WO2020103941A1 - 一种计算人体对糖醇及功能糖耐受量的方法 - Google Patents

一种计算人体对糖醇及功能糖耐受量的方法

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Publication number
WO2020103941A1
WO2020103941A1 PCT/CN2019/120304 CN2019120304W WO2020103941A1 WO 2020103941 A1 WO2020103941 A1 WO 2020103941A1 CN 2019120304 W CN2019120304 W CN 2019120304W WO 2020103941 A1 WO2020103941 A1 WO 2020103941A1
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Prior art keywords
rats
dose
xylitol
experimental
human body
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PCT/CN2019/120304
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English (en)
French (fr)
Inventor
左齐乐
韩菲菲
朱炫
李勉
张文瑶
石丽华
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浙江华康药业股份有限公司
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Application filed by 浙江华康药业股份有限公司 filed Critical 浙江华康药业股份有限公司
Priority to EP19886727.7A priority Critical patent/EP3799072B1/en
Priority to JP2020558452A priority patent/JP6889812B2/ja
Priority to US17/286,006 priority patent/US20210379204A1/en
Publication of WO2020103941A1 publication Critical patent/WO2020103941A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/0004—Screening or testing of compounds for diagnosis of disorders, assessment of conditions, e.g. renal clearance, gastric emptying, testing for diabetes, allergy, rheuma, pancreas functions
    • G—PHYSICS
    • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
    • G16H—HEALTHCARE INFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR THE HANDLING OR PROCESSING OF MEDICAL OR HEALTHCARE DATA
    • G16H50/00—ICT specially adapted for medical diagnosis, medical simulation or medical data mining; ICT specially adapted for detecting, monitoring or modelling epidemics or pandemics
    • G16H50/30—ICT specially adapted for medical diagnosis, medical simulation or medical data mining; ICT specially adapted for detecting, monitoring or modelling epidemics or pandemics for calculating health indices; for individual health risk assessment

Definitions

  • the invention belongs to the technical field of sugar alcohol application, and particularly relates to a method for calculating the tolerance of the human body to sugar alcohol and functional sugar.
  • sugar alcohol for the human body
  • excessive intake also has certain adverse effects on the human body, such as excessive intake of sugar alcohol every day can cause diarrhea and other situations.
  • sugar alcohol is not decomposed by gastric enzymes and enters the intestine directly, because of its different molecular structure and sugar in the small intestine, the absorption time is slower than glucose, and a large amount of short-term intake will cause bowel sounds and diarrhea.
  • the technical problem to be solved by the present invention is to provide a method for calculating the tolerance of the human body to sugar alcohol and functional sugar, and to obtain a more accurate range of the tolerance of the human body to sugar alcohol and functional sugar through animal experiments.
  • the present invention is achieved in this way, and provides a method for calculating the tolerance of the human body to sugar alcohol and functional sugar, including the following steps:
  • 200g rats were selected as the experimental animal objects, and 200g rats were divided into six experimental groups and a control group, each with ten numbered rats; the rats in the six experimental groups were gavaged differently every day.
  • a dose of xylitol ten rats in each group were given the same amount of gavage; ten rats in a control group were given the same dose of sucrose or saline every day; all experimental rats provided enough drinking water every day And common feed; check whether there is fecal matter in the anus of each group of rats every night. The fecal matter indicates that the rat has diarrhea, and the number and number of rats with diarrhea are counted;
  • the second step lasts 14 days for the first step
  • the third step is to combine the diarrhea of rats on the last day (day 14) with the results of intestinal section slices and diamine oxidase content of each group of rats.
  • the dose group obtained the maximum tolerated dose N of xylitol in this group of rats;
  • the maximum tolerated dose of 200g rat to xylitol N is converted to the tolerated dose R of human xylitol according to the following formula for the conversion of drug doses of experimental animals and humans.
  • the dose of 70kg human body R the maximum tolerated dose of 200g rats N ⁇ K,
  • K is a conversion factor between a 70kg human and a 200g rat, and K is 56.0; the unit of the rat's maximum tolerated dose of xylitol N and the human body's tolerated dose of xylitol is g / d; or,
  • the xylitol in the first step is replaced with L-arabinose, and the above first to fourth steps are repeated to obtain a 70kg human tolerant dose of L-arabinose; or,
  • the xylitol in the first step is replaced with sorbitol, and the first step to the fourth step are repeated to obtain a tolerable dose of 70 kg of human body to sorbitol.
