WO2021232614A1 - 壳寡糖口服液及其在制备减肥药物中的应用 - Google Patents

壳寡糖口服液及其在制备减肥药物中的应用 Download PDF

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WO2021232614A1
WO2021232614A1 PCT/CN2020/112801 CN2020112801W WO2021232614A1 WO 2021232614 A1 WO2021232614 A1 WO 2021232614A1 CN 2020112801 W CN2020112801 W CN 2020112801W WO 2021232614 A1 WO2021232614 A1 WO 2021232614A1
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oral liquid
parts
oligochitosan
liquid according
oligosaccharide
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PCT/CN2020/112801
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English (en)
French (fr)
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苏政权
白研
曹华
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广东药科大学
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    • 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
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/702—Oligosaccharides, i.e. having three to five saccharide radicals attached to each other by glycosidic linkages
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/716—Glucans
    • A61K31/722—Chitin, chitosan
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • 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
    • A61P3/04—Anorexiants; Antiobesity agents

Definitions

  • the invention relates to the technical field of oral liquids, in particular to a chitosan oligosaccharide oral liquid and its application in the preparation of anti-obesity drugs.
  • Obesity refers to a certain degree of obvious overweight and thick fat layer, which is a state caused by excessive accumulation of body fat, especially triglycerides. Excessive food intake or changes in the body's metabolism lead to excessive accumulation of fat in the body, resulting in excessive weight gain and causing pathological, physiological changes or latency in the body. In the past 50 years, the prevalence of obesity has been on the rise worldwide, reaching the level of a pandemic.
  • Obesity is a major health challenge because it greatly increases the risk of type 2 diabetes, fatty liver, high blood pressure, myocardial infarction, stroke, dementia, osteoarthritis, obstructive sleep apnea and some cancers, thus leading to quality of life and Life expectancy is declining, thus becoming a public health issue of universal concern worldwide.
  • Chitooligosaccharide is the only positively charged cationic basic amino oligosaccharide in nature. It is animal cellulose. Its molecular structure is: Chitooligosaccharides are small molecular oligosaccharides with amino groups that are degraded from chitosan derived from shrimp and crab shells, and are sugar chains with a degree of polymerization of 2-20. Because the molecular structure contains a large number of active chemical groups such as amino, acetamido and hydroxyl, COS has good plasticity and many physiological activities. COS has various beneficial biological activities, such as anti-bacterial, anti-inflammatory, and anti-oxidant.
  • Chitooligosaccharides are degraded from chitin. It has good water solubility, low viscosity, small molecular weight, easy absorption and utilization and degradability. However, in the production of chitooligosaccharide preparations, delamination, turbidity, and precipitation are prone to occur, which makes the shell The stability of oligosaccharide preparations is not good. Therefore, it is of great significance to develop a new chitosan oligosaccharide dosage form to solve the technical problem of unstable preparations in order to give full play to the effect of weight loss.
  • the first object of the present invention is to provide a chitosan oligosaccharide oral liquid, which has fast absorption, quick effect, safe and effective, stable preparation, stable quality and curative effect, suitable for industrial production, and strict preparation process. .
  • the present invention provides the following technical solutions:
  • a chito-oligosaccharide oral liquid which comprises the following raw materials in parts by weight: 30 to 45 parts of chitosan oligosaccharides, 1 to 2 parts of preservatives, 0.5 to 1.5 parts of buffers, 1 to 3 parts of correctives, and 5-8 parts of stabilizer.
  • the stabilizer is at least one of L-fucose and sodium carboxymethyl cellulose.
  • the stabilizer is composed of L-fucose and sodium carboxymethylcellulose, and the mass ratio of the L-fucose and sodium carboxymethylcellulose is 4:1.
  • the preservative is one or two of sodium benzoate and potassium sorbate.
  • the buffer is one or two of citric acid-sodium citrate and glacial acetic acid.
  • the buffer solution adjusts the pH of the oral liquid to 4.5-8.5.
  • the flavoring agent is one or two of aspartame and xylitol.
  • the second object of the present invention is to provide a preparation method of chitosan oligosaccharide oral liquid, which includes the following steps: take an appropriate amount of purified water, add chitosan, preservatives and stabilizers according to the prescription amount, and shake in a constant temperature air bath Until the dissolution and inclusion is complete, add the corrective agent, and finally add the buffer to adjust the pH to 4.5-8.5.
  • the pH value is adjusted to 6.5.
  • the third object of the present invention is the application of an oligochitosan oral liquid in the preparation of weight-loss drugs.
  • Sodium carboxymethyl cellulose is a carboxymethyl derivative of cellulose. It has hygroscopicity, emulsification stability, and is easy to disperse in water to form a transparent colloidal solution. It is an excellent emulsifier.
  • the inventors tried to add sodium carboxymethyl cellulose to the oligochitosan oral liquid and found In a short period of time, the stability of the chitosan oligosaccharide oral liquid is greatly enhanced, and the oral liquid does not undergo delamination, turbidity and precipitation.
  • the chitosan oligosaccharide oral liquid has the phenomenon of raw materials hanging on the wall, which may be due to carboxylic acid.
  • the viscosity of the colloidal solution formed by sodium methylcellulose is too large, causing the oligochitosan to hang on the wall, which leads to a decrease in the quality of the oligochitosan.
  • the present invention found that the compound of L-fucose and sodium carboxymethyl cellulose can make the chito-oligosaccharide oral liquid not appear wall hanging phenomenon, and it can also enhance its stability.
