CN115463209A - Oral hypoglycemic composition and application thereof - Google Patents

Oral hypoglycemic composition and application thereof Download PDF

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CN115463209A
CN115463209A CN202111177424.1A CN202111177424A CN115463209A CN 115463209 A CN115463209 A CN 115463209A CN 202111177424 A CN202111177424 A CN 202111177424A CN 115463209 A CN115463209 A CN 115463209A
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彭文
吕荟
张磊
梁晓晖
曹居祥
柏冠军
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Shandong Haibang Biotechnology Co ltd
Shanghai Hai'ao Biotechnology Co ltd
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Hefei Tianhui Anchao Biotechnology Co ltd
Shanghai Hai'ao Biotechnology Co ltd
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    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/56—Materials from animals other than mammals
    • A61K35/60—Fish, e.g. seahorses; Fish eggs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • 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

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Abstract

The invention relates to the technical field of polypeptides, and discloses an oral hypoglycemic composition and application thereof. The compositions of the invention include GLP-1 analogs, sodium N- (8- (2-hydroxybenzoyl) amino) caprylate and fish oil. The composition has high and lasting blood sugar lowering effect, can maintain good blood sugar lowering effect when being taken orally, and can be used for developing oral blood sugar lowering medicines.

Description

Oral hypoglycemic composition and application thereof
Technical Field
The invention relates to the technical field of polypeptides, in particular to an oral hypoglycemic composition and application thereof.
Background
Type 2 diabetes is a chronic metabolic disease caused by insufficient insulin secretion or insulin resistance in the body, and currently, diabetic patients are expected to number 4 billion worldwide. GLP-1 receptor agonists have been increasingly used in recent years for lowering blood glucose, and they enter the blood to bind to GLP-1 receptors, enhance glucose utilization in peripheral tissues by promoting insulin synthesis and secretion of pancreatic islets, inhibiting glucagon secretion, and reduce hepatic glucose output to thereby lower blood glucose.
Human glucagon-like peptide-1 (GLP-1) is incretin produced by L cells of ileum and colon, the activity of GLP-1 (1-37) is extremely low, GLP-1 (7-37) with biological activity is formed after N-terminal 6 peptide is removed, and the sequence of human GLP-1 (7-37) is as follows:
Figure BDA0003295847970000011
however, human GLP-1 (7-37) is secreted into the blood with a half-life of only 3-5 minutes due to its extreme susceptibility to degradation by DDP-IV and clearance by glomerular filtration.
GLP-1 analogs currently available generally work by injection. However, the disadvantages of the injections are more evident: 1. the use is inconvenient; 2. injections often cause significant pain. Therefore, the development of the medicine with high-efficiency and long-lasting oral blood sugar reducing effect has great application significance for the treatment of diabetes.
Disclosure of Invention
In view of the above, the present invention aims to provide an oral hypoglycemic composition and an application thereof. Experiments show that the hypoglycemic composition still has obvious hypoglycemic effect when being taken orally.
In order to achieve the above purpose, the invention provides the following technical scheme:
an oral hypoglycemic composition comprising GLP-1 analogue, sodium N- (8- (2-hydroxybenzoyl) amino) caprylate and fish oil;
the GLP-1 analogue is at least one of I) to III):
i) The polypeptide has an amino acid sequence shown in SEQ ID NO.1, and the 2 nd cysteine and the 13 th cysteine of the sequence shown in SEQ ID NO.1 form an intramolecular disulfide bond; or
II) a polypeptide having the same or similar function as I) obtained by substituting, deleting or adding one or more amino acids in the polypeptide of I); or
III), a polypeptide which has at least 90% homology with the amino acid sequence shown in I) and has the same or similar function with I).
