WO2009079822A1 - Produit d'extraction d'acide nucléique polysaccharidique du bcg et sa méthode de préparation - Google Patents

Produit d'extraction d'acide nucléique polysaccharidique du bcg et sa méthode de préparation Download PDF

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Publication number
WO2009079822A1
WO2009079822A1 PCT/CN2007/003598 CN2007003598W WO2009079822A1 WO 2009079822 A1 WO2009079822 A1 WO 2009079822A1 CN 2007003598 W CN2007003598 W CN 2007003598W WO 2009079822 A1 WO2009079822 A1 WO 2009079822A1
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Prior art keywords
nucleic acid
bcg
polysaccharide nucleic
bcg polysaccharide
acid extract
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PCT/CN2007/003598
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English (en)
Chinese (zh)
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Yunshan Ning
Jifeng Guan
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Hunan Jiuzhitang-Siqi Biopharmaceutical Co., Ltd
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Priority to CN2007800536233A priority Critical patent/CN101820891B/zh
Priority to PCT/CN2007/003598 priority patent/WO2009079822A1/fr
Publication of WO2009079822A1 publication Critical patent/WO2009079822A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/74—Bacteria
    • 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
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/02—Nasal agents, e.g. decongestants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/10—Expectorants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents

Definitions

  • a BCG-polysaccharide nucleic acid extract and a preparation method thereof TECHNICAL FIELD
  • the present invention relates to the field of biopharmaceuticals.
  • the present invention relates to a polysaccharide nucleic acid extract and a process for the preparation thereof.
  • Bacillus Calmette-Guerin is a bovine attenuated tuberculosis, non-pathogenic and immunogenic. It is the most widely used strain in the world by using Bacillus inoculation instead of tuberculosis for primary infection to obtain immunity against tuberculosis. One of the seedlings.
  • Hunan Jiuzhitang Siqi Bio-Pharmaceutical Co., Ltd. (formerly Changsha Shenjian Pharmaceutical Factory) cooperated with Changsha Medical Laboratories to conduct BCG extraction on the basis of research by Professor Tan Lizhi, a famous expert on respiratory diseases at Hunan Medical University.
  • BCG polysaccharide nucleic acid injection The 95th edition, 2000 edition of the "Chinese Biological Products Regulations", and named as BCG polysaccharide nucleic acid injection, the preparation is a mixture of polysaccharide nucleic acid and protein, wherein the polysaccharide is about 70% ⁇ 80%, and the nucleic acid is 10% ⁇ 20%.
  • the bacterial protein content is less than about 1%. Since the introduction of BCG polysaccharide nucleic acid injection, it has become a hot spot in clinical application research.
  • BCG polysaccharide nucleic acid injection It has a wide range of immunomodulatory effects, in addition to enhancing the cellular immune function of the human body, it also has a two-way immunomodulatory effect. It has a good effect in preventing and treating respiratory diseases such as colds, asthma, allergic rhinitis and skin diseases such as eczema, urticaria, flat warts, warts, and condyloma acuminata.
  • the currently introduced BCG polysaccharide nucleic acid injection is prepared by extracting the purified BCG polysaccharide nucleic acid extract extracted from Bacillus Calmette by the hot phenol method, and the current refined Bacillus polysaccharide nucleic acid extract quality standard and process According to the 2000 edition of the "Chinese Biological Products Regulations".
  • the quality standard of the refined BCG polysaccharide nucleic acid extract specified in the 2000 edition of the Chinese Biological Products Regulations is:
  • the preparation is a mixture of polysaccharides, nucleic acids and proteins, wherein the polysaccharide is about 70% to 80%, and the nucleic acid is 10% to 20%.
  • the Bacillus bacillus protein content is less than 1%, and the number of bacteria is not more than 100/g.
  • the BCG polysaccharide nucleic acid extract that meets the above quality standards can be used in the human body, it still has a certain amount of impurities because it still has a certain amount of impurities, for example, because the original purified BCG polysaccharide nucleic acid extract contains a high proportion.
  • Bacillus bacillus protein and bacteria, relative to the human body, BCG bacteria and bacteria are heterologous antigens or toxic substances, which can cause strong immune rejection and toxicity, which is clinically used. The preparation often has severe ulceration at the injection site of the patient, and about 5-10% of the patients have fever, and a few patients have severe allergic reactions.
