WO2021164523A1 - Composition d'akkermansia muciniphila - Google Patents

Composition d'akkermansia muciniphila Download PDF

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WO2021164523A1
WO2021164523A1 PCT/CN2021/074307 CN2021074307W WO2021164523A1 WO 2021164523 A1 WO2021164523 A1 WO 2021164523A1 CN 2021074307 W CN2021074307 W CN 2021074307W WO 2021164523 A1 WO2021164523 A1 WO 2021164523A1
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akkermansia
metformin
pharmaceutical composition
cfu
group
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PCT/CN2021/074307
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Chinese (zh)
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宁光
文彬
王卫庆
于鸿晶
洪洁
马新
顾卫琼
高远
王计秋
孙宁云
刘瑞欣
徐晓芬
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上海市内分泌代谢病研究所
上海上药信谊药厂有限公司
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Publication of WO2021164523A1 publication Critical patent/WO2021164523A1/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
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • 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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
    • A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin

Definitions

  • the present invention relates to an Akkermansia composition, and more specifically to an Akkermansia composition for the prevention and treatment of metabolic diseases.
  • Obesity is a worldwide health problem.
  • the Global Burden of Disease The Global Burden of Disease
  • the global epidemiology of obesity is gradually deteriorating, which has an adverse impact on physical hygiene and health economics.
  • Internationally, the body mass index (BMI) is usually used as the standard to judge the degree of obesity.
  • BMI body mass index
  • 18.5 ⁇ BMI ⁇ 24.9 it is in the normal range
  • BMI ⁇ 25 is overweight
  • BMI ⁇ 30 is obesity.
  • Research data from 195 countries around the world shows that the incidence of obesity has doubled since 1980. At present, 5% of children and 12% of adults are facing obesity. The incidence of obesity is similar to that of type 2 diabetes. The trend is 2025. One in five people worldwide will be obese.
  • Obesity and type 2 diabetes are affected by environmental and genetic factors.
  • the genes of the human flora also play an important role in the two diseases; the flora may affect obesity by affecting the absorption of calories, and obesity may in turn affect the intestinal flora. composition.
  • the flora may affect obesity by affecting the absorption of calories, and obesity may in turn affect the intestinal flora. composition.
  • the imbalance of intestinal flora is related to many diseases including obesity.
  • the anti-inflammatory Akkermansia muciniphila hereinafter referred to as "Ackermania" in obese patients decreases, and the phylum Proteobacteria, Bacteroides, Campylobacter and Shigella spp. increased.
  • the ratio of Firmicutes to Bacteroides phylum not only affects carbohydrate metabolism, but also changes the production of short-chain fatty acids. Increased blood acetic acid levels can lead to increased insulin resistance and ghrelin production.
  • the flora may be the most Important variables.
  • the intestinal flora can change a variety of metabolic pathways centered on the balance of energy metabolism, thereby affecting the occurrence and development of obesity.
  • Probiotics and prebiotics can play a role in resisting obesity by reducing intestinal bacterial lipopolysaccharide, changing the composition of the flora, and reducing fat storage.
  • the Chinese invention patent application with application number CN201380070847.0 and publication number CN 104918626 A discloses the "use of Akkermansia for the treatment of metabolic disorders", and the Akkermansia strain selected by this patent application is available. To promote weight loss of subjects in need.
  • the inventors have shown through research that although Akkermansia strain ATCC BAA835 is recognized as the most classic and best-effect Akkermansia strain, the strain has advantages in fermentation, storage stability, acid and bile resistance. And the effect on the treatment of metabolic diseases is not particularly ideal.
  • Metformin is a classic drug for the treatment of type 2 diabetes, and can reduce the complications and mortality of type 2 diabetes.
  • the single dosage form of metformin has limitations in preventing and treating diseases and enhancing health.
  • a survey on the status quo of oral drug treatment models for type 2 diabetes in my country shows that the most commonly used oral hypoglycemic regimen in China is dual-drug combination (45.4%), followed by single-drug therapy (35.8%), and the proportion of triple combination drugs is relatively small ( 17.0%), most patients need multi-drug combination therapy to achieve blood glucose standards, so the development and preparation of metformin compound preparations is particularly important.
  • metformin compound preparations mainly include dipeptidyl peptidase DPP-4 inhibitor metformin compound preparations (sitagliptin metformin, saxagliptin metformin, linagliptin metformin), sodium glucose coordinated transporter SGLT-2 inhibitor metformin Compound preparations (dapagliflozin metformin, pioglitazone metformin, empagliflozin metformin, canagliflozin metformin tablets, acarbose metformin).