  • the inventors have carried out The accelerated test showed that the chitosan oligosaccharide oral liquid of the present invention has no obvious changes in the aspects of shape, identification, pH value, relative density, difference in filling volume, content determination, microbial limit inspection and the like.
  • the chitosan oligosaccharide with a number average molecular weight of not greater than 3000 is named COSM
  • the chitosan oligosaccharide with a number average molecular weight of not greater than 1000 is COST to show the distinction.
  • the oral liquid prepared with COSM is COSM oral liquid
  • COST The prepared oral liquid is COST oral liquid.
  • the present invention has the following beneficial effects:
  • the chitosan oligosaccharide oral liquid provided by the present invention has fast absorption, rapid effect, safety and effectiveness, stable preparation, stable quality and curative effect, and is suitable for industrialized production.
  • the chitooligosaccharide oral liquid provided by the present invention when applied to weight-loss drugs, can significantly reduce the weight gain of C57BL/6 mice induced by high-fat diet-induced obesity, and significantly reduce the high-fat content caused by high-fat diet And fat/body ratio;
  • the chitosan oligosaccharide oral liquid provided by the present invention greatly improves the compliance of patients with medication and increases the number of users of the medication.
  • Chitooligosaccharides 30g sodium benzoate 1g Potassium Sorbate 0 L-fucose 4g Sodium carboxymethyl cellulose 1g Citric Acid-Sodium Citrate 0.5g glacial acetic acid 0 Aspartame 1g Xylitol 0
  • Preparation method including the following steps: take an appropriate amount of purified water, add chitosan, preservatives, buffers and stabilizers according to the prescription, shake in a constant temperature air bath until the dissolution and inclusion are complete, then add the correctives, and finally adjust The pH is 4.5.
  • Preparation method including the following steps: take an appropriate amount of purified water, add chitosan, preservatives, buffers and stabilizers according to the prescription, shake in a constant temperature air bath until the dissolution and inclusion are complete, then add the correctives, and finally adjust The pH is 5.5, that's it.
  • Preparation method including the following steps: take an appropriate amount of purified water, add chitosan, preservatives, buffers and stabilizers according to the prescription, shake in a constant temperature air bath until the dissolution and inclusion are complete, then add the correctives, and finally adjust The pH is 6.5, that's it.
  • Preparation method including the following steps: take an appropriate amount of purified water, add chitosan, preservatives, buffers and stabilizers according to the prescription, shake in a constant temperature air bath until the dissolution and inclusion are complete, then add the correctives, and finally adjust pH to 8.5, that's it.
  • Chitooligosaccharides 38g sodium benzoate 0.5g Potassium Sorbate 1g L-fucose 4.8g Sodium carboxymethyl cellulose 1.2g Citric Acid-Sodium Citrate 1.5g glacial acetic acid 0 Aspartame 1g Xylitol 0.5g
  • Preparation method including the following steps: take an appropriate amount of purified water, add chitosan, preservatives, buffers and stabilizers according to the prescription, shake in a constant temperature air bath until the dissolution and inclusion are complete, then add the correctives, and finally adjust The pH is 6.5, that's it.
  • Comparative Example 1 differs only in that the formula does not contain sodium carboxymethyl cellulose and L-fucose, and other parameters are the same as Example 5.
  • Comparative Example 2 only differs in that the formula does not contain L-fucose, and other parameters are the same as Example 5.
  • Comparative Example 3 only differs in that the formula does not contain sodium carboxymethyl cellulose, and other parameters are the same as Example 5.
  • Test example one stability test
  • Example 1 No precipitation, no wall hanging No precipitation, no wall hanging No precipitation, no wall hanging No precipitation, no wall hanging No precipitation, no wall hanging Example 2 No precipitation, no wall hanging No precipitation, no wall hanging No precipitation, no wall hanging Example 3 No precipitation, no wall hanging No precipitation, no wall hanging No precipitation, no wall hanging No precipitation, no wall hanging Example 4 No precipitation, no wall hanging No precipitation, no wall hanging No precipitation, no wall hanging No precipitation, no wall hanging Example 5 No precipitation, no wall hanging No precipitation, no wall hanging No precipitation, no wall hanging No precipitation, no wall hanging No precipitation, no wall hanging Comparative example 1 There is precipitation / / - Comparative example 2 No precipitation, no wall hanging No precipitation, hanging on the wall No precipitation, hanging on the wall No precipitation, hanging on the wall Comparative example 3 There is precipitation / / /
  • the chito-oligosaccharide oral liquids prepared in Examples 1 to 5 still did not appear to hang on the wall after 180 days, and the chito-oligosaccharide oral liquids did not exhibit delamination, turbidity, and precipitation.
  • the preparations prepared in Comparative Example 1 The chito-oligosaccharide oral liquid showed stratification, turbidity and precipitation on day 0, and the precipitation was more serious; the chito-oligosaccharide oral liquid prepared in Comparative Example 2 (without L-fucose) appeared to hang after one month.
  • the phenomenon of stratification, turbidity and precipitation is not easy to occur; the chitosan oral liquid prepared in Comparative Example 3 (without the addition of sodium carboxymethyl cellulose) has stratification, turbidity and precipitation on the 0th day The phenomenon of stratification, turbidity and precipitation is serious, indicating that the combination of L-fucose and sodium carboxymethyl cellulose can improve the technique of adding sodium carboxymethyl cellulose to the chitosan oral liquid.