  • the method for calculating the tolerance of the human body to sugar alcohol and functional sugar of the present invention uses the most commonly used xylitol, L-arabinose, sorbitol as the experimental material, with 200g in animal experiments Wistar rats are the experimental objects, combined with the conversion of human and animal doses in animal experiments, a method for calculating the tolerance of the human body to sugar alcohols and functional sugars is constructed, and a more accurate human body to sugar alcohols and functional sugars is obtained Tolerance range.
  • 1 is a statistical diagram of the diarrhea of rats in each experimental group when carrying out the xylitol tolerance test with rats in the present invention
  • FIG. 2 is a comparison chart of diarrhea of rats in each experimental group on the last day when the xylitol tolerance test was conducted with rats in the present invention
  • 3 is a statistical diagram of diarrhea of rats in each experimental group when L-arabinose tolerance test is performed on rats in the present invention
  • FIG. 4 is a comparison diagram of diarrhea of rats in each experimental group on the last day when the rat is subjected to the L-arabinose tolerance test;
  • 5 is a statistical diagram of the diarrhea of rats in each experimental group when the sorbitol tolerance test is performed on rats in the present invention
  • FIG. 6 is a comparison chart of diarrhea of rats in each experimental group on the last day of the sorbitol tolerance test conducted on rats in the present invention.
  • 200g rats were selected as the experimental animal objects, and 200g rats were divided into six experimental groups and a control group, each with ten numbered rats; the rats in the six experimental groups were gavaged differently every day.
  • the doses of xylitol are dose 1 experimental group, dose 2 experimental group, dose 3 experimental group, dose 4 experimental group, dose 5 experimental group and dose 6 experimental group.
  • Ten rats in each group were given the same dose of gavage; ten rats in a control group were given the same dose of sucrose or saline every day; all experimental rats provided sufficient drinking water and common feed every day; every night Observe whether there is fecal matter in the anus of each group of rats. The presence of fecal matter indicates that the rat has diarrhea. The number and number of rats with diarrhea are counted.
  • the second step lasts 14 days in the first step.
  • the third step is to combine the diarrhea of rats on the last day (day 14) with the results of intestinal section slices and diamine oxidase content of each group of rats.
  • the dose group obtained the maximum tolerated dose N of xylitol in this group of rats.
  • the maximum tolerated dose of 200g rat to xylitol N is converted to the tolerated dose R of human xylitol according to the following formula for the conversion of drug doses of experimental animals and humans.
  • the dose of 70kg human body R the maximum tolerated dose of 200g rats N ⁇ K,
  • K is a conversion factor between a 70kg human and a 200g rat, and K is 56.0.
  • the unit of the rat's maximum tolerated dose of xylitol N and the human body's tolerated dose of xylitol is the same as g / d. or,
  • the xylitol in the first step is replaced with L-arabinose, and the first step to the fourth step are repeated to obtain a 70 kg human tolerant dose of L-arabinose. or,
  • the xylitol in the first step is replaced with sorbitol, and the first step to the fourth step are repeated to obtain a tolerable dose of 70 kg of human body to sorbitol.
  • the maximum tolerable amount of a certain sugar alcohol or functional sugar recorded in the existing data is used as the reference value.
  • the existing company declares the daily intake of xylitol Should not exceed 50g, set 50g as the reference value of xylitol, and use it as a basis to estimate the experimental range.
  • the conversion of the experimental animal and human drug dose conversion formula to obtain 200g rat The daily experimental dose of xylitol, and then group experiments based on the daily experimental dose and daily statistics of the experimental results. Continue the experiment for 14 days.
  • the maximum tolerated dose of 200g rat to xylitol N was obtained.
  • the maximum tolerated amount of xylitol R is obtained by converting the animal animal and human drug dose conversion formula.
