CN117137864A - Carrageenan in-situ gel preparation and preparation method and application thereof - Google Patents

Carrageenan in-situ gel preparation and preparation method and application thereof Download PDF

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Publication number
CN117137864A
CN117137864A CN202311438862.8A CN202311438862A CN117137864A CN 117137864 A CN117137864 A CN 117137864A CN 202311438862 A CN202311438862 A CN 202311438862A CN 117137864 A CN117137864 A CN 117137864A
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China
Prior art keywords
situ gel
kali
lazine
polylactic acid
preparation
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CN202311438862.8A
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Chinese (zh)
Inventor
仇威王
孙弘
孙钲
贺敦伟
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Zezheng Shanghai Biotechnology Co ltd
Shandong Hi Qual Pharmatech Co ltd
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Zezheng Shanghai Biotechnology Co ltd
Shandong Hi Qual Pharmatech Co ltd
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Priority to CN202311438862.8A priority Critical patent/CN117137864A/en
Publication of CN117137864A publication Critical patent/CN117137864A/en
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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
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • 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
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia

Abstract

The invention provides a calicheazine in-situ gel preparation, and a preparation method and application thereof, and belongs to the field of pharmaceutical preparations. The kali-Lazine in-situ gel preparation comprises, by weight, 10% -50% of an active ingredient, 10% -60% of a gel matrix, 0.1% -10% of a rate regulator and 10% -80% of a solvent. The prepared kali lazine in situ gel preparation can achieve the purpose of regulating the release rate of the medicine in the in situ gel through the formula, so that the rate of the whole medicine release stage is controlled, the damage to the body caused by the fluctuation of the blood concentration is avoided, and the kali lazine in situ gel preparation has good tissue compatibility and is convenient to use.

Description

Carrageenan in-situ gel preparation and preparation method and application thereof
Technical Field
The invention belongs to the field of pharmaceutical preparations, and particularly relates to a kalirazine in-situ gel preparation, and a preparation method and application thereof.
Background
The calicheazine is an anti-schizophrenia D3R/D2R partial agonist, has the characteristic of combining the D3R and DA partial agonists, has the D3R/D2R selectivity of about 10 times, and can be used for treating bipolar disorder type I with mania or mixed attacks and adult schizophrenia patients.
Studies have shown that it is difficult to administer drugs by non-invasive routes, including the oral route, due to factors such as the physicochemical instability of some drugs in the gastrointestinal tract, the difficulty of the drug entering the body, and the short half-life of the drug in the blood. Although bioavailability can be ensured by enteral route, the half-life of the drug in the blood is short and there is a need to increase the frequency of injection. To solve these problems, a long-acting injection preparation is proposed as one solution. The long-acting injection preparation can maintain the concentration of the medicine for a longer time by continuously releasing the medicine, thereby obtaining better treatment effect. The long-acting injectable formulations have clinical advantages in the treatment of bipolar disorders and affective disorders.
One of the most significant advantages of the long-acting injectable formulation is the ability to continuously release the drug in a controlled manner over a target therapeutic range for a duration of up to several months, thereby maintaining the concentration of the drug in the blood to achieve therapeutic effects. The long-acting injectable formulation can reduce fluctuation of the drug concentration in blood, thereby reducing systemic side effects, and can locally deliver the drug to achieve therapeutic effect at a specific site, as compared to the conventional typical drug regimen. These properties also improve patient compliance by reducing the number of drug uses. Although preformed in vitro slow release systems also have these advantages, the use of a long-acting injectable formulation is more patient friendly than the use of a long-acting injectable formulation because of its less invasive manner of application and less painful sensation.
Compared with the traditional injection, the in-situ gel has the advantages of being applicable to local administration of lesion sites, prolonging the drug release period, reducing the administration dosage and adverse drug reaction, avoiding pain when the implant is opened and implanted, having good patient compliance, being relatively simple in preparation process and the like. Currently, in situ gels have been disclosed: doxycycline in situ gel injection (for periodontal disease treatment), leuprorelin acetate in situ gel injection (for prostate cancer), and the like.