  • the combination of multiple drugs in the treatment of metabolic diseases has the possibility of superimposing adverse effects of drugs, and the risk of hypoglycemia and blood glucose drift is high. Therefore, Cheng needs a mild and safe biological agent combined with metformin to form a compound preparation for the treatment of metabolic diseases.
  • the technical problem to be solved by the present invention is to overcome the superimposed side effects of the compound preparation of metformin in the prior art, and the technical problems of high risk of hypoglycemia events and blood glucose drift, and provide a method for preventing and treating metabolic diseases Compound preparation and its preparation method.
  • the Akkermansia metformin compound preparation prepared by the invention has a better effect of preventing and treating metabolic diseases, and has higher safety than the existing metformin compound preparation.
  • One aspect of this application provides a pharmaceutical composition comprising Akkermansia muciniphila (Akkermansia muciniphila) and metformin. Based on the quality of the pharmaceutical composition, the number of viable bacteria of the strain is 10 6 -10 12 CFU/g, the content of metformin is 20-60%.
  • the Akkermansia strain Akkermansiamuciniphila SSYD-3 has an accession number of CGMCC No. 14764.
  • the pharmaceutical composition includes Akkermansia and metformin as synergistic components.
  • the Akkermansia form is in the form of Akkermansia lyophilized powder.
  • the number of viable bacteria in the pharmaceutical composition is 10 8 -10 12 CFU/g, more preferably 10 9 -10 11 CFU/g, and most preferably 10 10 CFU/g.
  • the content of metformin is 30-60%, more preferably 40-60%, still more preferably 45-55%, and most preferably 50%.
  • the form of metformin is in the form of metformin granules.
  • Another aspect of the present application provides the use of the combination of Akkermansia and metformin in the preparation of drugs for the prevention and treatment of metabolic diseases, or the use of the combination of Akkermansia and metformin in the prevention and treatment of metabolic diseases.
  • the use includes reducing human or animal body weight, and/or improving glucose/insulin tolerance.
  • the combination of Akkermansia and metformin is a synergistic combination.
  • Figure 1 is the comparative effect of the application's effect example 1 in terms of weight reduction.
  • Figure 2 shows the comparative effect of the application effect example 1 in improving glucose tolerance.
  • Fig. 3 is a comparative effect of improving insulin tolerance in effect example 1 of the application.
  • metabolic diseases have conventional meanings in the art, including diabetes, obesity, insulin resistance, alcoholic and non-alcoholic fatty liver, hypertension, hyperlipidemia, high cholesterol, heart disease and other diseases.
  • the preventive and therapeutic effects refer to prevention of the occurrence and development of metabolic diseases, treatment and auxiliary treatment of metabolic diseases.
  • percentage (%) or parts refer to the weight percentage or parts by weight relative to the composition.
  • the sum of the parts of each component in the composition may be 100 parts by weight.
  • the numerical range "a-b” represents an abbreviated representation of any combination of real numbers between a and b, where both a and b are real numbers.
  • the numerical range "0-5" means that all real numbers between "0-5" have been listed in this article, and "0-5" is only an abbreviation of these numerical combinations.
  • the integer value range "a-b” represents an abbreviated representation of any combination of integers between a and b, where both a and b are integers.
  • the integer value range "1-N" means 1, 2...N, where N is an integer.
  • “combination thereof” means a multi-component mixture of the respective elements, for example, two, three, four, and up to the largest possible multi-component mixtures.
  • the percentages (including weight percentages) in the present invention are based on the total weight of the composition.
  • the “range” disclosed herein takes the form of the lower limit and the upper limit. There can be one or more lower limits, and one or more upper limits, respectively.
  • the given range is limited by selecting a lower limit and an upper limit.
  • the selected lower and upper limits define the boundaries of the special range. All ranges that can be defined in this way are inclusive and combinable, that is, any lower limit can be combined with any upper limit to form a range.
  • the ranges of 60-120 and 80-110 are listed for specific parameters, and the ranges of 60-110 and 80-120 are also expected.
  • the minimum range values 1 and 2 are listed, and if the maximum range values 3, 4, and 5 are listed, the following ranges can all be expected: 1-3, 1-4, 1-5, 2- 3, 2-4, and 2-5.
  • the ratio or weight of each component refers to the dry weight.
  • Akkermansia includes active ingredients derived from Akkermansia, or bacteria whose sequence identification result is at least 97% similar to the sequence of Akkermansia.
  • One aspect of this application provides a pharmaceutical composition
  • a pharmaceutical composition comprising Akkermansia muciniphila and metformin, and the number of viable bacteria of the strain is 10 6 -10 based on the mass of the pharmaceutical composition. 14 CFU/g, the content of metformin is 20-60%.