  • set 50g as a reference value of xylitol, and according to the reference value, set the estimated values of the experimental range of the human body for xylitol 20g / d, 30g / d, 40g / d, 50g / d, There are six groups of 60g / d and 70g / d.
  • the daily experimental dose of xylitol for 200g rats is respectively 0.36g / d, 0.54g / d, 0.71g / d, 0.89g / d, Six groups of 1.07g / d and 1.25g / d were tested separately.
  • the human body ’s estimated L-arabinose is set to 70g / d, 80g / d, 90g / d, 100g / d, 110g / d, 120g / d as the experimental range, according to the experimental animals
  • the daily experimental dose of L-arabinose for 200g rats is respectively 1.25g / d, 1.43g / d, 1.61g / d, 1.79g / d, 1.96g / d, 2.14g / d total six groups, and experimented separately.
  • the human body's estimated sorbitol is set to 5g / d, 10g / d, 15g / d, 20g / d, 25g / d, 30g / d as the experimental range, according to the experimental animal and After conversion of the human drug dose conversion formula, the daily experimental dose of sorbitol for 200g rats is respectively 0.09g / d, 0.18g / d, 0.27g / d, 0.36g / d, 0.45g / d , 0.54g / d total six groups, and experimented separately.
  • the experimental dose of 200g rats in the control group was 0.5g / d sucrose solution.
  • Figures 1 to 6 are the statistics of diarrhea of sugar alcohol and functional sugar in 200g rats during the experiment period, because for each sugar alcohol or functional sugar, the experimental rat theoretically has a largest sugar alcohol or functional sugar Tolerance threshold, so the following three situations may occur during feeding:
  • case (1) and case (2) are considered to be within the tolerable range
  • case (3) is considered to be beyond the tolerable range
  • the maximum dose of case (2) is It is considered to be the maximum tolerated amount of the sugar alcohol or functional sugar.