  • the chito-oligosaccharide oral liquid added with sodium carboxymethyl cellulose does not appear delamination, turbidity and precipitation, which enhances the stability of the chito-oligosaccharide oral liquid.
  • Solution preparation 80% phenol stock solution: use an electronic balance to weigh 8.00g of phenol, heat it to melt, and dilute it with double distilled water in a 10mL volumetric flask to obtain an 80% Phenol solution. Store in the dark at 4°C for later use.
  • 5% phenol solution Use a pipette to accurately draw 625ul of 80% phenol stock solution, and dilute it with double distilled water in a 10ml volumetric flask to obtain a 5% phenol stock solution, which is prepared for immediate use.
  • 10mg/ml GLC (glucosamine hydrochloride) standard solution accurately weigh 0.1049g of glucosamine hydrochloride with a 1/10,000 electronic balance, dissolve it in a 10ml volumetric flask with double distilled water, and obtain a 10mg/ml GLC standard solution at constant volume.
  • COST oral liquid and COSM oral liquid operating liquid directly use the oral liquid prepared above.
  • the average content of COST oral solution sample solution is 93.25%, RSD is 1.59%, the average content of COSM oral solution sample solution is 96.41%, RSD is 1.20%, indicating the precision of the method Degree is good.
  • the RSD should not be greater than 2.0%.
  • the average content of COST oral solution sample solution is 93.40%, RSD is 1.11%, the average content of COSM oral solution sample solution is 96.36%, RSD is 1.70%, indicating that the method is relatively stable .
  • the average content of COST oral solution sample solution is 93.46%, RSD is 1.76%, the average content of COSM oral solution sample solution is 96.28%, RSD is 1.65%, indicating the repeatability of the method good.
  • the average recovery rate of COST oral solution sample solution is 100.01%
  • the RSD is 1.15%
  • the average recovery rate of COSM oral solution sample solution is 100.65%
  • the RSD is 1.66%
  • the light source uses a 20W fluorescent lamp and a scattered shed device. Use a non-reflective black object for the background and a non-reflective white object for the bottom. Take the sterilized oral liquid and place it under the inspection device, at a distance of 20 cm from the light source, first compare it with the black background and then with the white background. When inspected with naked eyes, there must be no visible insoluble matter or turbidity.
  • the total number of aerobic bacteria of COST oral liquid and COSM oral liquid is less than 1 (cfu/ml), which is in line with the index; the total number of molds and yeasts is less than 1 (cfu/ml), which is in line with the index; Escherichia coli is not detected, which is in line with the index; Salmonella was not detected, which met the index; the bile salt-tolerant gram-negative bacteria ⁇ 10 (cfu/ml) met the index.
  • the phenol-sulfuric acid method accurately draw 6 parts of the sample solution, and determine the content in parallel.
  • the RSD should not be greater than 2.0%.
  • YB-6LF biological tissue paraffin embedding machine YGQ-3126F biological tissue slicer (Xiaogan Yaguang Medical Electronic Technology Co., Ltd.); Spectra Max i3x multifunctional microplate reader (Meigu Molecular Instruments (Shanghai) Co., Ltd.); Total Cholesterol (T-CHO) Kit, Triglyceride (TG) Kit, High Density Lipoprotein Cholesterol (HDL-C) Kit, Low Density Lipoprotein Cholesterol (LDL-C) Kit, Alanine Transaminase (ALT) ) Kit, aspartate aminotransferase (AST) kit, free fatty acid (FFA) kit, glucose (GLU) kit (Nanjing Jiancheng Institute of Bioengineering); BCA protein concentration determination kit (Biyuntian Institute of Biotechnology); Bio-Radbiorad electrophoresis instrument (Shandong Brocade Scientific Instrument Co., Ltd.).
  • C57BL/6 mice were adaptively fed with ordinary feed for 2 weeks, and they were randomly divided into two groups Among them, C57BL/6 mice were fed ordinary diet as a normal diet group, and the remaining C57BL/6 mice were fed D12492 high fat diet (HFD, High fat diet). After feeding for 2 weeks, the D12492 high-fat diet mice were sorted according to the order of weight gain, and the mice with less weight gain and obesity resistance were eliminated. The remaining C57BL/6 mice were fed with high-fat diet for 6 weeks. At the same time, the normal diet group was fed with normal diet. The weight of mice fed with high-fat diet exceeds the body weight of mice in the normal diet group by 20%, and it can be judged that the diet-induced obesity model has been successfully established.
  • HFD High fat diet
  • mice with normal diet are the blank group (Control).
  • 70 obese mice with successful modeling are randomly selected and divided into seven groups (10 mice in each group): high-fat model group (Model), orlistat positive The control group (Orlistat), the Examples 1 to 5 groups, a total of 8 groups.
  • Model high-fat model group
  • Orlistat The control group
  • Examples 1 to 5 groups a total of 8 groups.
  • each administration group was given different doses of test samples, and the blank group and model group were given the same amount of normal saline for intragastric administration.
  • Each C57BL/6 mouse was given intragastrically according to Examples 1 to 5 (1700 mg/Kg) and Orlistat's main drug dose (35 mg/Kg), and each C57BL/6 mouse was given 0.1 ml per 10 g of body weight. The amount is given to the stomach. Weigh the weight of each group of C57BL/6 regularly every week; observe the mental state, physical signs and physiological status of C57BL/6 regularly every day for abnormalities. The results are shown in Table 2.
  • the adipocytes in the Control group were of normal structure, closely arranged, uniform in size, larger in number, and smaller in cell size, while the white adipose tissue cells in the Model group were uneven in size and larger in size.