However, the existing in-situ gel technology also has the defects, such as abrupt drug release, difficulty in adjusting the drug release rate and the like. In most in situ gel formulations, there is a problem of drug burst, which is very prone to cause adverse reactions, and has become a bottleneck problem restricting development and application thereof. In addition, how to control the overall drug release rate of the in situ gel formulation to achieve the desired clinical efficacy is also a difficult problem restricting the application of the in situ gel technology.
The prior art CN102580056B discloses a sustained release injection containing antidiuretic components and a preparation method thereof; the weight percentage of desmopressin acetate as a main medicine is preferably 10% -50%; the slow release auxiliary material is preferably 50-90 percent of PLA and 50-90 percent of PLGA (3:1); the suspending agent is preferably 1.5% sodium carboxymethyl cellulose, 1.5% sodium carboxymethyl cellulose and 0.1% tween 80, 1.5% sodium carboxymethyl cellulose and 15% sorbitol and 0.1% tween 80; the release amount of the preparation for 24 hours is 18.2 percent respectively, the initial release rate is high, the components are more, and the process operation is complex.
The prior art CN104027299A discloses an itraconazole temperature-sensitive gel preparation, and a preparation method and application thereof; the components are as follows: 0.02-3% of medicine, 0.05-15% of solubilizer, 5-50% of gel matrix, 0-15% of bioadhesive, 0.001-2% of preservative, 0-10% of other additives and the balance of solvent. The components are complex, and the prepared gel preparation has uneven drug release rate, thus causing the problems of unstable absorption and the like.
Disclosure of Invention
In order to solve the problems, the invention develops a kali-Lazine in-situ gel preparation and a preparation method thereof, and the kali-Lazine in-situ gel preparation prepared by the invention can effectively control the drug release rate of in-situ gel.
In one aspect, the invention provides an in situ gel formulation of calicheazine.
Specifically, the kali lazine in-situ gel preparation comprises 10% -50% of active ingredient, 10% -60% of gel matrix, 0.1% -10% of rate regulator and 10% -80% of solvent according to weight ratio.
Specifically, the gel matrix is selected from one or more of polylactic acid, polycaprolactone, polylactic acid-glycolic acid copolymer, polyethylene glycol-polylactic acid-glycolic acid block copolymer, polyethylene glycol-polylactic acid block copolymer, sucrose acetate isobutyrate, polyethylene carbonate, poly N-isopropyl acrylamide and sucrose acetate isobutyrate.
Preferably, the gel matrix comprises polylactic acid-glycolic acid copolymer; the number average molecular weight of the polylactic acid-glycolic acid copolymer can be 4000-50000.
Specifically, the molar ratio of the polylactic acid-glycolic acid copolymer monomer may be 5 to 95:95-5.
Preferably, the molar ratio of the polylactic acid-glycolic acid copolymer monomer may be 50:50; the polylactic acid-glycolic acid copolymer end cap is selected from one or more of ester end cap, carboxylic acid end cap, amino end cap and methanesulfonic acid end cap.
Specifically, the polyethylene glycol-polylactic acid-glycolic acid block copolymer is selected from diblock copolymer PEG-PLGA or triblock copolymer PLGA-PEG-PLGA, and the number average molecular weight of the polyethylene glycol-polylactic acid-glycolic acid block copolymer can be 4000-50000.
The polyethylene glycol-polylactic acid segmented copolymer is a diblock copolymer PEG-PDLLA or a triblock copolymer PDLLA-PEG-PDLLA, and the molecular weight can be 4000-50000.
Specifically, the rate regulator is one or more selected from polyvinylpyrrolidone, ethyl heptanoate, glyceryl triacetate and glycerin.