  • the maximum glucose tolerance dose is the dose 3, that is, the intragastric dose in rats is 0.71g / d.
  • the maximum tolerated amount of xylitol of 40g obtained by the method of the present invention is more specific, more accurate, and more accurate than the currently known amount of xylitol ingested by the human body should not exceed 50g per day. in accordance with.
  • the maximum glucose tolerance dose is the dose 3, that is, the intragastric dose in rats is 1.61g / d.
  • the maximum glucose tolerance dose is the dose 4, that is, the intragastric dose in rats is 0.36g / d, which is determined by experimental animals and humans.

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Abstract

一种计算人体对糖醇及功能糖耐受量的方法，步骤如下：选取200g大鼠作为实验动物对象，将200g大鼠分成六个实验组和一个对照组，每组各十只已编号的大鼠；向六个实验组的大鼠每天灌胃不同剂量的木糖醇；向一个对照组的大鼠每天灌胃的蔗糖；所有实验大鼠每天提供足够的饮用水及普通饲料；每晚察看并统计腹泻大鼠的数量；持续14天；根据最后一天大鼠腹泻情况结合各组大鼠的肠段切片图及二胺氧化酶含量的结果得到该组大鼠对木糖醇的最大耐受剂量；再根据实验动物及人的药物剂量换算公式将大鼠的最大耐受剂量转换得出人体对该木糖醇的耐受剂量。所述方法通过动物实验的方式来得出较为准确的人体对糖醇及功能糖耐受量的范围。

Description

一种计算人体对糖醇及功能糖耐受量的方法 技术领域
本发明属于糖醇应用技术领域，特别涉及一种计算人体对糖醇及功能糖耐受量的方法。
 背景技术
糖醇对于人体的诸多好处不言而喻，但是过多的摄入对人体也存在一定的不良影响，比如每天过多的摄入糖醇会导致腹泻等情况。因为糖醇不被胃酶分解，直接进入肠部，在小肠中因其分子结构和糖不同，所以吸收时间比葡萄糖慢，短时间大量摄入会造成肠鸣腹泻等情况，同时一些企业也曾声明，每日摄取木糖醇的量不宜超过50g、麦芽糖醇不宜超过100g、L-阿拉伯糖的量不宜超过120g、山梨糖醇不宜超过50g等等，但缺乏相应的实验方法及实验数据来佐证，对于剂量的规定也太过宽泛，对于产品中糖醇的添加量不具有显著的指导意义。
 技术问题
本发明所要解决的技术问题在于，提供一种计算人体对糖醇及功能糖耐受量的方法，通过动物实验的方式来得出较为准确的人体对糖醇及功能糖耐受量的范围。
 技术解决方案
本发明是这样实现的，提供一种计算人体对糖醇及功能糖耐受量的方法，包括如下步骤：
第一步骤，选取200g大鼠作为实验动物对象，将200g大鼠分成六个实验组和一个对照组，每组各十只已编号的大鼠；向六个实验组的大鼠每天灌胃不同剂量的木糖醇，每组内的十只大鼠的灌胃剂量相同；向一个对照组的十只大鼠每天灌胃相同剂量的蔗糖或者生理盐水；所有实验大鼠每天提供足够的饮用水及普通饲料；每晚察看各组大鼠的肛门处是否存在排泄物，有排泄物表明该大鼠有腹泻，统计存在腹泻情况的大鼠数量和编号；
第二步骤，持续第一步骤14天；
第三步骤，以最后一天（第14天）的大鼠腹泻情况结合各组大鼠的肠段切片图及二胺氧化酶含量的结果，以该组内所有大鼠均不存在腹泻情况的最大剂量组得到该组大鼠对木糖醇的最大耐受剂量N；
第四步骤，再根据下面实验动物及人的药物剂量换算公式将200g大鼠对木糖醇的最大耐受剂量N转换得出人体对该木糖醇的耐受剂量R，实验动物及人的药物剂量换算公式：
70kg人体的剂量R=200g大鼠的最大耐受剂量N×K，
其中，K为70kg人与200g大鼠之间的换算系数，K为56.0；大鼠对木糖醇的最大耐受剂量N和人体对该木糖醇的耐受剂量R的单位同为g/d；或者，