  • the adipocytes of the Examples 1 to 5 group were significantly reduced, the size was uniform, the volume was smaller, and the pathological changes were better improved, indicating that Examples 1 to 5 can inhibit the induction of high-fat diet.
  • the fat cell hypertrophy can improve the growth and expansion of fat cells, reduce fat accumulation, and improve obesity and other symptoms.
  • the liver tissue was sectioned by HE staining and observed.
  • the control group mice had very little liver lipid accumulation, and the Model group mice had more liver lipid droplets, and the lipid accumulation was serious.
  • the liver lipid droplet content and lipid droplet size of the mice in groups 1 to 5 were significantly reduced, and lipid accumulation was improved.
  • the small intestine tissue was sectioned by HE staining and observed.
  • the small intestinal villi of the mice in the Control group are highly regular, while the villi of the mice in the Model group are disordered, the intestinal barrier is severely damaged, and the intestinal permeability increases.
  • the intestinal villi of the mice in groups 1 to 5 were significantly neater, and the damage to the intestines was improved.

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Abstract

一种壳寡糖口服液及其在制备减肥药物中的应用，所述口服液包括以下重量份数计的原料：壳寡糖30～45份、防腐剂1～2份、缓冲剂0.5～1.5份、矫味剂1～3份和稳定剂5～8份。所述的壳寡糖口服液吸收快，奏效迅速，安全有效，制剂稳定，质量和疗效稳定，适用于工业化生产。

Description

壳寡糖口服液及其在制备减肥药物中的应用 技术领域
本发明涉及口服液技术领域，尤其是涉及一种壳寡糖口服液及其在制备减肥药物中的应用。
背景技术
肥胖是指一定程度的明显超重与脂肪层过厚，是体内脂肪，尤其是甘油三酯积聚过多而导致的一种状态。由于食物摄入过多或机体代谢的改变而导致体内脂肪积聚过多造成体重过度增长并引起人体病理、生理改变或潜伏。在过去的50年里，肥胖的患病率在世界范围内呈上升趋势，达到大流行程度。肥胖是一个重大的健康挑战，因为它大大增加了2型糖尿病、脂肪肝、高血压、心肌梗塞、中风、痴呆、骨关节炎、阻塞性睡眠呼吸暂停和一些癌症的风险，因此导致生活质量和预期寿命下降，从而成为全球普遍关注的公共健康问题。
由于肥胖可以导致严重的健康问题，因此肥胖症的防治也就成为医药学界进行研究的重要课题，虽然医学界普遍认为改善生活方式、合理饮食，加强运动是减肥的主要措施，但也认为对于过度肥胖患者经合理饮食、运动治疗未能达到满意控制者，可首选药物治疗。
自19世纪末开始使用药物治疗肥胖至今，已经有较多的减肥药物陆续上市，但普遍存在着疗效不稳定，功效成份不明，难以在国际市场销售等问题。临床使用的各种化学减肥药，虽然有一定的疗效，但大多数有一定的副作用。
壳寡糖(COS)是自然界中唯一带正电荷阳离子碱性氨基低聚糖，是动物性纤维素,其分子结构式为：
Figure PCTCN2020112801-appb-000001
壳寡糖是由来源于虾蟹壳的壳聚糖降解成的带有氨基的小分子寡糖，是聚合度2-20的糖链。由于分子机构上含有数量极多的氨基、乙酰氨基以及羟基等活性化学基团，COS具备良好的可塑性和众多生理活性，COS具备各种有益的生物活性，如抗细菌，抗炎症，抗氧化，降脂，抗糖尿病，加速体内钙和铁的吸收、降低血糖以及促进关节组织的修复等功能，壳寡糖已成为国际上新兴的一种功能性低聚糖。