Preferably, the rate modifier comprises polyvinylpyrrolidone.
Specifically, the rate regulator further comprises one or more of hypromellose, methylcellulose, microcrystalline cellulose, PVP, PEG1500, PEG4000 and PEG 6000.
Specifically, the solvent is selected from one or more of N-methyl pyrrolidone, N-dimethylformamide, N-dimethylacetamide, dimethyl sulfoxide, acetone, benzyl alcohol, absolute ethyl alcohol, tetraethylene glycol, ethyl acetate, glyceryl triacetate, ethyl benzoate, benzyl benzoate, propylene carbonate, glyceraldehyde, tetrahydrofuran polyethylene glycol ether, 2-pyrrolidone and water for injection.
Preferably, the solvent comprises N-methylpyrrolidone.
Specifically, the active ingredient is selected from one or more of the group consisting of the kali-lazil, the lauric acid kali-lazil and the hydrochloric acid kali-lazil.
Preferably, the active ingredient comprises a calicheazine hydrochloride.
The in situ gel preparation of the calicheazine can be an injection. The volume of the injection can be 0.1mL-3mL. Preferably, the volume of the injection can be 0.1mL-1mL.
On the other hand, the invention provides a preparation method of the kali-Lazine in-situ gel preparation.
Specifically, the preparation method comprises the steps of adding the gel matrix into a solvent for dissolution, carrying out ultrasonic treatment, adding a rate regulator for dissolution, adding an active ingredient, and carrying out ultrasonic treatment.
Preferably, the ultrasonic time may be 20-60min.
In a further aspect, the invention provides the use of an in situ gel formulation of calicheazine as described above in the manufacture of a medicament for the treatment and/or prophylaxis of schizophrenia, bipolar disorders and/or acute mania.
The invention has the beneficial effects that:
the invention provides a calicheazine in-situ gel preparation and a preparation method thereof. The kali-Lazine in-situ gel preparation comprises, by weight, 10% -50% of an active ingredient, 10% -60% of a gel matrix, 0.1% -10% of a rate regulator and 10% -80% of a solvent. The prepared kali lazine in situ gel preparation can achieve the purpose of regulating the release rate of the medicine in the in situ gel through the formula, so that the rate of the whole medicine release stage is controlled, the damage to the body caused by the fluctuation of the blood concentration is avoided, and the kali lazine in situ gel preparation has good tissue compatibility and is convenient to use.
Drawings
FIG. 1 is an initial in vitro release profile of example 4.
FIG. 2 is an initial in vitro release profile of example 5.
FIG. 3 is an initial in vitro release profile of example 6.
FIG. 4 is an initial in vitro release profile of example 10.
FIG. 5 is an initial in vitro release profile of example 11.
FIG. 6 is an initial in vitro release profile of example 12.
Detailed Description
The present invention will be described in further detail with reference to the following examples, which are not intended to limit the present invention, but are merely illustrative of the present invention. The experimental methods used in the following examples are not specifically described, but the experimental methods in which specific conditions are not specified in the examples are generally carried out under conventional conditions, and the materials, reagents, etc. used in the following examples are commercially available unless otherwise specified.
Example 1
150mg of PLGA (polylactic acid-glycolic acid copolymer) having a number average molecular weight Mn of 4500 is weighed out; LA, ga=50:50; dissolving the weighed PLGA in 600 mu L of NMP (N-methylpyrrolidone), carrying out ultrasonic treatment for 30min, adding 50mg of the kallizine hydrochloride after the PLGA is completely dissolved, and carrying out ultrasonic treatment for 30min to obtain the kallizine in-situ gel long-acting injection.
Example 2
150mg of PLGA (Mn=11000, LA:GA=50:50) is weighed and dissolved in 600 mu L of NMP, ultrasonic treatment is carried out for 30min, 50mg of kallizine hydrochloride is added after PLGA is completely dissolved, ultrasonic treatment is carried out for 30min, and the kallizine in-situ gel long-acting injection is prepared.