  • the Akkermansia refers to a living organism or a pasteurized inactivated organism.
  • the Akkermansia strains described in the present application can be obtained through commercial channels, and can also be obtained through existing technologies.
  • the Chinese invention patent application with application number CN201380070847.0 and publication number CN 104918626 A discloses "the use of Akkermansia for the treatment of metabolic disorders", and the patent application discloses Akkermansia strain ATCC BAA835.
  • the Akkermansia muciniphila strain is named Akkermansia muciniphila SSYD-3, and its deposit number is CGMCC No. 14764.
  • the Akkermansia can be found in Chinese patent application CN201811132882.1, the full text of which is incorporated herein by reference.
  • the Akkermansia muciniphila SSYD-3 (strain W03 for short) of the present invention has been deposited in the General Microbiology Center (CGMCC) of the China Microbial Culture Collection Management Committee (CGMCC) on September 29, 2017. The preservation address: No. 1 Beichen West Road, Chaoyang District, Beijing Hospital No. 3, Zip Code: 100101, the deposit numbers are: CGMCC No. 14764, the name of the culture is Akkermansia muciniphila SSYD-3, and the classification name is Akkermansia muciniphila.
  • CGMCC General Microbiology Center
  • CGMCC China Microbial Culture Collection Management Committee
  • the Akkermansia can be made into various suitable forms, such as solutions, tablets, capsules, orally disintegrating tablets, freeze-dried powders, and the like.
  • the form is freeze-dried powder.
  • the dosage form is a tablet.
  • the dosage form is preferably a lyophilized powder.
  • the number of viable Akkermansia bacteria is preferably 10 10 CFU/g.
  • the effective dose means that the solid pharmaceutical composition made of Akkermansia as the main active ingredient of the medicine contains a total number of viable bacteria of 10 6 -10 14 CFU/g.
  • the effective dose means that the total number of viable bacteria contained in the liquid pharmaceutical composition made of Akkermansia as the main active ingredient of the medicine is 10 6 -10 14 CFU/mL.
  • the Akkermansia bacterium is preferably prepared as a pharmaceutical composition in the form of Akkermansia lyophilized powder.
  • the preparation method of the Akkermansia lyophilized powder preferably includes the following steps:
  • the centrifuged cells of Akkermansia are preferably obtained as follows: the fermentation broth of Akkermansia is centrifuged to collect the bacteria.
  • the centrifugation is a conventional operation in the field, for example, a centrifugation treatment is performed for 20 minutes at a rotation speed of 8000 rpm.
  • the number of viable Akkermansia in the Akkermansia lyophilized powder is preferably 10 6 -10 14 CFU/g, more preferably 10 10 CFU/g.
  • the raw material of the freeze-dried protective agent is a conventional freeze-dried protective agent in the field.
  • the freeze-dried protective agent is a mixture of sodium glutamate, mannitol, trehalose and milk powder; wherein, in the preparation step of the Akkermansia freeze-dried powder In the lyophilized liquid obtained by uniform mixing, the mass percentages of sodium glutamate, mannitol, trehalose and milk powder are respectively 2%, 2%, 4% and 8%.
  • the Akkermansia lyophilized powder can be pulverized, sieved with 40 meshes, and stored in a turnover bucket, sealed and stored for later use.
  • metalformin means metformin or its derivatives, its pharmaceutically acceptable salts, its pharmaceutically acceptable esters, or its prodrugs.
  • metformin is preferably in the form of metformin granules to prepare the pharmaceutical composition.
  • the preparation method of metformin granules is conventional in the art, and preferably includes the following steps: uniformly mixing metformin with a binder, wet granulation, drying, granulating, and mixing uniformly with the lubricant.
  • metformin is often used as its hydrochloride, sulfate, etc. as raw materials for medicines, namely metformin hydrochloride, metformin sulfate and the like.
  • Metformin hydrochloride and metformin sulfate are preferably crushed, and then sieved with 40 mesh.
  • the adhesive is a conventional substance in the field, such as povidone K30.
  • the lubricant is a conventional substance in the field, such as magnesium stearate.
  • metformin granules can be stored in a turnover bucket and sealed for later use in accordance with the conventional practice in the art.
  • the pharmaceutical composition can usually be made into any suitable dosage form by adding a pharmaceutically acceptable carrier, such as oral liquid, tablet, capsule, orally disintegrating tablet, injection and the like.
  • a pharmaceutically acceptable carrier such as oral liquid, tablet, capsule, orally disintegrating tablet, injection and the like.
  • the present application also provides a method for preparing the above-mentioned pharmaceutical composition, which includes the following steps: mixing the raw materials of the pharmaceutical composition uniformly.
