Method for evaluating in-vivo and in-vitro correlation of carbocisteine tablets

Abstract

The invention discloses a method for evaluating in-vivo and in-vitro correlation of carbocisteine, which comprises the following steps of: establishing a PBPK model and an IVIVC model of carbocisteine by using GastroPlus software and adopting an ACAT absorption model and inputting physicochemical property parameters of medicines and preparations, human physiological information parameters and pharmacokinetic actual measurement data, predicting a drug-time curve of carbocisteine tablets according to an actual measurement dissolution curve, and evaluating the in-vivo and in-vitro correlation of carbocisteine. The method is of great significance in accelerating research and development of imitated drugs.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical testing, and in particular to a method for evaluating the in vivo and in vitro correlation of carbocysteine ​​tablets, a method for building a PBPK model of carbocysteine ​​tablets, a method for establishing an IVIVC model of carbocysteine ​​tablets, a PBPK model / IVIVC model of carbocysteine ​​tablets and applications thereof. Background Art

[0002] Carbocisteine, also known as S-carboxymethyl-L-cysteine ​​(SCMC), was introduced into clinical use in the early 1960s as a mucolytic agent and is well tolerated in the treatment of respiratory diseases that require clearance of excess mucus.

[0003] As an alternative method to evaluate the consistency of therapeutic effects between generic drugs and original drugs in addition to clinical trials, bioequivalence (BE) plays an important role in the consistency evaluation of drugs. If a good correlation is established between the in vitro characteristics obtained by the dissolution experiment and the in vivo characteristics, the in vitro dissolution behavior of the drug can better reflect its absorption behavior in vivo. Therefore, by establishing an in vivo-in vitro correlation (IVIVC) model of the drug, the in vitro dissolution test can be used to replace the human BE study to a certain extent, which is of great significance for accelerating the research and development of generic drugs.

[0004] With the rapid development of computer simulation technology, GastroPlus TM The software can simulate and predict the absorption rate and extent of drugs in the body, opening up a new way to evaluate the quality of drugs. TM The software can well simulate the absorption process of raw materials and related preparations in humans and animals. The U.S. Food and Drug Administration (FDA) highly recognizes the ACAT model, and the ACAT model has a high authority in the FDA and the pharmaceutical industry. TM The software has been widely used in many aspects such as in vitro and in vivo correlation of drugs, virtual bioequivalence experiments to determine biowaiver, etc., providing support for generic drug process improvement and drug bioequivalence evaluation.

[0005] Among the many research points in drug evaluation, in vitro-in vivo correlation study is the key and difficult point of drug evaluation. Good in vitro-in vivo correlation study can enable researchers to achieve the purpose of bioequivalence between the re-evaluated drug and the reference drug by controlling the similarity of certain in vitro characteristics between the re-evaluated drug and the reference drug.

[0006] Carbocisteine ​​is a BCS Class I drug. Although the types of excipients used in its tablets vary greatly from manufacturer to manufacturer, its preparations usually dissolve rapidly, and it is difficult to make bioequivalence judgments based on the dissolution differences of its tablets. Therefore, the current evaluation method for carbocisteine ​​tablets cannot effectively evaluate the pharmacokinetic characteristics in vivo.

[0007] Therefore, it is particularly important to develop an evaluation method that can well evaluate the pharmacokinetic characteristics of carbocysteine ​​tablets in vivo to accelerate the development of generic drugs. Summary of the invention

[0008] Based on the above problems, the present invention provides a method for evaluating the in vivo and in vitro correlation of carbocysteine ​​tablets. The method can predict the drug-time curve of carbocysteine ​​tablets according to the measured dissolution curve, which is of great significance for accelerating the research and development of generic drugs.

[0009] This method calculates the in vivo absorption curve of carbocysteine ​​tablets based on the PBPK model of carbocysteine ​​or the IVIVC model of carbocysteine ​​tablets and the in vivo pharmacokinetic parameters.