壳寡糖由甲壳素降解而来，其水溶性好，低粘度，分子量小，容易吸收利用及可降解， 但是在壳寡糖制剂生产中，容易出现分层、浑浊、沉淀等现象，使得壳寡糖制剂稳定性不佳，因此，研制出一种新的壳寡糖剂型，解决制剂不稳定的技术问题，以充分发挥减肥功效，具有重大意义。
发明内容
针对现有技术存在的不足，本发明的第一目的在于提供一种壳寡糖口服液，吸收快，奏效迅速，安全有效，制剂稳定，质量和疗效稳定，适用于工业化生产，且制备工艺严格。
为实现上述目的，本发明提供了如下技术方案：
一种壳寡糖口服液，所述口服液包括以下重量份数的原料：壳寡糖30～45份、防腐剂1～2份、缓冲剂0.5～1.5份、矫味剂1～3份和稳定剂5～8份。
优选地，所述稳定剂为L-岩藻糖和羧甲基纤维素钠中的至少一种。
更优选地，所述稳定剂由L-岩藻糖和羧甲基纤维素钠组成，所述L-岩藻糖和羧甲基纤维素钠的质量比为4:1。
优选地，所述防腐剂为苯甲酸钠和山梨酸钾中的一种或两种。
优选地，所述缓冲液为柠檬酸-柠檬酸钠、冰醋酸中的一种或两种。
优选地，所述缓冲液调节口服液的pH值为4.5～8.5。
优选地，所述矫味剂为阿司帕坦和木糖醇中的一种或两种。
本发明的第二目的是提供了一种壳寡糖口服液的制备方法，包括以下步骤：取纯化水适量，按照处方量加入壳寡糖、防腐剂和稳定剂，在恒温空气浴中振摇至溶解包合完全，再加入矫味剂，最后加入缓冲剂调节pH至4.5～8.5，即可。
优选地，所述pH值调节至6.5。
本发明的第三目的是一种壳寡糖口服液在制备减肥药物中的应用。
羧甲基纤维素钠是纤维素的羧甲基化衍生物，具有吸湿性，乳化稳定性，易于分散在水中形成透明的胶体溶液，是一种优秀的乳化剂。在壳寡糖制剂生产过程中，由于口服液在长时间放置过程中容易出现分层、浑浊、沉淀等现象，本发明人尝试将羧甲基纤维素钠添加至壳寡糖口服液中，发现短时间内壳寡糖口服液的稳定性大大增强，口服液不发生分层、浑浊和沉淀等现象，但是经过长时间放置观察，壳寡糖口服液出现了原料挂壁现象，可能是因为羧甲基纤维素钠形成胶体溶液的粘度太大，使得壳寡糖出现了挂壁现象，导致壳寡糖的质量下降。
本发明经过大量的研究探索，发现将L-岩藻糖和羧甲基纤维素钠复配，可使得壳寡糖口服液不出现挂壁现象，其还能增强其稳定性，本发明人进行了加速试验表明，本发明壳寡糖 口服液在形状、鉴别、pH值、相对密度、装量差异、含量测定、微生物限度检查等方面都无明显变化。
在本发明中，将数均分子量不大于3000的壳寡糖命名为COSM，将数均分子量不大于1000的壳寡糖为COST，以示区分，用COSM制备的口服液为COSM口服液，COST制备的口服液为COST口服液。
与现有技术相比，本发明具有以下有益效果：
1.本发明提供的壳寡糖口服液，吸收快，奏效迅速，安全有效，制剂稳定，质量和疗效稳定，适用于工业化生产。
2.本发明提供的壳寡糖口服液，将其应用于减肥药物当中，可以显著降低高脂饲料饮食性诱导肥胖C57BL/6小鼠体重增重，显著降低了高脂饮食导致的高脂肪含量和脂/体比；
3.本发明提供的壳寡糖口服液大大提高了患者用药的顺应性，增加了该药物的使用人群。
具体实施方式
以下结合实施例，对本发明作进一步详细说明。
实施例1、本发明壳寡糖口服液
配方：
壳寡糖 30g
苯甲酸钠 1g
山梨酸钾 0
L-岩藻糖 4g
羧甲基纤维素钠 1g
柠檬酸-柠檬酸钠 0.5g
冰醋酸 0
阿司帕坦 1g
木糖醇 0
制备方法：包括以下步骤：取纯化水适量，按照处方量加入壳寡糖、防腐剂、缓冲剂和稳定剂，在恒温空气浴中振摇至溶解包合完全，再加入矫味剂，最后调节pH至4.5，即可。
实施例2、本发明壳寡糖口服液
配方：
壳寡糖 35g
苯甲酸钠 0.5g
山梨酸钾 0.5g
L-岩藻糖 4.8g
羧甲基纤维素钠 1.2g
柠檬酸-柠檬酸钠 1g
冰醋酸 0
阿司帕坦 0.5g
木糖醇 0.5g
制备方法：包括以下步骤：取纯化水适量，按照处方量加入壳寡糖、防腐剂、缓冲剂和稳定剂，在恒温空气浴中振摇至溶解包合完全，再加入矫味剂，最后调节pH至5.5，即可。
实施例3、本发明壳寡糖口服液
配方：
壳寡糖 40g
苯甲酸钠 1g
山梨酸钾 1g
L-岩藻糖 5.6g
羧甲基纤维素钠 1.4g
柠檬酸-柠檬酸钠 1g
冰醋酸 0
阿司帕坦 1g
木糖醇 1g
制备方法：包括以下步骤：取纯化水适量，按照处方量加入壳寡糖、防腐剂、缓冲剂和稳定剂，在恒温空气浴中振摇至溶解包合完全，再加入矫味剂，最后调节pH至6.5，即可。
实施例4、本发明壳寡糖口服液
配方：
壳寡糖 45g
苯甲酸钠 1g
山梨酸钾 1g
L-岩藻糖 6.4g
羧甲基纤维素钠 1.6g
柠檬酸-柠檬酸钠 1.5g
冰醋酸 0
阿司帕坦 2g
木糖醇 1g
制备方法：包括以下步骤：取纯化水适量，按照处方量加入壳寡糖、防腐剂、缓冲剂和稳定剂，在恒温空气浴中振摇至溶解包合完全，再加入矫味剂，最后调节pH至8.5，即可。
实施例5、本发明壳寡糖口服液
配方：
壳寡糖 38g
苯甲酸钠 0.5g
山梨酸钾 1g
L-岩藻糖 4.8g
羧甲基纤维素钠 1.2g
柠檬酸-柠檬酸钠 1.5g
冰醋酸 0
阿司帕坦 1g