  • the number of viable bacteria is 10 6 -10 14 CFU/g, preferably 10 8 -10 12 CFU/g, more preferably 10 9 -10 11 CFU/g g, most preferably 10 10 CFU/g.
  • the content of metformin is 20-60%, preferably 30-60%, more preferably 40-60%, even more preferably 45- 55%, most preferably 50%.
  • the pharmaceutical composition includes Akkermansia and metformin as synergistic components.
  • the quality of Akkermansia lyophilized powder and metformin granules is different.
  • it is 1:2 ⁇ 1:10.
  • the compound preparation is a tablet, which is obtained by the following method: mixing Akkermansia lyophilized powder and metformin granules at a mass ratio of 1:10 and compressing them into tablets.
  • the thickness of the tablet is controlled to be a conventional thickness, for example, 5.0 mm to 5.5 mm.
  • the compound preparation is an enteric-coated capsule, which is obtained by the following method: Ackermania lyophilized powder, metformin granules and carboxymethyl cellulose in a mass ratio of 1 :2:2 Mix evenly, then put into capsule.
  • the mixing is performed uniformly according to conventional operating conditions, for example, 8 rpm, 30 min.
  • the capsule is an enteric-coated capsule commonly used in the field.
  • the reagents and raw materials used in the present invention are all commercially available.
  • the positive and progressive effects of the present invention are: Akkermansia has a relatively prominent effect in reducing blood sugar, and it is a resident of the human intestinal tract, and the safety of symbiosis with the host is guaranteed. Metformin is the first-line drug for the treatment of type 2 diabetes.
  • the Akkermansia metformin compound preparation prepared by the present invention can exert a synergistic effect, achieve better effects of preventing and treating metabolic diseases, and is safer than a compound preparation made of metformin and chemical drugs.
  • Another aspect of the application provides the use of the combination of Akkermansia and metformin in the preparation of drugs for the prevention and treatment of metabolic diseases.
  • Another aspect of the present application provides the use of the combination of Akkermansia and metformin in the prevention and treatment of metabolic diseases.
  • the number of viable bacteria is 10 6 -10 12 CFU/g, preferably 10 8 -10 12 CFU/g, more preferably 10 9 -10 11 CFU/g g, most preferably 10 10 CFU/g.
  • the content of metformin is 20-60%, preferably 30-60%, more preferably 40-60%, even more preferably 45- 55%, most preferably 50%.
  • the use includes reducing human or animal body weight, and/or improving glucose/insulin tolerance.
  • Freeze drying protective agent sodium glutamate, mannitol, trehalose, milk powder.
  • the cells obtained by centrifugation of Akkermansia are mixed with freeze-drying protective agent and water, so that the mass percentages of sodium glutamate, mannitol, trehalose, and milk powder in the solution before freeze-drying are 2% and 2%, respectively. 4% and 8% were freeze-dried to obtain freeze-dried bacterial powder.
  • the number of live bacteria of the Akkermansia strain with the preservation number of CGMCC No. 14764 in the bacterial powder was 10 10 CFU/g.
  • the obtained W03 bacterial powder is pulverized and stored in a turnover bucket, sealed and stored for later use.
  • metformin hydrochloride (Shandong Shouguang Fukang Pharmaceutical Co., Ltd.) was pulverized and sieved with 40 meshes.
  • the obtained metformin hydrochloride was mixed with 10kg of binder povidone K30, and then wet granulated and dried. Put the dry granules into the lifting granulator for dry granule granulation, and transfer the granulated granules to the mixing box. Mix the sized granules with magnesium stearate, add them to the mixing cabinet and mix for 10 minutes, and then discharge.
  • the obtained metformin granules are stored in a turnover bucket and sealed for later use.
  • W03 bacterial powder and metformin granules are mixed and compressed at a mass ratio of 1:10.
  • the thickness of the compressed tablet is controlled to be 5.0mm ⁇ 5.5mm during tablet compression, and after the tablet compression is completed, the compressed Akkermansia metformin compound tablet is sealed and stored.
  • Freeze drying protective agent sodium glutamate, mannitol, trehalose, milk powder.
  • the fermentation broth was centrifuged at 8000 rpm for 20 minutes, and the bacteria were collected.
  • the cells obtained by centrifugation of Akkermansia are mixed with freeze-drying protective agent and water, so that the mass percentages of sodium glutamate, mannitol, trehalose, and milk powder in the solution before freeze-drying are 2% and 2%, respectively. 4% and 8% were freeze-dried to obtain freeze-dried bacterial powder.