Preferably, the mass ratio of the GLP-1 analogue, the sodium N- (8- (2-hydroxybenzoyl) amino) caprylate and the fish oil is (7-15): (30-300): (20 to 84). In some embodiments, the mass ratio of the GLP-1 analogue, sodium N- (8- (2-hydroxybenzoyl) amino) caprylate and fish oil is 10.
Preferably, the GLP-1 analog is: 6-7 20 common amino acids are additionally added at the C end of the amino acid sequence shown in SEQ ID NO.1, and the 2 nd cysteine and the 13 th cysteine form an intramolecular disulfide bond.
In some embodiments of the invention, the amino acid sequence of the GLP-1 analog is the amino acid sequence shown in any one of SEQ ID No.2 or SEQ ID No.3, and the cysteine at position 2 and the cysteine at position 13 of the sequence shown in any one of SEQ ID No.2 or SEQ ID No.3 form an intramolecular disulfide bond.
Experiments show that compared with the existing product, the GLP-1 analogue provided by the invention has more excellent capability of controlling blood sugar and more lasting effect after being optimized.
According to the GLP-1 analogue, a liquid phase synthesis process, a solid phase synthesis process or a solid-liquid combined synthesis process is adopted to synthesize linear polypeptide according to an amino acid sequence of the GLP-1 analogue, and then the linear polypeptide is oxidized to form a disulfide bond to obtain the GLP-1 analogue.
In a specific embodiment of the invention, the GLP-1 analogue is synthesized by a solid phase synthesis process, the method for purifying the linear polypeptide adopts an HPLC method, and the oxidation for forming the disulfide bond adopts ammonium bicarbonate or DMSO for oxidation for forming the disulfide bond.
The composition takes a specific GLP-1 analogue as an active ingredient, and the active ingredient is reasonably matched with a specific component of sodium N- (8- (2-hydroxybenzoyl) amino) caprylate and fish oil according to a specific proportion. The blood sugar reduction experiment result shows that the obtained composition has lasting and effective blood sugar reduction effect after oral administration; based on the excellent technical effect, the invention provides the application of the oral hypoglycemic composition in preparing the medicines for treating or preventing diabetes.
The invention relates to a medicine for preventing or treating diabetes, which comprises an oral hypoglycemic composition. As a further preferred embodiment, it may further comprise pharmaceutically acceptable auxiliary materials and/or pharmaceutical ingredients for the treatment of other diseases without affecting the activity of the GLP-1 analogue.
The medicine can be prepared into any form of dosage forms in clinic, and mainly comprises oral dosage forms or injection dosage forms, wherein the injection dosage forms comprise transfusion type medicine dosage forms, and the dosage forms comprise but are not limited to tablets, granules, pills, oral liquid, freeze-dried powder, injection, capsules and microcapsules.
The composition of the invention comprises GLP-1 analogues, sodium N- (8- (2-hydroxybenzoyl) amino) caprylate and fish oil. The composition has high and lasting blood sugar lowering effect, can maintain good blood sugar lowering effect when being taken orally, and can be used for developing oral blood sugar lowering medicines.
Drawings
FIG. 1 shows the hypoglycemic effect of GLP-1 analogues in the hypoglycemic composition of the present invention;
FIG. 2 is a line graph of mean blood glucose over time for the composition of example 4 of the present invention.
Detailed Description
The embodiment of the invention discloses an oral hypoglycemic composition and application thereof, and a person skilled in the art can appropriately improve process parameters by referring to the content. It is expressly intended that all such similar substitutes and modifications which would be obvious to those skilled in the art are deemed to be included within the invention. While the oral hypoglycemic composition and the application thereof of the present invention have been described in the preferred embodiments, it is obvious to those skilled in the art that the oral hypoglycemic composition and the application thereof described herein can be modified or properly changed and combined to realize and apply the technology of the present invention without departing from the content, spirit and scope of the present invention.
In the comparison experiment in the specific embodiment of the invention, except the due differences of the settings of each group, other experiment conditions, raw materials, reagents and the like which are not explicitly mentioned are kept consistent, so that the comparability of the comparison experiment is ensured.