木糖醇 0.5g
制备方法：包括以下步骤：取纯化水适量，按照处方量加入壳寡糖、防腐剂、缓冲剂和稳定剂，在恒温空气浴中振摇至溶解包合完全，再加入矫味剂，最后调节pH至6.5，即可。
对比例1、本发明壳寡糖口服液
对比例1与实施例5相比，区别仅在于，配方中不含有羧甲基纤维素钠和L-岩藻糖，其他参数与实施例5相同。
对比例2、本发明壳寡糖口服液
对比例2与实施例5相比，区别仅在于，配方中不含有L-岩藻糖，其他参数与实施例5 相同。
对比例3、本发明壳寡糖口服液
对比例3与实施例5相比，区别仅在于，配方中不含有羧甲基纤维素钠，其他参数与实施例5相同。
试验例一、稳定性试验
将实施例1～5及对比例1～3制备的壳寡糖口服液，置于常温(40±2℃)，常湿(75±5％)条件下放置3个月，在第0天、第30天、第60天和第180天，观察口服液是否出现挂壁现象和沉淀现象。结果见表1：
表1
组别 第0天 第30天 第60天 第180天
实施例1 无沉淀、无挂壁 无沉淀、无挂壁 无沉淀、无挂壁 无沉淀、无挂壁
实施例2 无沉淀、无挂壁 无沉淀、无挂壁 无沉淀、无挂壁 无沉淀、无挂壁
实施例3 无沉淀、无挂壁 无沉淀、无挂壁 无沉淀、无挂壁 无沉淀、无挂壁
实施例4 无沉淀、无挂壁 无沉淀、无挂壁 无沉淀、无挂壁 无沉淀、无挂壁
实施例5 无沉淀、无挂壁 无沉淀、无挂壁 无沉淀、无挂壁 无沉淀、无挂壁
对比例1 有沉淀 / / -
对比例2 无沉淀、无挂壁 无沉淀、有挂壁 无沉淀、有挂壁 无沉淀、有挂壁
对比例3 有沉淀 / / /
根据表1可知，实施例1～5制备的壳寡糖口服液，180天后仍然不出现挂壁现象，同时壳寡糖口服液也没有出现分层、浑浊和沉淀等现象，对比例1制备的壳寡糖口服液在第0天便出现出现分层、浑浊和沉淀等现象，沉淀较为严重；对比例2(未添加L-岩藻糖)制备的壳寡糖口服液在一个月后出现挂壁等现象，但是不容易出现分层、浑浊和沉淀等现象；对比例3(未添加羧甲基纤维素钠)制备的壳寡糖口服液在第0天便出现出现分层、浑浊和沉淀等现象，分层、浑浊和沉淀现象严重，说明L-岩藻糖和羧甲基纤维素钠的复配，可以改善加入羧甲基纤维素钠至壳寡糖口服液出现挂壁现象的技术问题，且加入羧甲基纤维素钠的壳寡糖口服液不出现分层、浑浊和沉淀等现象，增强了壳寡糖口服液的稳定性。
试验例二、COST口服液和COSM口服液的含量测定
根据《中国药典》(2015)测定多糖的方法，选用苯酚-硫酸法测定COST口服液和COSM 口服液中的主药含量。
1.1吸收曲线和氨基葡萄糖绘制：溶液制备：80％苯酚储备液：使用电子天平称取8.00g苯酚，加热熔融，用双蒸水定容于10mL的容量瓶中，即得80％的Phenol溶液，避光保存于4℃中，备用。
5％苯酚溶液：用移液器精密吸取80％苯酚储备液625ul，用双蒸水定容于10ml的容量瓶中，即得到5％苯酚储备液，现配现用。
10mg/mlGLC(盐酸氨基葡萄糖)标准溶液：用万分之一电子天平精密称取0.1049g盐酸氨基葡萄糖，用双蒸水溶解到10ml容量瓶中，定容即得到10mg/mlGLC标准溶液。
COST口服液和COSM口服液操作液：直接使用上述制备的口服液即可。
精密吸取0.4mL的10mg/mL的GLC标准液定容于10mL容量瓶中，得A溶液；取10mL试管，分别依次加入5％的苯酚溶液1.0mL、浓硫酸5.0mL，标准管加入A溶液2mL，空白管加入双蒸水2mL，以空白管为参比，扫描标准管溶液的吸收曲线，测得最大吸收波长，以空白试剂为参比时，COS在浓硫酸作用下脱水形成糠醛，接而与苯酚发生缩合反应生成的化合物的最大吸收峰在490nm波长处，因此，在后续的实验中选择测定波长为490nm。
精密吸取0mL，0.1mL，0.2mL，0.3mL，0.4mL，0.5mL，0.6mL，0.7mL，0.8mL的10mg/mL的GLC标准液，用双蒸水分别定容于10mL容量瓶中，即得一系列梯度的标准液；接而从中精密吸取2.0mL于10mL的试管中，分别依次加入5％的苯酚溶液1.0mL，浓硫酸5.0mL，摇匀，沸水浴30-45min，静置冷却；待反应完全后与490nm波长下测定其吸光度，并绘制标准曲线。
1.2精密度试验
精密吸取适量同一份样品溶液，连续测定含量6次，计算RSD值，其RSD应不大于2.0％。
根据表2-1和表2-2，COST口服液样品溶液的平均含量为93.25％，RSD为1.59％，COSM口服液样品溶液的平均含量为96.41％，RSD为1.20％，说明该方法的精密度好。
表2-1 COST口服液精密度试验结果
Figure PCTCN2020112801-appb-000002
表2-2 COSM口服液精密度试验结果
Figure PCTCN2020112801-appb-000003
Figure PCTCN2020112801-appb-000004
2.3稳定性试验
精密吸取同一份样品溶液，分别于0,、2、4、6、8、10、12h小时内测定含量，计算RSD值，其RSD应不大于2.0％。
根据表2-3和表2-4，COST口服液样品溶液的平均含量为93.40％，RSD为1.11％，COSM口服液样品溶液的平均含量为96.36％，RSD为1.70％，说明该方法比较稳定。
