的用途，其中含有亚铁氨基酸螯合物的组合物具有调控肝功能的功效。
为达到上述发明目的，本发明所采用的技术手段为提供一种含有亚铁氨基酸螯合物的组合物用于制造治疗肝功能异常的医药品的用途，其中医药品含有有效剂量的亚铁氨基酸螯合物的组合物以及其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介于1：1至1：4之间。
较佳的，所述的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的有效剂量于人是介于每日每公斤0.5毫克(mg/kg/day)至4mg/kg/day。以上剂量是根据2005年美国食品药物管理局所公告的实验初期估算方法(Estimating the maximum safe starting dose in initial clinical trials for therapeutics in adult healthy volunteers)计算而得。
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于小鼠是介于5mg/kg/day至20mg/kg/day。
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于犬只是介于2mg/kg/day至5mg/kg/day。
更佳的，所述的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重量比例介于1：1.2至1：1.5之间。
更佳的，所述的无机铁为硫酸亚铁、氯化亚铁、焦磷酸亚铁或其组合；所述氨基酸为甘氨酸。
更佳的，所述的含有亚铁氨基酸螯合物的组合物为含有重量百分比为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。
更佳的，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)、丁二酸(succinic acid)或其组合。
本发明所述的“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降低肝功能相关血清生化学数值的有效的量；依据本发明，是指通过施予特定范围量的含有亚铁氨基酸螯合物的组合物，能够使得肝功能相关血清生化学数值ALT、AST及ALKP降低，或是降低至正常范围；依据本发明，另指能改善老化的肝脏功能。
本发明所述的“肝功能”，是指以检验血液中ALT与AST等血清生化学数值的高低， 作为判定肝脏功能是否正常的依据，此外，亦会以ALKP作为辅助判断依据；其中ALT参考标准值为10U/L至100U/L，AST参考标准值为0U/L至50U/L。
本发明所述的“医药学上可接受的载剂”包含，但不限于溶剂(solvent)、乳化剂(emulsifier)、悬浮剂(suspending agent)、分解剂(decomposer)、黏结剂(binding agent)、赋形剂(excipient)、安定剂(stabilizing agent)、螯合剂(chelating agent)、稀释剂(diluent)、胶凝剂(gelling agent)、防腐剂(preservative)、润滑剂(lubricant)、表面活性剂(surfactant)，及其他类似或适用本发明的载剂。
本发明所述的“医药品”可以多种形式存在，这些形式包含，但不限于液体、半固体及固体药剂形式，诸如溶液(solution)、乳剂(emulsion)、悬浮液(suspension)、粉末(powder)、锭剂(tablet)、丸剂(pill)、口含锭(lozenge)、片剂(troche)、口嚼胶(chewing gum)、胶囊(slurry)、脂质体、栓剂以及其他类似或适用本发明的剂型。
较佳的，所述的医药品是经肠道的或非经肠道的剂型。
更佳的，所述的经肠道的剂型为口服剂型，其口服剂型是溶液、乳剂、悬浮液、粉末、锭剂、丸剂、口含锭、片剂、口嚼胶或胶囊。
本发明的优点在于本发明的含有亚铁氨基酸螯合物的组合物可有效降低肝功能相关血清生化学数值ALT、AST及ALKP；对于长期服用SAMe无法改善肝脏功能的动物，改施予本发明的含有亚铁氨基酸螯合物的组合物能获得有效改善；再者，本发明的含有亚铁氨基酸螯合物的组合物能改善老化的肝脏功能。
附图说明
以下附图仅旨在于对本发明作示意性说明和解释，并不限定本发明的范围。其中：
图1为本发明的A1组合物连续施予严重组与轻微组犬只的ALT的折线图。
图2为本发明的A1组合物连续施予轻微组的犬只的AST的折线图。
图3为本发明的A1组合物中途停止施予犬只的ALT的柱状图。
图4为本发明的A1组合物中途停止施予犬只的AST的柱状图。
图5为本发明的A1组合物施予老化小鼠的AST的柱状图。
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介于1：1至1：4之间，并以A1代称该组合物。
实施例1持续施予犬只A1组合物
检测11只肝功能异常的犬，并施予A1组合物每日每10公斤27毫克(2.7mg/kg)，并不定期追踪至160天，抽血检验肝功能相关血清生化学数值ALT、AST及ALKP；其中ALT参考标准值为10U/L至100U/L，AST参考标准值为0U/L至50U/L。于第0天作为施予A1组合物之前的数据，其中3只犬在施予A1组合物之前ALT数值超过500U/L归类于严重组，其他8只犬在施予A1组合物之前ALT数值介于100U/L至200U/L归类于轻微组。