In the invention, the amino acid sequence shown in SEQ ID NO.1 is as follows:
HCEGTFTSDVSSCYLEKQAAKEFIAXLVK。
wherein, amino acid X = Trp or Tyr at position 26.
The GLP-1 analogue provided by the invention is further optimized on the basis of the amino acid sequence shown in SEQ ID NO.1, and the obtained polypeptide shows high-efficiency and lasting hypoglycemic effect, and can be widely used in development of diabetes drugs.
In some embodiments, the GLP-1 analogs provided by the invention have 6-7 additional 20 common amino acids at the C-terminal of the amino acid sequence shown in SEQ ID No.1, and the cysteine at position 2 and the cysteine at position 13 form an intramolecular disulfide bond.
In some embodiments, the GLP-1 analogue has 7 common amino acids added to the C-terminal of the amino acid sequence shown in SEQ ID No.1, the obtained polypeptide amino acid sequence is shown in SEQ ID No.2, and the cysteine at position 2 and the cysteine at position 13 form an intramolecular disulfide bond.
The sequence of SEQ ID NO.2 is as follows:
HCEGTFTSDVSSCYLEKQAAKEFIAWLVKAECHYGR。
in some embodiments, the GLP-1 analogue has an additional 6 common amino acids at the C-terminus of the amino acid sequence shown in SEQ ID No.1, the obtained polypeptide amino acid sequence is shown in SEQ ID No.3, and the cysteine at position 2 and the cysteine at position 13 form an intramolecular disulfide bond.
The sequence of SEQ ID NO.3 is as follows:
HCEGTFTSDVSSCYLEKQAAKEFIAYLVKFSQERG。
the GLP-1 analogue provided by the invention and a preparation method and application thereof are further explained below.
Example 1: preparation of GLP-1 analogs
Solid phase peptide synthesis by Fmoc strategy was performed using a peptide synthesizer according to the manufacturer's instructions. Sequentially synthesizing according to the sequence of an amino acid sequence shown in SEQ ID NO.2, removing a protecting group and resin to obtain a crude GLP-1 analogue intermediate product, dissolving the crude GLP-1 analogue intermediate product in water, purifying by using preparative HPLC (high performance liquid chromatography) and a C8 column, and purifying by using acetonitrile/water (V/V) =90: and 10, concentrating and freeze-drying to obtain a pure intermediate product of the GLP-1 analogue with free sulfhydryl. Dissolving the pure GLP-1 analogue intermediate product in water, oxidizing the pure GLP-1 analogue intermediate product by using ammonium bicarbonate or DMSO to form a disulfide bond, and purifying to obtain the GLP-1 analogue, wherein the sequence of the obtained GLP-1 analogue is as follows:
Figure BDA0003295847970000041
the dashed line indicates the intramolecular disulfide bond formed by the two cysteines.
SEQ ID NO.2：
HCEGTFTSDVSSCYLEKQAAKEFIAWLVKAECHYGR
EXAMPLE 2 preparation of GLP-1 analogs
Solid phase peptide synthesis by Fmoc strategy was performed using a peptide synthesizer according to the manufacturer's instructions. Sequentially synthesizing according to the sequence of an amino acid sequence shown in SEQ ID NO.3, removing a protecting group and resin to obtain a crude GLP-1 analogue intermediate product, dissolving the crude GLP-1 analogue intermediate product in water, purifying by using preparative HPLC (high performance liquid chromatography) and a C8 column, and purifying by using acetonitrile/water (V/V) =90: and 10, concentrating and freeze-drying to obtain a pure intermediate product of the GLP-1 analogue with free sulfhydryl. Dissolving the pure GLP-1 analogue intermediate product in water, oxidizing the pure GLP-1 analogue intermediate product with ammonium bicarbonate or DMSO to form a disulfide bond, and purifying to obtain the GLP-1 analogue, wherein the sequence of the obtained GLP-1 analogue is as follows:
Figure BDA0003295847970000051
the dashed line indicates the intramolecular disulfide bond formed by the two cysteines.