[0010] In one or more specific embodiments of the present application, in the PBPK modeling of the carbocysteine ​​tablets, solubility testing, particle size testing, in vitro permeability testing, and plasma protein binding rate determination of the carbocysteine ​​API were performed; or

[0011] In the IVIVC model building of the carbocysteine ​​tablets, the dissolution test of the carbocysteine ​​tablets was carried out, and the solubility, particle size, in vitro permeability and plasma protein binding rate of the carbocysteine ​​raw material were measured.

[0012] The present invention also provides a method for modeling a PBPK model of carbocysteine ​​tablets.

[0013] A method for modeling a PBPK model of carbocysteine ​​tablets comprises the following steps:

[0014] S1, obtain modeling parameters, including:

[0015] S11, determining the key parameters for building a PBPK model, wherein the key parameters include solubility, particle size, log P, pKa, Papp, and plasma protein binding rate of carbocysteine ​​API;

[0016] S12, in vivo concentration-time curve data and dissolution data of carbocysteine ​​preparation;

[0017] S2 with GastroPlus TM The software built the PBPK model of carbocysteine ​​and obtained the simulated drug-time curve.

[0018] In one or more specific embodiments of the present application, S1 further includes: S13, first-pass effect value.

[0019] In one or more specific embodiments of the present application, the P of carbocysteine app They are 5.97×10 - 6 cm / s (A→B direction) and 7.34×10 -7 cm / s (B→A direction), the efflux rate of carbocysteine ​​is 0.12; the plasma protein binding rate of carbocysteine ​​is 65.48%.

[0020] In one or more specific embodiments of the present application, the solubility determination method is: weigh 100 mg of carbocysteine ​​raw material and place it in a headspace bottle, add 2 mL of 11 solvents with different pH values, in triplicate, seal, shake at 37°C for 24 hours, take the supernatant after centrifugation, dilute 10 times for dissolution content determination; or / and

[0021] The particle size determination method is: using laser scattering method to analyze the particle size of carbocysteine ​​raw material; wherein, firstly, a methodological investigation is carried out, and the dispersion pressure of 0.5 bar, 1 bar, 2 bar, 3 bar, 4 bar and the vibration injection rate of 20%, 40%, 50%, 70%, 100% are investigated respectively, and the particle size determination method finally determined is the dispersion pressure of 4 bar and the vibration injection rate of 100%; or / and

[0022] The method for determining the Papp value is: when the drug concentration is 1.00 μM, the permeability of carbocysteine ​​MDCK cells is determined, and the Papp values ​​in the directions of A→B and B→A are calculated; or / and

[0023] The method for determining the plasma protein binding rate is: when the administration concentration is 10 μM, the binding of the carbocysteine ​​raw material drug and the plasma protein in human plasma is determined.

[0024] In one or more specific embodiments of the present application, the modeling parameters of the PBPK model are:

[0025] Chemical structure; molecular formula C5H9NO4S; relative molecular mass 179.1900; melting point 185-187℃; log P-4.24; pKa1 1.84; pKa2 4.05; pKa3 9.14; pH 3.0; solubility 1.92mg / mL; average particle size 79.731μm; Papp 0.597cm / s×10 5 ; Unbound percentage in plasma 34.52%; Whole blood-plasma distribution ratio 1.23Rbp; Clearance, CL, 8.3059L / h; Renal Clearance, CL, 2.4918L / h; Volume of Distribution 0.343 L / kg; The dosage form is 750mg carbocysteine ​​tablets, 1000mg carbocysteine ​​tablets, 750mg carbocysteine ​​capsules, 1500mg carbocysteine ​​capsules or 1500mg carbocysteine ​​syrup.

[0026] The present invention also provides a method for establishing an IVIVC model of carbocysteine ​​tablets.