  • the number of live bacteria of the Akkermansia strain with the preservation number of CGMCC No. 14764 in the bacterial powder was 10 10 CFU/g.
  • the obtained W03 bacterial powder is pulverized and stored in a turnover bucket, sealed and stored for later use.
  • metformin hydrochloride (Shandong Shouguang Fukang Pharmaceutical Co., Ltd.) was pulverized and sieved with 40 meshes.
  • the obtained metformin hydrochloride was mixed with 10kg of binder povidone K30 and then wet-granulated and dried. Put the dry granules into the lifting granulator for dry granule granulation, and transfer the granulated granules to the mixing box. Mix the sized granules with magnesium stearate, add them to the mixing cabinet and mix for 10 minutes, and then discharge.
  • the metformin granules are stored in a turnover bucket and sealed for later use.
  • mice Eight-week-old male C57 BL/6 mice (no specific pathogens, Shanghai Experimental Animal Center) were grouped with 3 mice per cage (filter cage), and they were allowed to eat freely during a strict 12-hour photoperiod. After they adapt to the new environment, they are fed a standard diet or a high-fat diet with 60kcal% fat for 12 consecutive weeks (Research Diet, D12492i).
  • the animals were randomly divided into 4 groups, and they were administrated with 200 microliters of sterile phosphate buffered saline solution PBS (denoted as the PBS group) and 200 microliters of Akkermansia single-use group (by 0.1g of Akkermansia with a bacterial content of 10 10 CFU/g (Ackermannia strain with the deposit number of CGMCC No.
  • PBS sterile phosphate buffered saline solution
  • Akkermansia single-use group by 0.1g of Akkermansia with a bacterial content of 10 10 CFU/g (Ackermannia strain with the deposit number of CGMCC No.
  • the body weight was measured before gavage and at the end of the experiment.
  • the food intake for 7 consecutive days was recorded by cage (3 mice per cage), and the average food intake of each mouse per day was calculated.
  • Stool samples were collected before gavage and at the end of the experiment, and immediately stored in a refrigerator at -80°C for further analysis. Collect whole blood from the tail vein of the mouse, and measure the blood glucose level and insulin level with a blood glucose meter (LifeScan). In order to ensure the same starting point, this study did not use random allocation, but grouped the mice that had adapted to the environment according to their body weight. All operations were approved by the Animal Ethics Committee of Shanghai Jiaotong University School of Medicine.
  • Figure 1 shows the test results at the end of the eighth week of the test. The data is shown in Table 1.
  • the test results showed that: Compared with the control Akkermansia group and the metformin group, the Akkermansia metformin compound combination group had significantly improved glucose and insulin tolerance, showing a synergistic effect.
  • the results of the glucose tolerance test are shown in Figure 2.
  • Figure 2 shows the blood glucose test results within 2 hours after glucose injection at the end of the eighth week of the test. The data is shown in Table 2-5.
  • the data with P value less than or equal to 0.05 in the table indicates that there is a statistical difference.
  • the data with P value less than or equal to 0.05 in the table indicates that there is a statistical difference.
  • Figure 3 shows the blood glucose test results within 2 hours after insulin injection at the end of the eighth week of the test.
  • the data is shown in Table 6-9.
  • the data with P value less than or equal to 0.05 in the table indicates that there is a statistical difference.
  • the data with P value less than or equal to 0.05 in the table indicates that there is a statistical difference.
  • the W03 group has an effect on glucose tolerance, but has no effect on islet tolerance.
  • the reason is as follows: the improvement of glucose metabolism is achieved through many mechanisms. It mainly includes reducing the source of glucose and increasing the way of glucose. It is found through experiments that W03 can improve glucose tolerance, which may be achieved mainly by increasing the utilization of glucose by peripheral tissues and organs, and reducing glycogen output. However, W03 does not significantly improve insulin tolerance, suggesting that W03 application does not increase the sensitivity of individuals to exogenous insulin, and its effect of improving glucose metabolism is not achieved by increasing insulin sensitivity.

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Abstract

L'invention concerne une composition d'Akkermansia muciniphila. L'invention concerne une composition pharmaceutique, la composition pharmaceutique comprenant de l'Akkermansia muciniphila et de la metformine ; et, en fonction de la masse de la composition pharmaceutique, le nombre viable d'Akkermansia muciniphila est de 106-1014 UFC/g, et la teneur en metformine est de 20-60 %.
PCT/CN2021/074307 2020-02-17 2021-01-29 Composition d'akkermansia muciniphila WO2021164523A1 (fr)

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CN111202752A (zh) * 2020-02-17 2020-05-29 上海市内分泌代谢病研究所 阿克曼氏菌组合物
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