SEQ ID NO.3：
HCEGTFTSDVSSCYLEKQAAKEFIAYLVKFSQERG。
Example 3: blood sugar lowering experiment
Grouping:
24 normal mice were divided into 4 groups, blank, positive control, drug 1, drug 2, each group consisting of 6 mice.
The administration scheme is as follows:
the blank group of injection medicines is physiological saline;
the positive control group injected drug is liraglutide;
the medicine 1 group injection medicine is the GLP-1 analogue prepared in the embodiment 1 of the invention;
drug 2 group of injected drugs are GLP-1 analogs prepared in example 2 of the present invention.
After fasting for 12 hours before administration, fasting blood glucose of each group of mice is measured, 200 mul of physiological saline is injected subcutaneously into a blank group, 200 mul of liraglutide of 0.2mg/ml is injected into a positive control group, 200 mul of GLP-1 analogue of 0.2mg/ml prepared in the invention example 1 is injected into a drug 1 group, 200 mul of GLP-1 analogue of 0.2mg/ml prepared in the invention example 2 is injected into a drug 2 group, 200mg of glucose is immediately intragastrically injected into each group of mice after administration, and 200mg of glucose is repeatedly intragastrically injected into each group of mice every 12 hours. Glucose tolerance was measured at 6h, 24h, 36h, and 48h after administration, and blood glucose values at 15min, 30min, and 60min were measured to calculate blood glucose value AUC (mg/dl.min). The results are shown in FIG. 1.
The blood sugar measuring method comprises the following steps: a blood glucose meter.
FIG. 1 illustrates:
after administration for 4h, the medicine 1 group and the medicine 2 group have blood sugar lowering effect;
after 24 hours of administration, the positive control group has no hypoglycemic effect;
after 48 hours of administration, the 1 group of medicine and the 2 group of medicine still have obvious blood sugar reducing effect, and particularly the 2 group of medicine has more obvious blood sugar reducing effect.
EXAMPLE 4 preparation of GLP-1 analog-containing compositions
(1) Preparation of composition A
TABLE 1 composition of composition A
GLP-1 analogs prepared in example 1 10mg
Sodium N- (8- (2-hydroxybenzoyl) amino) caprylate 30mg
Fish oil 20mg
The preparation method comprises the following steps:
10mg of the GLP-1 analog prepared in example 1, 30mg of sodium N- (8- (2-hydroxybenzoyl) amino) caprylate and 20mg of fish oil were mixed, and the mixture was filled into a capsule and coated. Weighing Eudragit L30D, talcum powder and polyethylene glycol, dissolving with dichloromethane and isopropanol to obtain a coating solution, and spraying the coating solution onto the surface of the capsule to obtain the enteric-coated capsule. The flow rate of the coating solution is 1.5ml/min, the coating temperature is 35 ℃, and the coating weight is increased by 10%. Wherein, eudragit L30D: talc powder: polyethylene glycol =9:1:1 (weight ratio), dichloromethane: isopropanol =10 (volume ratio).
(2) Composition B
TABLE 2 composition of composition B
GLP-1 analogs prepared in example 1 12mg
Sodium N- (8- (2-hydroxybenzoyl) amino) caprylate 120mg
Fish oil 84mg
The preparation method comprises the following steps:
12mg of the GLP-1 analog prepared in example 1, 120mg of sodium N- (8- (2-hydroxybenzoyl) amino) caprylate and 84mg of fish oil were mixed, and the mixture was encapsulated and coated in a capsule. Weighing Eudragit L30D, talcum powder and polyethylene glycol, dissolving with dichloromethane and isopropanol to obtain a coating solution, and spraying the coating solution onto the surface of the capsule to obtain the enteric-coated capsule. The flow rate of the coating liquid is 1.2ml/min, the coating temperature is 33 ℃, and the coating weight is increased by 10 percent.