表2-3 COST口服液稳定性试验结果
Figure PCTCN2020112801-appb-000005
表2-4 COSM口服液稳定性试验结果
Figure PCTCN2020112801-appb-000006
2.4重复性试验
精密吸取同一批样品溶液6份，平行测定含量，其RSD应不大于2.0％。
根据表2-5和表2-6，COST口服液样品溶液的平均含量为93.46％，RSD为1.76％，COSM口服液样品溶液的平均含量为96.28％，RSD为1.65％，说明该方法重复性好。
表2-5 COST口服液重复性试验结果
Figure PCTCN2020112801-appb-000007
表2-6 COSM口服液重复性试验结果
Figure PCTCN2020112801-appb-000008
Figure PCTCN2020112801-appb-000009
2.5加标回收率试验
精密吸取已知含量的COS样品溶液6份，加入定量的标准物质，测定总含量后计算加标回收率，其RSD应不大于2.0％。
根据表2-7和表2-8，COST口服液样品溶液加标回收率的平均值为100.01％，RSD为1.15％，COSM口服液样品溶液加标回收率的平均值为100.65％，RSD为1.66％，说明该方法的正确度高。
表2-7 COST口服液加标回收率试验结果
Figure PCTCN2020112801-appb-000010
表2-8 COSM口服液加标回收率试验结果
Figure PCTCN2020112801-appb-000011
2.6 COST口服液和COSM口服液的质量检查
2.6.1明度检查
光源用20W的日光灯，采用散棚式装置。背景用不反光的黑色物，底部用不反光的白色物。取灭菌后口服液置检查装置下，距光源20cm处，先与黑色背景对照，后与白色背景对照。用肉眼检视，不得有可见的不溶物或浑浊现象出现。
通过肉眼检视，COST口服液和COSM口服液未发现有不溶物或浑浊现象出现。
2.6.2微生物限度检查
除另有规定外，照非无菌产品微生物限度检查：微生物计数法(通则1105)和控制菌检査法(通则1106)及非无菌药品微生物限度标准(通则1107)检查，应符合规定。
COST口服液和COSM口服液的需氧菌总数＜1(cfu/ml),符合指标；霉菌和酵母菌总数＜1(cfu/ml)，符合指标；未检出大肠埃希菌，符合指标；未检出沙门菌，符合指标；耐胆盐革兰阴性菌＜10(cfu/ml)符合指标。
表2-9 COST口服液微生物限度
Figure PCTCN2020112801-appb-000012
表2-10 COSM口服液微生物限度
Figure PCTCN2020112801-appb-000013
2.6.3含量检测
采用苯酚硫酸法，精密吸取样品溶液6份，平行测定含量，其RSD应不大于2.0％。
从表2-11和表2-12，COST口服液平均含量为93.37％，RSD为1.72％。COSM口服液平均含量为96.55％，RSD为1.45％。
表2-11 COST口服液含量检测结果
Figure PCTCN2020112801-appb-000014
表2-12 COSM口服液含量检测结果
Figure PCTCN2020112801-appb-000015
试验例三、壳寡糖口服液减肥降脂试验研究
1.材料和方法
1.1实验动物：SPF级雄性C57BL/6小鼠(单位许可证号：SYXK(粤)2017-00125)，定购于湖南斯莱克景达实验动物有限公司，3-4周龄，出售单位许可证号：SCXK(湘)2016-0002。奥利司他胶囊(购买于重庆植恩药业有限公司)；D12492高脂饲料(购买于美国Research Diet公司)；饲料配方成分：酪蛋白，L-胱氨酸，玉米淀粉，麦芽糊精，蔗糖，纤维素，豆油，猪油，复合矿物质，磷酸氢钙，碳酸钙，柠檬酸钾，复合维生素，重酒石酸氢胆碱，蓝色染料。
1.2试验仪器
YB-6LF生物组织石蜡包埋机、YGQ-3126F生物组织切片机(孝感市亚光医用电子技术有限公司)；Spectra Max i3x型多功能酶标仪(美谷分子仪器(上海)有限公司)；总胆固醇(T-CHO)试剂盒、甘油三酯(TG)试剂盒、高密度脂蛋白胆固醇(HDL-C)试剂盒、低密度脂蛋白胆固醇(LDL-C)试剂盒、谷丙转氨酶(ALT)试剂盒、谷草转氨酶(AST)试剂盒、游离脂肪酸(FFA)试剂盒、葡萄糖(GLU)试剂盒(南京建成生物工程研究所)；BCA蛋白浓度测定试剂盒(碧云天生物技术研究所)；Bio-Radbiorad电泳仪(山东博科科学仪器有限公司)。
1.3动物造模
在温度为24±2℃，相对湿度为50％-60％，光照节律为12小时的实验动物中心SPF级环境下，用普通饲料适应性喂养C57BL/6小鼠2周后，随机分成两组，其中C57BL/6小鼠喂养普通饲料作为正常饮食组，剩下的C57BL/6小鼠喂养D12492高脂饲料(HFD，High fat diet)。喂养2周后，按体重增重由高到低的顺序给D12492高脂饲料喂养小鼠排序，将体重增重较少肥胖抵抗的小鼠淘汰。剩下的C57BL/6小鼠维持高脂饲料喂养6周，同时，正常饮食组给予普通饲料喂养。高脂饲料喂养小鼠的体重超出正常饮食组小鼠的体重20％，即可判断为饮食性诱导肥胖模型造模成功。