Example 3
150mg of PLGA (Mn=12000, LA:GA=50:50) is weighed and dissolved in 600 mu L of NMP, ultrasonic treatment is carried out for 30min, 50mg of kallizine hydrochloride is added after PLGA is completely dissolved, ultrasonic treatment is carried out for 30min, and the kallizine in-situ gel long-acting injection is prepared.
Example 4
150mg of PLGA (Mn=24000, LA:GA=50:50) is weighed and dissolved in 600 mu L of NMP, ultrasonic treatment is carried out for 30min, 50mg of kallizine hydrochloride is added after PLGA is completely dissolved, ultrasonic treatment is carried out for 30min, and the kallizine in-situ gel long-acting injection is prepared.
Example 5
150mg of PLGA (Mn=29000, LA:GA=50:50) is weighed and dissolved in 600 mu L of NMP, ultrasonic treatment is carried out for 30min, 50mg of kallizine hydrochloride is added after PLGA is completely dissolved, ultrasonic treatment is carried out for 30min, and the kallizine in-situ gel long-acting injection is prepared.
Example 6
150mg of PLGA (Mn=42000, LA:GA=50:50) is weighed and dissolved in 600 mu L of NMP, ultrasonic treatment is carried out for 30min, 50mg of kallizine hydrochloride is added after PLGA is completely dissolved, ultrasonic treatment is carried out for 30min, and the kallizine in-situ gel long-acting injection is prepared.
Example 7
150mg of PLGA (Mn=4500, LA: GA=50:50) is weighed and dissolved in 600 mu L of NMP, ultrasonic treatment is carried out for 30min, after PLGA is completely dissolved, 1wt% of polyvinylpyrrolidone is added, finally 50mg of kali-Lazine hydrochloride is added, and ultrasonic treatment is carried out for 30min, so that the kali-Lazine in-situ gel long-acting injection is prepared.
Example 8
150mg of PLGA (Mn=11000, LA:GA=50:50) is weighed and dissolved in 600 mu L of NMP, ultrasonic treatment is carried out for 30min, after PLGA is completely dissolved, 1wt% of polyvinylpyrrolidone is added, finally 50mg of kali-Lazine hydrochloride is added, and ultrasonic treatment is carried out for 30min, thus obtaining the kali-Lazine in-situ gel long-acting injection.
Example 9
150mg of PLGA (Mn=12000, LA:GA=50:50) is weighed and dissolved in 600 mu L of NMP, ultrasonic treatment is carried out for 30min, after PLGA is completely dissolved, 1wt% of polyvinylpyrrolidone is added, finally 50mg of kali-Lazine hydrochloride is added, and ultrasonic treatment is carried out for 30min, thus obtaining the kali-Lazine in-situ gel long-acting injection.
Example 10
150mg of PLGA (Mn=24000, LA:GA=50:50) is weighed and dissolved in 600 mu L of NMP, ultrasonic treatment is carried out for 30min, after PLGA is completely dissolved, 1wt% of polyvinylpyrrolidone is added, and finally 50mg of kali-Lazine hydrochloride is added, and ultrasonic treatment is carried out for 30min, so that the kali-Lazine in-situ gel long-acting injection is prepared.
Example 11
150mg of PLGA (Mn=29000, LA:GA=50:50) is weighed and dissolved in 600 mu L of NMP, ultrasonic treatment is carried out for 30min, after PLGA is completely dissolved, 1wt% of polyvinylpyrrolidone is added, finally 50mg of kali-Lazine hydrochloride is added, and ultrasonic treatment is carried out for 30min, so that the kali-Lazine in-situ gel long-acting injection is prepared.