  • Phenol has a strong corrosive effect on skin and mucous membranes, and can inhibit central nervous system or damage liver and kidney function. Inhalation of high concentrations of phenol vapor can cause headache, dizziness, fatigue, blurred vision, pulmonary edema, etc. Inadvertently causing burns in the digestive tract, burning pain, exhaled breath with phenolic odor, vomit or large blood, gastrointestinal perforation, shock, pulmonary edema, liver or kidney damage, acute renal failure, Can die of respiratory failure. Eye contact can cause burns. Can be absorbed by burned skin Acute renal failure occurs after the incubation period.
  • An object of the present invention is to provide a BCG polysaccharide nucleic acid extract having higher quality and less side effects.
  • Another object of the present invention is to provide a method for preparing the BCG polysaccharide nucleic acid extract, which has the characteristics of high degree of automation, short production cycle, stable production process, low labor intensity, and safer production environment.
  • an aspect of the present invention provides a BCG polysaccharide nucleic acid extract comprising a polysaccharide, a nucleic acid, a residual BCG protein, and a moisture content of less than 10% by mass (W/W).
  • the characteristics are as follows: the mass percentage of the polysaccharide is 70-78% (W/W), the mass percentage of the nucleic acid is 12-20% (W/W), and the percentage of residual BCG bacteria protein is 0. -0.5% (W/W), the residual amount of phenol is zero.
  • the number of bacteria therein is 0-20 / gram.
  • Another aspect of the present invention also provides a method of preparing a BCG polysaccharide nucleic acid extract, the method comprising the steps of:
  • the physical method described in the above step (b) is selected from one or more of ultrasonic, grinding, mechanical mashing, high-speed homogenization;
  • the above step (c) may comprise: adding 0.5-2.0 volumes of 30-100 ° C phenol to the BCG polysaccharide nucleic acid suspension and stirring well, and then separating the obtained suspension by high-speed centrifugation.
  • the supernatant is a mixture of BCG polysaccharide nucleic acids; wherein, after adding 0.5-2.0 volumes of 30-100 ° C phenol to the BCG polysaccharide nucleic acid suspension and stirring well, the obtained suspension is centrifuged by high speed.
  • the suspension Before the separation, the suspension may be allowed to settle naturally, the supernatant is aspirated, and the aspirated supernatant is further separated by high-speed centrifugation, and the resulting supernatant is a mixture of BCG polysaccharide nucleic acids.
  • the above-mentioned BCG polysaccharide nucleic acid mixture is treated by gel column chromatography as described in the above step (d), preferably by using an industrial gel filtration chromatography medium, by gel filtration column chromatography for 30-100 ° C.
  • the phenol is separated from the high speed centrifuged BCG polysaccharide nucleic acid mixture.
  • the above-mentioned industrial gel filtration chromatography medium should be able to be used for industrialization or large-scale production.
  • the gel medium should be able to withstand phenol with a mass concentration of less than or equal to 70% for a long time, and the separation of the gel medium.
  • the range is preferably from 0.1 KD to 1000 KD; the gel column chromatography is preferably a molecular exclusion chromatography, more preferably a GH-25 gel medium.
  • the further separating the BCG polysaccharide nucleic acid extract from the BCG polysaccharide nucleic acid extract in the above step (d) may include: performing alcohol precipitation on the BCG polysaccharide extract, collecting sediment, and depositing the precipitate After washing, it is dried, and the dried product is a BCG polysaccharide nucleic acid extract. More specifically, the process may be: adding ethanol to the BCG polysaccharide nucleic acid extract for alcohol precipitation, the alcohol content is 70-75% by weight, collecting the precipitate after natural precipitation, and the precipitate is thoroughly stirred by absolute ethanol.
  • the hooks were washed by centrifugation 2-5 times, then washed with diethyl ether for 2-5 times, and then placed in a desiccator to dry, and the dried product was a purified BCG polysaccharide nucleic acid extract.
  • the new process is automatically completed by the system from sample loading, separation, collection and elution.
  • the system can automatically complete data recording, storage, map drawing, etc., which facilitates the whole process of production.
  • Monitoring, and due to the high degree of process automation, the phenol removal process completed in the original three days, the new method can be completed in only 5 hours.
  • the original dialysis process is that the feed liquid is packed with dialysis bags and then subjected to running water for dialysis. The time is also long, and the probability of contamination of the liquid is very high.