1.4动物分组
正常饮食10只小鼠为空白组(Control)，将造模成功的肥胖小鼠随机挑选70只，随机分成七组(每组10只)：高脂模型组(Model)、奥利司他阳性对照组(Orlistat)、实施例1～5组，一共8组。
1.5给药方法
造模成功后，各给药组给予不同剂量的受试样品，空白组和模型组给与等量生理盐水进行灌胃。分别按照实施例1～5(1700mg/Kg)和Orlistat主药剂量(35mg/Kg)给每只C57BL/6 小鼠进行灌胃，每只C57BL/6小鼠按照每10g体重给予0.lml的量进行灌胃。每周定时称量各组C57BL/6体重；每日定时观察C57BL/6精神状态、外表体征和生理状态有无异常。结果见表2。
表2壳寡糖口服液对饮食性诱导肥胖小鼠体重的影响
Figure PCTCN2020112801-appb-000016
注：与Control组相比，*P<0.05，**P<0.01；与Model组相比，#P<0.05，##P<0.01。
表3壳寡糖口服液对C57BL/6肥胖小鼠脂肪的影响
Figure PCTCN2020112801-appb-000017
注：与Control组相比，*P<0.05，**P<0.01；与Model组相比，#P<0.05，##P<0.01。
由表2可知，造模完成后，测得Control组的平均体重为24.29g，给予高脂饲料的C57BL/6小鼠体重均超过31.18g，大于20％，表明造模成功。在给药第8周时，Orlistat组、实施例1～5组均显著低于Model组，表明各给药组均能显著降低饮食性诱导的体重。相比于Model组，Orlistat组、实施例1～5的体重增长趋势均有所减缓。
由表3可知，Control组的脂肪垫和脂/体比均显著低于Model组；Orlistat组的脂肪垫和脂/体比显著低于Model组；与Model组相比，实施例1～5组的脂肪垫和脂/体比显著降低，表明实施例1～5组均显著降低了高脂饮食导致的高脂肪含量和脂/体比。
对内脏脂肪组织进行HE切片冰染色，对其进行观察。Control组的脂肪细胞结构正常，排列紧密，大小均一，数目较多，细胞体积较小，而Model组的白色脂肪组织细胞大小不均一，体积较大。给药之后，实施例1～5组较Model组脂肪细胞明显减小，大小均一，体积较小，病变的情况得到了较好的改善，说明了实施例1～5能够抑制因高脂饮食诱导的脂肪细胞肥大，改善脂肪细胞的生长以及扩增，减少脂肪积累，改善肥胖等症状。
对肝脏组织进行HE染色切片，对其进行观察。Control组小鼠的肝脏脂质积累很少，Model组小鼠的肝脏脂滴较多，脂质积累严重。实施例1～5组小鼠的肝脏脂滴含量和脂滴大小与Model组相比明显减少，脂质积累得到改善。
对小肠组织进行HE染色切片，对其进行观察。Control组小鼠的小肠绒毛高整，Model组小鼠的绒毛杂乱无章，肠道屏障受损严重，肠道通透性增加。实施例1～5组小鼠的肠道绒毛与Model组相比明显整齐，肠道受损得到改善。
本具体实施方式的实施例均为本发明的较佳实施例，并非依此限制本发明的保护范围，故：
凡依本发明的结构、形状、原理所做的等效变化，均应涵盖于本发明的保护范围之内。

Claims (10)

  1. 一种壳寡糖口服液，其特征在于，所述口服液包括以下重量份数计的原料：壳寡糖30～45份、防腐剂1～2份、缓冲剂0.5～1.5份、矫味剂1～3份和稳定剂5～8份。
  2. 根据权利要求1所述的壳寡糖口服液，其特征在于，所述稳定剂为L-岩藻糖和羧甲基纤维素钠中的至少一种。
  3. 根据权利要求1或2所述的壳寡糖口服液，其特征在于，所述稳定剂由L-岩藻糖和羧甲基纤维素钠组成，所述L-岩藻糖和羧甲基纤维素钠的质量比为4:1。
  4. 根据权利要求1所述的壳寡糖口服液，其特征在于，所述防腐剂为苯甲酸钠和山梨酸钾中的一种或两种。
  5. 根据权利要求1所述的壳寡糖口服液，其特征在于，所述缓冲液为柠檬酸-柠檬酸钠、冰醋酸中的一种或两种。
  6. 根据权利要求5所述的壳寡糖口服液，其特征在于，所述缓冲液调节口服液的pH值为4.5～8.5。
  7. 根据权利要求1所述的壳寡糖口服液，其特征在于，所述矫味剂为阿司帕坦和木糖醇中的一种或两种。
  8. 根据权利要求1所述的壳寡糖口服液的制备方法，其特征在于，包括以下步骤：取纯化水适量，按照处方量加入壳寡糖、防腐剂和稳定剂，在恒温空气浴中振摇至溶解包合完全，再加入矫味剂，最后加入缓冲剂调节pH至4.5～8.5，即可。
  9. 根据权利要求7所述的壳寡糖口服液的制备方法，其特征在于，所述pH值调节至6.5。
  10. 根据权利要求1～9任一所述的壳寡糖口服液在制备减肥药物中的应用。
PCT/CN2020/112801 2020-05-22 2020-09-01 壳寡糖口服液及其在制备减肥药物中的应用 WO2021232614A1 (zh)

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