Example 12
150mg of PLGA (Mn=42000, LA:GA=50:50) is weighed and dissolved in 600 mu L of NMP, ultrasonic treatment is carried out for 30min, after PLGA is completely dissolved, 1wt% of polyvinylpyrrolidone is added, and finally 50mg of kallizine hydrochloride is added, and ultrasonic treatment is carried out for 30min, so that the kallizine in-situ gel long-acting injection is prepared.
Test examples
Drug release experiments were performed on the calicheazine in situ gel depot injections of examples 4-6 and examples 10-12. The method comprises the step of slowly injecting the prepared long-acting injection of the kali-Lazine in-situ gel into 2mL of release medium, wherein the release medium is phosphate buffer solution with the pH value of 3.0. After forming solid blocks, the solid blocks are placed in a constant temperature oscillator at 37 ℃ for oscillation release, and the rotating speed is 110rmp/min. Samples were taken after 1, 2, 3, 4, 5 days and replaced with new release medium after sampling. The cumulative percent release was tested by high-performance liquid chromatography.
The test instrument and the equipment comprise: high performance liquid chromatograph Agilent 1260; dissolution instrument 705-DS/805-DS; filter PTFE (0.45 μm).
The specific detection method comprises the following steps:
chromatographic conditions: high performance liquid chromatography (VWD); the chromatographic column is TSKgel ODS-100V (250 mm. Times.4.6 mm, 5 μm); mobile phase 10mM KH 2 PO 4 Solution (pH 3.0) -acetonitrile (50:50); detection wavelength 215nm; a sample injection volume of 20 mu L; the flow rate is 1.0mL/min; column temperature is 30 ℃; run time was 5min.
API (pharmaceutically active ingredient) solution: weighing about 10mg of API, precisely weighing, placing into a 100ml measuring flask, dissolving with mobile phase, diluting to scale, and shaking; two portions were prepared in parallel.
The calculation formula is as follows:
；/>；
wherein:
c is the concentration of the solution of the test sample, mg/mL;
A U 、A S the main peak area of the sample solution and the main peak area of the API solution are respectively;
C S concentration of API solution, mg/mL;
C n 、C n-i sequentially sampling the sample for the nth time and the first time to calculate the concentration (mg/mL) of the obtained sample solution;
m is the sample amount of the test sample and mg;
V n to dissolve the medium volume, mL.
The detection result is as follows:
the initial in vitro release profiles for examples 4-6 are shown in FIGS. 1-3, with 24h release of 24.1%, 23.2% and 21.7%, respectively.
The initial in vitro release profiles for examples 10-12 are shown in FIGS. 4-6, with 24h release rates of 14.0%, 13.7% and 10.7%, respectively.
From the results of examples 4-6 and examples 10-12, it is clear that the present invention is effective in controlling the initial burst of pharmaceutically active ingredient from a gel formulation by adding the rate modifier polyvinylpyrrolidone to the formulation. After the rate regulator polyvinylpyrrolidone is added into the prescription of the in-situ gel preparation, the 24-hour initial release amount of the long-acting injection of the calicheazine in-situ gel is lower than 14.0%, and the risk caused by sudden increase of blood concentration is effectively avoided.
Comparative example 1
150mg of PLGA (Mn=3000, LA:GA=50:50) is weighed and dissolved in 600 mu L of NMP, ultrasonic treatment is carried out for 30min, 50mg of kallizine hydrochloride is added after PLGA is completely dissolved, ultrasonic treatment is carried out for 30min, and the kallizine in-situ gel long-acting injection is prepared. After the prepared long-acting injection of the kali-Lazine in-situ gel is slowly injected into 2mL of release medium, wherein the release medium is phosphate buffer solution with pH of 3.0, stable massive solids cannot be formed, and stable gel-like drug storage cannot be formed.