第五步骤，将第一步骤中的木糖醇替换成L-阿拉伯糖，重复上述第一步骤至第四步骤，得到70kg人体对L-阿拉伯糖的耐受剂量；或者，
将第一步骤中的木糖醇替换成山梨糖醇，重复第一步骤至第四步骤，得到70kg人体对山梨糖醇的耐受剂量。
 有益效果
与现有技术相比，本发明的计算人体对糖醇及功能糖耐受量的方法，使用最常用的木糖醇、L-阿拉伯糖、山梨糖醇为实验材料，以动物实验中的200g的Wistar大鼠为实验对象，结合动物实验中人与动物的药量换算，构建了一种计算人体对糖醇及功能糖耐受量的方法，得出较为准确的人体对糖醇及功能糖耐受量的范围。
 附图说明
图1为本发明以大鼠进行木糖醇耐受量实验时各实验组大鼠的腹泻情况统计图；
图2为本发明以大鼠进行木糖醇耐受量实验时最后一天各实验组大鼠的腹泻情况比较图；
图3为本发明以大鼠进行L-阿拉伯糖耐受量实验时各实验组大鼠的腹泻情况统计图；
图4为本发明以大鼠进行L-阿拉伯糖耐受量实验时最后一天各实验组大鼠的腹泻情况比较图；
图5为本发明以大鼠进行山梨糖醇耐受量实验时各实验组大鼠的腹泻情况统计图；
图6为本发明以大鼠进行山梨糖醇耐受量实验时最后一天各实验组大鼠的腹泻情况比较图。
 本发明的最佳实施方式
为了使本发明所要解决的技术问题、技术方案及有益效果更加清楚明白，以下结合附图及实施例，对本发明进行进一步详细说明。应当理解，此处所描述的具体实施例仅仅用以解释本发明，并不用于限定本发明。
本发明计算人体对糖醇及功能糖耐受量的方法的较佳实施例，包括如下步骤：
第一步骤，选取200g大鼠作为实验动物对象，将200g大鼠分成六个实验组和一个对照组，每组各十只已编号的大鼠；向六个实验组的大鼠每天灌胃不同剂量的木糖醇，分别为剂量①实验组、剂量②实验组、剂量③实验组、剂量④实验组、剂量⑤实验组和剂量⑥实验组。每组内的十只大鼠的灌胃剂量相同；向一个对照组的十只大鼠每天灌胃相同剂量的蔗糖或者生理盐水；所有实验大鼠每天提供足够的饮用水及普通饲料；每晚察看各组大鼠的肛门处是否存在排泄物，有排泄物表明该大鼠有腹泻，统计存在腹泻情况的大鼠数量和编号。
第二步骤，持续第一步骤14天。
第三步骤，以最后一天（第14天）的大鼠腹泻情况结合各组大鼠的肠段切片图及二胺氧化酶含量的结果，以该组内所有大鼠均不存在腹泻情况的最大剂量组得到该组大鼠对木糖醇的最大耐受剂量N。
因为，大鼠的肠段切片及二胺氧化酶的结果证明通过观察得到的腹泻大鼠确实存在因超出正常耐受量而导致大鼠肠胃出现机体损伤，最后一天（第14天）仍旧存在腹泻情况的大鼠其肠段切片图及二胺氧化酶含量与对照组和不存在腹泻情况的大鼠之间具有显著性差异，因此，可以以最后一天该组内所有大鼠均不存在腹泻情况的最大剂量组作为最大耐受剂量。
第四步骤，再根据下面实验动物及人的药物剂量换算公式将200g大鼠对木糖醇的最大耐受剂量N转换得出人体对该木糖醇的耐受剂量R，实验动物及人的药物剂量换算公式：
70kg人体的剂量R=200g大鼠的最大耐受剂量N×K，
其中，K为70kg人与200g大鼠之间的换算系数，K为56.0。大鼠对木糖醇的最大耐受剂量N和人体对该木糖醇的耐受剂量R的单位同为g/d。或者，
第五步骤，将第一步骤中的木糖醇替换成L-阿拉伯糖，重复上述第一步骤至第四步骤，得到70kg人体对L-阿拉伯糖的耐受剂量。或者，
将第一步骤中的木糖醇替换成山梨糖醇，重复第一步骤至第四步骤，得到70kg人体对山梨糖醇的耐受剂量。
 本发明的实施方式
具体实施时，先根据现有资料上记载的人体对某种糖醇或功能糖的最大耐受量为基准值，以木糖醇为例，现有企业声明人体每日摄取木糖醇的量不宜超过50g，设定以50g作为木糖醇的基准值，并以此为依据进行上下浮动作为实验范围的预估值，通过实验动物及人的药物剂量换算公式换算后得出200g大鼠的木糖醇的每日实验剂量，再根据该每日实验剂量进行分组实验并每日统计实验结果。持续实验14天。综合考虑实验结果及验证结果，得到200g大鼠的对木糖醇的最大耐受剂量N。然后再根据该最大耐受剂量N通过实验动物及人的药物剂量换算公式换算后得出最适合的人体对木糖醇的最大耐受量R。
同理，可以得出人体对L-阿拉伯糖最大耐受量和对山梨糖醇最大耐受量。
具体地，设定以50g作为木糖醇的基准值，根据该基准值设定人体对木糖醇的实验范围的预估值分别20g/d、30g/d、40g/d、50g/d、60g/d、70g/d共六组。按照实验动物及人的药物剂量换算公式换算后得出200g大鼠的木糖醇的每日实验剂量对应地分别为0.36g/d、0.54g/d、0.71g/d、0.89g/d、1.07g/d、1.25g/d共六组，分别进行实验。