(3) Composition C
TABLE 3 composition of composition C
Example 2GLP-1 analogs 7mg
Sodium N- (8- (2-hydroxybenzoyl) amino) caprylate 35mg
Fish oil 21mg
The preparation method comprises the following steps:
7mg of the GLP-1 analog prepared in example 2, 35mg of sodium N- (8- (2-hydroxybenzoyl) amino) caprylate and 21mg of fish oil were mixed, and the mixture was encapsulated and coated in a capsule. Weighing Eudragit L30D, talcum powder and polyethylene glycol, dissolving with dichloromethane and isopropanol to obtain a coating solution, and spraying the coating solution onto the surface of the capsule to obtain the enteric-coated capsule. The flow rate of the coating liquid is 0.5ml/min, the coating temperature is 30 ℃, and the coating weight is increased by 8 percent.
(4) Composition D
TABLE 4 composition of composition D
EXAMPLE 2GLP-1 analogs prepared 15mg
Sodium N- (8- (2-hydroxybenzoyl) amino) caprylate 300mg
Fish oil 30mg
The preparation method comprises the following steps:
15mg of the GLP-1 analog prepared in example 2, 300mg of sodium N- (8- (2-hydroxybenzoyl) amino) caprylate and 30mg of fish oil were mixed, and filled into a capsule and coated. Weighing Eudragit L30D, talcum powder and polyethylene glycol, dissolving with dichloromethane and isopropanol to obtain a coating solution, and spraying the coating solution onto the surface of the capsule to obtain the enteric-coated capsule. The flow rate of the coating liquid is 0.8ml/min, the coating temperature is 45 ℃, and the coating weight is increased by 5%.
Comparative example 1 preparation of composition E (placebo)
TABLE 5 composition of composition E
EXAMPLE 2GLP-1 analogs prepared 0mg
Sodium N- (8- (2-hydroxybenzoyl) amino) caprylate 30mg
Fish oil 20mg
The preparation method comprises the following steps:
mixing 30mg of sodium N- (8- (2-hydroxybenzoyl) amino) caprylate and 20mg of fish oil, encapsulating, and coating. Weighing Eudragit L30D, talcum powder and polyethylene glycol, dissolving with dichloromethane and isopropanol to obtain a coating solution, and spraying the coating solution onto the surface of the capsule to obtain the enteric-coated capsule. The flow rate of the coating liquid is 1.0ml/min, the coating temperature is 40 ℃, and the coating weight is increased by 7 percent.
EXAMPLE 5 oral composition hypoglycemic assay
Grouping:
the healthy beagle dogs are randomly divided into 5 groups, 15 beagle dogs with the weight of 10-12 kg are adopted, double-crossing administration is adopted, 6 dogs are in each group, the elution period is 1-2 weeks, and the groups are (1) A; (2) group B; (3) group C; (4) group D; and (5) group E.
Administration dose:
group a oral composition a prepared in example 4;
group B oral composition B prepared in example 4;
group C oral composition C prepared in example 4;
group D oral composition D prepared in example 4;
group E composition E prepared in comparative example 1 was taken orally.
Blood sugar monitoring:
the animals in each group were fasted overnight for 12h, fasting blood glucose was measured, and then each group was orally administered one capsule of the corresponding group. After 30min of administration, each group of animals was intragastrically administered with 8g/kg of glucose. The blood glucose levels of the animals in each group were measured at 0h, 0.5h, 1h, and 1.5h after administration of glucose. And measuring the blood sugar by adopting a glucometer. Each blood glucose value on the coordinate axis is the average blood glucose value of 6 beagle dogs of the corresponding group at the corresponding time. The experimental results are shown in FIG. 2.