Comparative example 2
150mg of PLGA (Mn=65000, LA:GA=50:50) is weighed and dissolved in 600 mu L of NMP, ultrasonic treatment is carried out for 30min, 50mg of kallizine hydrochloride is added after PLGA is completely dissolved, ultrasonic treatment is carried out for 30min, and the kallizine in-situ gel long-acting injection is prepared. After the prepared long-acting injection of the kali-Lazine in-situ gel is slowly injected into 2mL of release medium, wherein the release medium is phosphate buffer solution with pH of 3.0, stable massive solids cannot be formed, and stable gel-like drug storage cannot be formed.
Comparative example 3
150mg of PLGA (Mn=85000, LA:GA=50:50) is weighed and dissolved in 600 mu L of NMP, ultrasonic treatment is carried out for 30min, 50mg of kallizine hydrochloride is added after PLGA is completely dissolved, ultrasonic treatment is carried out for 30min, and the kallizine in-situ gel long-acting injection is prepared. After the prepared long-acting injection of the kali-Lazine in-situ gel is slowly injected into 2mL of release medium, wherein the release medium is phosphate buffer solution with pH of 3.0, stable massive solids cannot be formed, and stable gel-like drug storage cannot be formed.

Claims (8)

1. The kali-Lazine in-situ gel preparation is characterized by comprising, by weight, 10% -50% of an active ingredient, 10% -60% of a gel matrix, 0.1% -10% of a rate regulator and 10% -80% of a solvent;
the active ingredient is selected from one or more of the following components of the kali lazine, the lauric acid kali lazine and the hydrochloric acid kali lazine;
the rate regulator is one or more selected from polyvinylpyrrolidone, ethyl heptanoate, glyceryl triacetate and glycerin.
2. The in situ gel formulation of claim 1, wherein the gel matrix is selected from one or more of polylactic acid, polycaprolactone, polylactic acid-glycolic acid copolymer, polyethylene glycol-polylactic acid-glycolic acid block copolymer, polyethylene glycol-polylactic acid block copolymer, sucrose acetate isobutyrate, polyethylene carbonate, poly N-isopropylacrylamide, sucrose acetate isobutyrate; the number average molecular weight of the polylactic acid-glycolic acid copolymer is 4000-50000.
3. The kali lazine in situ gel formulation according to claim 2, wherein the molar ratio of polylactic acid-glycolic acid copolymer monomers is 5-95:95-5.
4. The kali lazine in situ gel formulation according to claim 3, wherein the molar ratio of polylactic acid-glycolic acid copolymer monomers is 50:50; the polylactic acid-glycolic acid copolymer end cap is selected from one or more of ester end cap, carboxylic acid end cap, amino end cap and methanesulfonic acid end cap.
5. The in situ gel formulation of claim 4, wherein the rate modifier further comprises one or more of hypromellose, methylcellulose, microcrystalline cellulose, PVP, PEG1500, PEG4000, and PEG 6000.
6. The in situ gel formulation of claim 1, wherein the solvent is selected from one or more of N-methylpyrrolidone, N-dimethylformamide, N-dimethylacetamide, dimethylsulfoxide, acetone, benzyl alcohol, absolute ethyl alcohol, tetraethylene glycol, ethyl acetate, glyceryl triacetate, ethyl benzoate, benzyl benzoate, propylene carbonate, glyceraldehyde, polyethylene glycol tetrahydrofurane ether, 2-pyrrolidone, and water for injection.
7. A method for preparing a kali lazine in situ gel formulation according to any of claims 1 to 6, comprising dissolving the gel matrix in a solvent, performing an ultrasonic treatment, adding a rate regulator, dissolving, adding an active ingredient, and performing an ultrasonic treatment; the ultrasonic time is 20-60min.
8. Use of a brilazine in situ gel formulation according to any one of claims 1 to 6 in the manufacture of a medicament for the treatment or prophylaxis of schizophrenia, bipolar disorders or mania.
CN202311438862.8A 2023-11-01 2023-11-01 Carrageenan in-situ gel preparation and preparation method and application thereof Pending CN117137864A (en)

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