请参阅图1所示，严重组持续施予A1组合物15天后，ALT从平均545U/L显著下降至245U/L，降幅高达300U/L；严重组中的其中一只犬甚至施予1天即下降约200U/L。轻微组持续施予A1组合物20天后，平均已下降至92U/L的正常值范围内，且持续服用三个月至五个月以上都能维持正常范围，显示施予A1组合物能有效改善犬只ALT异常的状况。
请参阅图2所示，轻微组于第0天作为施予A1组合物之前的数据，其AST数值介于70U/L至200U/L。轻微组持续施予A1组合物20天后，平均已下降至50U/L的正常值范围内，且持续服用三个月以上都能维持正常范围，显示施予A1组合物能有效改善犬只AST异常的状况。
严重组中其中一只肝功能异常的犬持续施予A1组合物15天后，ALKP数值从大于2000U/L下降至705U/L，降幅高达大于1300U/L；另一只犬持续施予A1组合物18天后，ALKP数值从大于1834U/L下降至1035U/L，降幅高达约800U/L，显示施予A1组合物能有效改善犬只ALKP异常的状况。
实施例2中途停止施予犬只A1组合物后再继续服用
检测5只肝功能异常的犬，并施予A1组合物每日每10公斤27毫克(2.7mg/kg)，直到抽血检测肝功能相关血清生化学数值ALT、AST及ALKP大幅下降后停止施予A1组合物；当后续肝功能相关血清生化学数值ALT、AST及ALKP大幅上升后继续施予A1组合物。
请参阅图3所示，肝功能异常的犬只持续施予A1组合物平均约20天，即可观察ALT 数值下降约73U/L；然而停用A1组合物后约20天再次抽血检验，发现ALT数值上升约92U/L，因此再次施予A1组合物；经过继续施予A1组合物后约30天可发现，ALT数值下降约163U/L。
请参阅图4所示，肝功能异常的犬只持续施予A1组合物平均约20天，即可观察AST数值下降约8U/L；然而停用A1组合物后约20天再次抽血检验，发现AST数值上升约12U/L，因此再次施予A1组合物；经过继续施予A1组合物后约30天可发现，AST数值下降约26U/L。
实施例3先使用SAMe后改施予犬只A1组合物
在临床上发现有多数犬只对于施予现有药物SAMe后，仍无法改善肝脏功能。因此针对施予SAMe后仍无法改善肝脏功能的3只犬只改施予A1组合物，并检测肝功能相关血清生化学数值ALT、AST及ALKP。
编号1号的犬只改施予A1组合物后4个月发现，ALT数值下降约45U/L、AST数值下降约50U/L皆能达标准范围；编号2号犬只改施予A1组合物后20天，ALT数值下降约50U/L；编号3号犬只改施予A1组合物后2天，ALT数值下降约35U/L。因此对于长期服用SAMe无效的犬只改施予A1组合物，将能有效降低犬只的肝功能相关数值。
实施例4老化小鼠施予A1组合物
选用12月龄小鼠(C57BL/6J)作为老化模式的实验动物，持续施予(1)4个月及(2)6个月每日每只小鼠200微克(μg)的剂量，然后测定与比较控制组与施予A1组合物组别的肝功能相关血清生化学数值ALT及AST。
(1)施予4个月：
表1、肝功能ALT及AST数值
Figure PCTCN2017073865-appb-000001
*代表与控制组相比P<0.05
由于当肝脏为急性发炎时ALT数值会大幅上升，而当肝脏为慢性发炎时AST数值则会持续升高，从上表1可知老化小鼠的肝脏可能已呈现老化且有慢性发炎的情形，因此在肝脏没有急性发炎的情况下ALT数值在正常范围内，而AST数值则高达302U/L。经过施 予4个月A1组合物后，发现在肝功能方面ALT数值没有改变仍维持在正常范围内，但AST则有显著的下降，从302U/L下降至162U/L共下降了46％，因此A1组合物有助于肝功能的修复。
(2)施予6个月：
请参阅图5所示，经过施予6个月A1组合物后，发现在肝功能方面AST有下降的趋势，因此A1组合物有助于肝功能的修复。
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，任何本领域技术人员，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 (9)

  1. 一种含有亚铁氨基酸螯合物的组合物的用途，其特征在于，其是用于制造治疗肝功能异常的医药品，所述医药品含有有效剂量的亚铁氨基酸螯合物的组合物以及其药学上可接受的载剂。
  2. 根据权利要求1所述的用途，其特征在于，所述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介于1：1至1：4之间。
  3. 根据权利要求1所述的用途，其特征在于，所述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，其特征在于，所述含有亚铁氨基酸螯合物的组合物的有效剂量介于每日每公斤0.5毫克至4mg/kg/day。
  5. 根据权利要求1至4中任一项所述的用途，其特征在于，所述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重量比例介于1：1.2至1：1.5之间。
  6. 根据权利要求5所述的用途，其特征在于，所述无机铁为硫酸亚铁、氯化亚铁、焦磷酸亚铁或其组合；所述氨基酸为甘氨酸。
  7. 根据权利要求5所述的用途，其特征在于，所述含有亚铁氨基酸螯合物的组合物中包括还原剂，所述还原剂为抗坏血酸、柠檬酸、乙酸、丙酸、丁酸、乳酸、羟琥珀酸、磺酸、丁二酸或其组合。
  8. 根据权利要求1所述的用途，其特征在于，所述医药品是经肠道的或非经肠道的剂型。
  9. 根据权利要求8所述的用途，其特征在于，所述经肠道的剂型为口服剂型，其口服剂型为溶液、乳剂、悬浮液、粉末、锭剂、丸剂、口含锭、片剂、口嚼胶或胶囊。
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