  • the new process is highly automated. The liquid is loaded from a sample to a collection under relatively tight conditions and is virtually uncontaminated.
  • the original dialysis method is basically manual operation, the operator is exposed to phenol, and the new process is fully automatic operation. The operator only needs to use the computer for monitoring. To a large extent, the harm of phenol to the operator is reduced.
  • the BCG polysaccharide nucleic acid extract provided by the present invention has higher quality and less side effects than the BCG polysaccharide nucleic acid extract obtained by the known technique.
  • BEST MODE FOR CARRYING OUT THE INVENTION The innovation and application of the present invention will be described in detail below by way of specific examples and experimental results to help the reader to better understand the spirit and substance of the invention, but not to limit the scope of the invention.
  • Example 1 Cultivation and harvesting of BCG
  • Bacterial culture The strains that are cryopreserved in liquid (Chinese BCG strain D2PB302, China National Institute for the Control of Pharmaceutical and Biological Products) are dissolved at room temperature, inoculated into potato Sutong medium, and continuously cultured at 37 °C 14-20 Days; or after 15 days of continuous culture at 37 ° C, transfer to modified liquid Sutong medium, continuous culture at 37 ° C for 14-20 days.
  • the preparation method of potato Sutong medium can be -
  • Bacterial disruption and hot phenol treatment The collected cells were added to purified water in a ratio of 10:1, and the cells were disrupted by a tissue crushing machine (12000 rpm/min), 3 min x 3 times, and the cells were minced. Then, 0.5-2.0 times the volume of hot phenol (30 ⁇ 100 ° C) of the disrupted bacterial suspension is added, and the mixture is kept in a low speed stirring for 30 minutes to 1 hour.
  • BCG polysaccharide nucleic acid mixture The mixture of hot phenolic mixture is naturally precipitated for 1 to 10 days, the supernatant is aspirated, and the supernatant is centrifuged at 480 um, and the supernatant is filtered through a 0.45 um sterile filter. BCG polysaccharide nucleic acid mixture.
  • Example 3 Preparation of Refined Bacillus Calmette Polysaccharide Nucleic Acid Extract
  • the BCG polysaccharide nucleic acid mixture was manually loaded into a dialysis bag (cutoff molecular weight > 5000 Daltons) and dialyzed in 100 volumes of purified water for 7 to 10 days.
  • the purified water in the dialysis tank was changed every day and sampled from the dialysis bag every day. Phenol residue.
  • An appropriate amount of ethanol was added to the dialyzed BCG polysaccharide nucleic acid mixture to make the alcohol content 60 to 85%. After natural precipitation for 1 to 10 days, the precipitate was thoroughly stirred with anhydrous ethanol and washed by centrifugation 3 times. Then, the mixture was washed with diethyl ether for 3 times, dried in a desiccator, and dried for 2 to 5 days to obtain a purified BCG polysaccharide nucleic acid extract.
  • Example 4 Detection of purified BCG polysaccharide nucleic acid extract prepared by the two methods
  • the nine batches of purified BCG polysaccharide nucleic acid extract prepared by the original method and the method respectively are in accordance with the 2000 edition of the Chinese Biological Products Regulations and the 2005 edition.
  • the Chinese Pharmacopoeia was tested and the results are shown in Table 1, Table 2 and Table 3 below.
  • the purified BCG polysaccharide nucleic acid extracts prepared by the two methods were dissolved in physiological saline and formulated into appropriate concentrations.
  • Kunming mice (body weight 18 ⁇ 22 g), male and female, were provided by the Department of Laboratory Animal Science of Central South University.
  • mice were randomly divided into groups according to gender and weight, with 10 in each group.
  • the purified BCG-polysaccharide nucleic acid extract prepared by the method was intraperitoneally or intramuscularly injected at 500 mg/kg, 1000 mg/kg and 2000 mg/kg, respectively, and the injection amount was 0.4 ml/20 g. After continuous administration for 14 days, the abnormal lesions and deaths of the animals were recorded.
  • the purified BCG polysaccharide nucleic acid extract prepared by the original method was intraperitoneally administered at different doses of 100 mg/kg, 200 mg/kg and 500 mg/kg, respectively. Or intramuscular injection, the injection volume is 0.4 ml / 20g. After 14 days of continuous administration, the number of abnormal lesions and deaths of the animals was recorded.
  • the animals were killed and abnormally induced by intraperitoneal and intramuscular injection of the purified BCG polysaccharide nucleic acid extract prepared by the two methods (see Tables 4 and 5).