[0027] A method for establishing an IVIVC model of carbocysteine ​​tablets comprises the following steps:

[0028] Q1, obtain PBPK modeling parameters through the above modeling method;

[0029] Q2, using the modeling parameters of Q1 to model the IVIVC model through the IVIVC module in the GastroPlusTM software;

[0030] Q3, obtain the dissolution curves of different carbocysteine ​​tablets in different dissolution media;

[0031] Q4, based on the established IVIVC model, the dissolution curves of Q3 were input respectively to obtain the simulated drug-time curves of different dissolution media.

[0032] In one or more specific embodiments of the present application, the dissolution medium is a pH 6.6 phosphate buffer.

[0033] In one or more specific embodiments of the present application, the dissolution curve method is: the second paddle method of Part IV General Rules 0931 of the 2020 edition of the Chinese Pharmacopoeia, temperature 37°C, speed 75r / min, sampling at 5, 10, 15, 30, 45, and 60 minutes, and replenishing the fluid at the same time, filtering with a 0.45μm filter membrane, and taking the filtrate.

[0034] The present invention also provides a PBPK model / IVIVC model of carbocysteine ​​tablets.

[0035] A PBPK model / IVIVC model of carbocysteine ​​tablets, wherein the PBPK model is constructed by the above-mentioned modeling method or the IVIVC model is constructed by the above-mentioned modeling method.

[0036] The present invention also provides the PBPK model / IVIVC model application of the above-mentioned carbocysteine ​​tablets.

[0037] The above-mentioned PBPK model / IVIVC model of carbocysteine ​​tablets is used to guide generic drug development and virtual bioequivalence evaluation.

[0038] The beneficial effects of this application are:

[0039] The present invention adopts GastroPlus TM The software built a PBPK model for carbocysteine. On this basis, by increasing the first-pass effect value, it was surprisingly found that after the first-pass effect value was set, the prediction results of the constructed model significantly improved the matching degree with the measured drug-time curve. On the basis of the PBPK model, the IVIVC model was further obtained, and the in vivo and in vitro dissolution correlation was good.

[0040] The present invention combines the physicochemical properties of carbocysteine ​​itself and provides a new idea for the exemption of human bioequivalence of BCS Class I drugs, which can encourage domestic pharmaceutical companies to reasonably carry out research on generic drugs and innovative drugs, improve the research and development level of generic drugs, reduce the research and development costs of domestic generic drugs, and improve the bioequivalence of generic drugs. BRIEF DESCRIPTION OF THE DRAWINGS

[0041] Figure 1 Comparison chart of the drug's in vivo PK curve predicted by the carbocysteine ​​PBPK model established before optimization and the measured value (oral administration of 750 mg carbocysteine ​​tablets);

[0042] Figure 2 Comparison diagram of the drug's in vivo PK curve predicted by the optimized PBPK model of carbocysteine ​​and the measured value (oral administration of 750 mg carbocysteine ​​tablets);

[0043] Figure 3 Comparison chart of the drug's in vivo PK curve predicted by the optimized PBPK model of carbocysteine ​​and the measured value (oral administration of 1000 mg carbocysteine ​​tablets);

[0044] Figure 4 Comparison diagram of the drug's in vivo PK curve predicted by the optimized PBPK model of carbocysteine ​​and the measured value (oral administration of 750 mg carbocysteine ​​capsules);

[0045] Figure 5 Comparison diagram of the drug's in vivo PK curve predicted by the optimized PBPK model of carbocysteine ​​and the measured value (oral administration of 1500mg carbocysteine ​​capsules);

[0046] Figure 6 Comparison diagram of the drug's in vivo PK curve predicted by the optimized PBPK model of carbocysteine ​​and the measured value (oral administration of 750 mg carbocysteine ​​syrup);

[0047] Figure 7Comparison chart of the drug's in vivo PK curve predicted by the optimized PBPK model of carbocysteine ​​and the measured value (oral administration of 1500 mg carbocysteine ​​syrup);