And (4) conclusion:
the composition A, the composition B, the composition C and the composition D all show the effect of reducing the blood sugar.
The foregoing is only for the purpose of understanding the method of the present invention and the core concept thereof, and it will be understood by those skilled in the art that various changes and modifications may be made without departing from the principle of the invention, and the invention also falls within the scope of the appended claims.
Sequence listing
<110> Shanghai \36188
<120> oral hypoglycemic composition and application thereof
<130> MP21025484
<160> 3
<170> SIPOSequenceListing 1.0
<210> 1
<211> 29
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> UNSURE
<222> (26)..(26)
<223> Xaa = Trp or Tyr
<220>
<221> UNSURE
<222> (26)..(26)
<223> The 'Xaa' at location 26 stands for Gln, Arg, Pro, or Leu.
<400> 1
His Cys Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Cys Tyr Leu Glu
1 5 10 15
Lys Gln Ala Ala Lys Glu Phe Ile Ala Xaa Leu Val Lys
20 25
<210> 2
<211> 36
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 2
His Cys Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Cys Tyr Leu Glu
1 5 10 15
Lys Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Ala Glu Cys
20 25 30
His Tyr Gly Arg
35
<210> 3
<211> 35
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 3
His Cys Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Cys Tyr Leu Glu
1 5 10 15
Lys Gln Ala Ala Lys Glu Phe Ile Ala Tyr Leu Val Lys Phe Ser Gln
20 25 30
Glu Arg Gly
35

Claims (9)

1. An oral hypoglycemic composition comprising a GLP-1 analog, sodium N- (8- (2-hydroxybenzoyl) amino) caprylate and fish oil;
the GLP-1 analogue is at least one of I) to III):
i) The polypeptide has an amino acid sequence shown in SEQ ID NO.1, and the 2 nd cysteine and the 13 th cysteine of the sequence shown in SEQ ID NO.1 form an intramolecular disulfide bond; or
II) a polypeptide having the same or similar function as that of I) obtained by substituting, deleting or adding one or more amino acids in the polypeptide of I); or
III), a polypeptide which has at least 90% homology with the amino acid sequence shown in I) and has the same or similar function with I).
2. The oral hypoglycemic composition of claim 1, wherein the mass ratio of the GLP-1 analogue, the sodium N- (8- (2-hydroxybenzoyl) amino) caprylate and the fish oil is (7-15): (30-300): (20 to 84).
3. The oral hypoglycemic composition of claim 1, wherein said GLP-1 analog is: 6-7 20 common amino acids are additionally added at the C end of the amino acid sequence shown in SEQ ID NO.1, and the 2 nd cysteine and the 13 th cysteine form an intramolecular disulfide bond.
4. The oral hypoglycemic composition according to claim 1 or 2, wherein the amino acid sequence of the GLP-1 analogue is the amino acid sequence shown in any one of SEQ ID No.2 or SEQ ID No.3, and the cysteine-2 and cysteine-13 of the sequence shown in any one of SEQ ID No.2 or SEQ ID No.3 form an intramolecular disulfide bond.
5. The use of the oral hypoglycemic composition as claimed in any of claims 1 to 4 in the preparation of a medicament for the treatment or prevention of diabetes.
6. A medicament for preventing or treating diabetes, which comprises the oral hypoglycemic composition of any one of claims 1 to 4.
7. The medicament of claim 6, further comprising pharmaceutically acceptable excipients and/or pharmaceutical ingredients for treating other diseases without affecting the activity of the GLP-1 analogue.
8. The medicament of claim 6 or 7, wherein the medicament is in an oral dosage form or an injectable dosage form.
9. The medicament of claim 8, wherein the oral dosage form comprises tablets, granules, pills, oral liquids, lyophilized powders, capsules and microcapsules.
CN202111177424.1A 2021-10-09 2021-10-09 Oral hypoglycemic composition and application thereof Pending CN115463209A (en)

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