  • the results showed that the minimum lethal dose of refined BCG polysaccharide nucleic acid extract prepared by this method was more than 2000 mg/kg in the peritoneal and muscle pathways of mice; the purified Bacillus polysaccharide cDNA extracted by the original method was in the peritoneal cavity of mice.
  • the minimum lethal dose of the muscle route is 100 mg/kg; the minimum lethal dose of the refined BCG polysaccharide nucleic acid extract prepared by the method in the mouse abdominal cavity and muscle pathway is smaller than the original method It is 20 times higher, indicating that the refined BCG polysaccharide nucleic acid extract prepared by the method for a long time is safer than the purified BCG polysaccharide nucleic acid extract prepared by the original method.
  • Table 4 Acute toxicity test of purified BCG polysaccharide nucleic acid extract prepared by the method
  • Kunming mice (body weight 18 ⁇ 22 g) and guinea pigs (body weight 250 ⁇ 350 g), male and female, were provided by the Department of Experimental Animal Science of Central South University.
  • the test was carried out according to the experimental requirements of the "Testing Procedures for Abnormal Toxicity of Biological Products” in the “Procedures for the Manufacture and Verification of Bacillus Polysaccharide Nucleic Acid Preparations” in the 2000 edition of the Chinese Biological Products Regulations.
  • the experiment was divided into experimental group and control group.
  • the experimental group and the control group were divided into two groups: low dose and high dose. There were 30 mice in each group and 10 samples in each batch. 15 guinea pigs in each group, 5 samples in each batch. .
  • each mouse was intraperitoneally injected with 0.5 ml of BCG polysaccharide nucleic acid injection prepared by the method, and 5 ml of each guinea pig was intraperitoneally injected for 7 days;
  • the experimental group high dose group
  • each The mice were intraperitoneally injected with 1.0 ml of BCG polysaccharide nucleic acid injection prepared by the method, and 10 ml of each guinea pig was intraperitoneally injected for 7 days.
  • all the animals in the test group survived, no abnormal reaction, and the weight of each animal at the end of the expiration was judged as qualified.
  • each A sample of BCG-polysaccharide nucleic acid injection prepared by the original method of mice was intraperitoneally injected with 1.0 ml, and each guinea pig was intraperitoneally injected with 10 ml for 7 days.
  • all the animals in the test group survived, no abnormal reaction, and the weight of each animal at the end of the expiration was judged as qualified.
  • mice and guinea pigs In the low-dose group, the mice and guinea pigs all survived, and no abnormal reaction was observed. Compared with before administration, the body weight of each animal increased on the 7th day after administration, and the three batches of the original method were prepared. Nucleic acid injections were not abnormally toxic; however, mice and guinea pigs in the high-dose group died partially and lost weight (see Tables 6 and 7); therefore, the three batches of the original method of BCG-polysaccharide nucleic acid were tested in the high-dose group. The injection has abnormal toxicity. The above results indicate that the refined BCG polysaccharide nucleic acid extract prepared by the method for a long time is safer than the purified BCG polysaccharide nucleic acid extract prepared by the original method.
  • the original method and the method prepare a total of three batches of BCG polysaccharide nucleic acid injection, the specification: 1.0 ml / branch (the purified BCG polysaccharide nucleic acid powder prepared by the original method of 0.5 mg and the method is dissolved in 1 ml of physiological saline).
  • each batch of samples was diluted to 0.1 mg/ml with saline before injection.
  • Each batch of the experimental group and the high-dose group of the control group was diluted with physiological saline for injection to 0.25 mg/ml before the test.
  • Each animal was slowly injected into the ear vein at a dose of 0.1 mg/kg to pre-heat to a diluted sample of 1 ml/kg at 38 °C, and the body temperature was measured once every 30 minutes for 6 times. The difference between the normal body temperature of each animal and the highest temperature after administration (i.e., the response of the rabbit) was recorded, and a negative value was calculated as zero. For example, if the temperature of the three rabbits is lower than 0.60 °C, and the sum of the three rabbits does not exceed 1.40 °C, it is judged as qualified.
  • the response of each animal was lower than 0.60 °C, and the sum of the three animals in the same group was less than 1.40 °C.
  • the response of each animal was lower than 0.60 °C, and the sum of the three animals in the same group was less than 1.40 °C, but the body temperature of the three animals in the high-dose group was higher than 0.80 °C. The quality was judged as unsatisfactory (see Table 8 for the results).