[0048] Figure 8 These are the dissolution curves of tablets from different manufacturers in aqueous dissolution media;

[0049] Fig. 9 These are the dissolution curves of tablets from different manufacturers in 0.1 mol / L HCl solution dissolution medium;

[0050] Fig.10 The dissolution curves of tablets from different manufacturers in pH 4.5 acetate buffer dissolution medium;

[0051] Fig.11 The dissolution curves of tablets from different manufacturers in pH 6.6 phosphate buffer dissolution medium;

[0052] Fig.12 Comparison chart of the drug's in vivo PK curve predicted by the established carbocysteine ​​IVIVC model and the measured value (oral administration of 750 mg carbocysteine ​​tablets);

[0053] Fig.13 Comparison chart of the in vivo dissolution curve of the drug predicted by the established carbocysteine ​​IVIVC model and the measured value of the in vitro dissolution curve (oral administration of 750mg carbocysteine ​​tablets);

[0054] Fig.14 Comparison chart of the drug's in vivo PK curve predicted by the established carbocysteine ​​IVIVC model and the measured value (oral administration of 750 mg carbocysteine ​​capsules);

[0055] Fig.15 Comparison chart of the in vivo dissolution curve of the drug predicted by the established carbocysteine ​​IVIVC model and the measured value of the in vitro dissolution curve (oral administration of 750mg carbocysteine ​​capsules);

[0056] Fig.16 It is the correlation curve of in vivo and in vitro dissolution;

[0057] Fig.17 This is the concentration-time curve of the reference preparation of carbocysteine ​​tablets predicted by the IVIVC model based on the dissolution curve (dissolution medium: water, dose: oral 750 mg);

[0058] Fig.18 A virtual BE comparison between the reference product and the IVIVC modeled product based on the predicted concentration-time profile (dissolution medium: water, dose: oral 750 mg);

[0059] Fig.19This is the concentration-time curve of the reference preparation of carbocysteine ​​tablets predicted by the IVIVC model based on the dissolution curve (dissolution medium: 0.1 mol / L HCl solution, dose: oral 750 mg);

[0060] Fig. 20 A virtual BE comparison between the reference product and the IVIVC modeled product based on the predicted drug-time profile (dissolution medium: 0.1 mol / L HCl solution, dose: oral 750 mg);

[0061] Fig.21 This is the concentration-time curve of the reference preparation of carbocysteine ​​tablets predicted by the IVIVC model based on the dissolution curve (dissolution medium: pH 4.5 acetate buffer, dose: oral 750 mg);

[0062] Fig. 22 A virtual BE comparison between the reference product and the IVIVC modeled product based on the predicted concentration-time profile (dissolution medium: pH 4.5 acetate buffer, dose: oral 750 mg);

[0063] Fig.23 This is the concentration-time curve of the reference preparation of carbocysteine ​​tablets predicted by the IVIVC model based on the dissolution curve (dissolution medium: pH 6.6 phosphate buffer, dose: oral 750 mg);

[0064] Fig.24 A virtual BE comparison was performed between the reference product and the IVIVC modeled product based on the predicted drug-time profile (dissolution medium: pH 6.6 phosphate buffer, dose: oral 750 mg). DETAILED DESCRIPTION

[0065] The present invention will be further described below.

[0066] The embodiments provided in the present invention are only for further explaining the present invention and should not be construed as any limitation to the present invention.

[0067] It should be clear to those skilled in the art that, unless otherwise specified, the materials and operating methods used in the present invention are well known in the art.

[0068] In the present invention, the method for determining the dissolution content is: high performance liquid chromatography, the chromatographic column is an octadecylsilane bonded silica gel chromatographic column as a filler, 0.005 mol / L sodium decane sulfonate 0.06 mol / L sodium dihydrogen phosphate solution (the pH value is adjusted to 2.2±0.02 with phosphoric acid)-methanol (85:15) is used as the mobile phase, the flow rate is 1.0 ml / min, the column temperature is 30°C, the detector wavelength is 215 nm, and the injection volume is 20 μL.