同理，人体对L-阿拉伯糖的预估值分别设定为70g/d、80g/d、90g/d、100g/d、110g/d、120g/d共六组作为实验范围，按照实验动物及人的药物剂量换算公式换算后得出200g大鼠的L-阿拉伯糖的每日实验剂量对应地分别为1.25g/d、1.43g/d、1.61g/d、1.79g/d、1.96g/d、2.14g/d共六组，分别进行实验。
同理，人体对山梨糖醇的预估值分别设定为5g/d、10g/d、15g/d、20g/d、25g/d、30g/d共六组作为实验范围，按照实验动物及人的药物剂量换算公式换算后得出200g大鼠的山梨糖醇的每日实验剂量对应地分别为0.09g/d、0.18g/d、0.27g/d、0.36g/d、0.45g/d、0.54g/d共六组，分别进行实验。
对照组的200g大鼠的实验剂量为0.5g/d蔗糖溶液。
附图1~附图6是实验期内200g大鼠对于糖醇及功能糖腹泻情况的统计，因为对于每种糖醇或功能糖，实验大鼠理论上都有一个最大的糖醇或功能糖耐受量阈值，所以在喂养过程中可能会出现下面三种情况：
（1）、实验期内未出现腹泻情况；
（2）、刚开始出现腹泻，后腹泻情况好转直至不出现腹泻（大鼠产生耐受适应）；
（3）、实验期内一直存在腹泻情况。
因此，最大耐受剂量则是按照上面来划分：情况（1）、情况（2）视作在耐受范围内，情况（3）则视作超出耐受范围，情况（2）的最大剂量则被认为是该糖醇或功能糖最大耐受量。
请参看附图1和图2所示，以大鼠进行木糖醇耐受量实验时，最大糖耐量的剂量为剂量③，即大鼠灌胃剂量为0.71g/d，由实验动物及人的药物剂量换算公式换算得到人体对于木糖醇的最大耐受量为0.71*56.0=40g/d。通过本发明的方法得出的人体对于木糖醇的最大耐受量40g比现有的已知的人体每日摄取木糖醇的量不宜超过50g来说就更具体、更准确，且更有依据。
请参看附图3和图4所示，以大鼠进行L-阿拉伯糖耐受量实验时，最大糖耐量的剂量为剂量③，即大鼠灌胃剂量为1.61g/d，由实验动物及人的药物剂量换算公式换算得到人体对于木糖醇的最大耐受量为1.61*56.0=90g/d。
请参看附图5和图6所示，以大鼠进行山梨糖醇耐受量实验时，最大糖耐量的剂量为剂量④，即大鼠灌胃剂量为0.36g/d，由实验动物及人的药物剂量换算公式换算得到人体对于木糖醇的最大耐受量为0.36*56.0=20g/d。
以上所述仅为本发明的较佳实施例而已，并不用以限制本发明，凡在本发明的精神和原则之内所作的任何修改、等同替换和改进等，均应包含在本发明的保护范围之内。
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  1. 一种计算人体对糖醇及功能糖耐受量的方法，其特征在于，包括如下步骤：
    第一步骤，选取200g大鼠作为实验动物对象，将200g大鼠分成六个实验组和一个对照组，每组各十只已编号的大鼠；向六个实验组的大鼠每天灌胃不同剂量的木糖醇，每组内的十只大鼠的灌胃剂量相同，向一个对照组的十只大鼠每天灌胃相同剂量的蔗糖或者生理盐水；所有实验大鼠每天提供足够的饮用水及普通饲料，每晚察看各组大鼠的肛门处是否存在排泄物，有排泄物表明该大鼠有腹泻，统计存在腹泻情况的大鼠数量和编号；
    第二步骤，持续第一步骤14天；
    第三步骤，以最后一天（第14天）的大鼠腹泻情况结合各组大鼠的肠段切片图及二胺氧化酶含量的结果，以该组内所有大鼠均不存在腹泻情况的最大剂量组得到该组大鼠对木糖醇的最大耐受剂量N；
    第四步骤，再根据下面实验动物及人的药物剂量换算公式将200g大鼠对木糖醇的最大耐受剂量N转换得出人体对该木糖醇的耐受剂量R，实验动物及人的药物剂量换算公式：
    70kg人体的剂量R=200g大鼠的最大耐受剂量N×K，
    其中，K为70kg人与200g大鼠之间的换算系数，K为56.0；大鼠对木糖醇的最大耐受剂量N和人体对该木糖醇的耐受剂量R的单位同为g/d；或者，
    第五步骤，将第一步骤中的木糖醇替换成L-阿拉伯糖，重复上述第一步骤至第四步骤，得到70kg人体对L-阿拉伯糖的耐受剂量；或者，
    将第一步骤中的木糖醇替换成山梨糖醇，重复第一步骤至第四步骤，得到70kg人体对山梨糖醇的耐受剂量。
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