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Abstract

Cette invention concerne un produit d'extraction d'acide nucléique polysaccharidique du BCG. Dans le produit d'extraction, la teneur en humidité est inférieure à 10 % (p/p), la teneur en polysaccharide est comprise entre 70 et 78 % (p/p), la teneur en acide nucléique est comprise entre 12 et 20 % (p/p), la teneur en protéine bactérienne du BCG résiduelle est comprise entre 0 et 0,5 % (p/p), le résidu phénol vaut zéro et le nombre des bactéries mélangées est compris entre 0 à 20 par gramme. L'invention concerne également une méthode de préparation du produit d'extraction d'acide nucléique polysaccharidique du BCG, ledit procédé comprenant les étapes suivantes consistant à : mettre en culture le BCG, dissocier la culture par des méthodes physiques pour obtenir une suspension d'acide nucléique polysaccharidique du BCG, traiter la suspension d'acide nucléique polysaccharidique du BCG par la méthode du phénol chaud et par centrifugation à grande vitesse pour obtenir un mélange d'acide nucléique polysaccharidique du BCG, isoler la solution d'extraction d'acide nucléique polysaccharidique du BCG du mélange d'acide nucléique polysaccharidique du BCG par chromatographie sur gel, et purifier la solution d'extraction d'acide nucléique polysaccharidique du BCG pour obtenir un produit d'extraction d'acide nucléique polysaccharidique du BCG.
PCT/CN2007/003598 2007-12-14 2007-12-14 Produit d'extraction d'acide nucléique polysaccharidique du bcg et sa méthode de préparation WO2009079822A1 (fr)

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Application Number Priority Date Filing Date Title
CN2007800536233A CN101820891B (zh) 2007-12-14 2007-12-14 一种卡介菌多糖核酸提取物及其制备方法
PCT/CN2007/003598 WO2009079822A1 (fr) 2007-12-14 2007-12-14 Produit d'extraction d'acide nucléique polysaccharidique du bcg et sa méthode de préparation

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CN107446886A (zh) * 2016-05-31 2017-12-08 湖南斯奇生物制药有限公司 卡介菌多糖核酸在促进cik细胞增殖和提高cik细胞的杀瘤活性中的应用
CN111662870A (zh) * 2016-12-02 2020-09-15 中国计量大学 卡介菌多糖核酸在cik细胞体外培养及制备肿瘤药物中的应用
CN111388401A (zh) * 2018-12-14 2020-07-10 湖南斯奇生物制药有限公司 一种面膜及其制备方法和用途
CN113462762B (zh) * 2020-03-30 2022-05-27 湖南斯奇生物制药有限公司 多糖核酸免疫调节药物的质量检测方法

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YAN, Z. H. ET AL.: "Experimental Preparation of BCG-Polysaccharide Nucleic Acid(BCG-PSN).", CHIN J BIOLOGICALS., vol. 12, no. 4, 1999, pages 208 - 209, 224 *

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