[0069] In the present invention, the particle size determination method is: the particle size of the carbocysteine ​​raw material is analyzed by laser scattering method (dry method). First, a methodological investigation is conducted, and the dispersion pressures of 0.5 bar, 1 bar, 2 bar, 3 bar, and 4 bar and the vibration injection rates of 20%, 40%, 50%, 70%, and 100% are investigated respectively. The particle size determination method finally determined is the dispersion pressure of 4 bar and the vibration injection rate of 100%.

[0070] In the present invention, the method for determining the in vitro permeability is: when the drug concentration is 1.00 μM, the permeability of carbocysteine ​​MDCK cells is determined, and the Papp values ​​in the directions A→B and B→A are calculated.

[0071] In the present invention, the method for determining the plasma protein binding rate is: when the administration concentration is 10 μM, the binding of carbocysteine ​​to plasma protein in human plasma is determined.

[0072] Example 1 PBPK model of carbocysteine ​​tablets

[0073] A method for establishing a PBPK model of carbocysteine ​​tablets comprises the following steps:

[0074] S1, obtain modeling parameters, including:

[0075] S11, determine the key parameters for building the PBPK model, such as solubility, particle size, log P, pKa and other physicochemical properties, Papp, plasma protein binding rate, and P of carbocysteine. app They are 5.97×10 -6 cm / s (A→B direction) and 7.34×10 -7 cm / s (B→A direction), the efflux rate of carbocysteine ​​is 0.12; the plasma protein binding rate of carbocysteine ​​is 65.48%.

[0076] In this step, the solubility is determined by:

[0077] Weigh 100 mg of carbocysteine ​​raw material and place it in a headspace bottle. Add 2 mL of 11 solvents with different pH values ​​(refer to the general rules of Part IV of the 2020 edition of the Chinese Pharmacopoeia) in triplicate, seal it, shake it at 37°C for 24 hours, take the supernatant after centrifugation, and dilute it 10 times for determination. The solubility of carbocysteine ​​raw material in 11 different media, including hydrochloric acid solution (pH 1.0, 2.0), citrate buffer (pH 3.0), acetate buffer (pH 4.0, 5.0), and phosphate buffer (pH 6.0, 7.0, 8.0, 9.0, 10.0, 11.0), was investigated.

[0078] The solubility of carbocysteine ​​in different pH media is shown in Table 1, and the particle size of carbocysteine ​​API is shown in Table 2.

[0079] Table 1 Solubility of carbocisteine ​​in different pH media

[0080]

[0081] Table 2 Carbocisteine ​​API particle size

[0082] factory <![CDATA[D 10 (μm)]]> <![CDATA[D 50 (μm)]]> <![CDATA[D 90 (μm)]]> Yunpeng 4.27 15.41 41.46 Yishu 12.06 88.22 248 Yanhetang 7.06 30.78 103.80 Wuhan Yuanda Hongyuan 6.67 29.00 97.12

[0083] S12, obtain the in vivo drug-dose curve data of 750 mg oral carbocysteine ​​tablets (by consulting relevant literature).

[0084] S2, with GastroPlus TM The software built the PBPK model of carbocysteine ​​and obtained the simulated drug-time curve.

[0085] S3, compare the simulated drug-time curve with the drug-time curve of S12, the results are as follows Figure 1 , Figure 1 In the figure, the curve is the drug-time curve simulated by the software, and □ is the actual drug-time curve data.

[0086] The results showed that the drug-time curve simulated by the software was significantly higher than the measured drug-time curve.

[0087] Example 2 PBPK model of carbocysteine ​​tablets

[0088] A method for establishing a PBPK model of carbocysteine ​​tablets comprises the following steps:

[0089] S1, obtain modeling parameters, including:

[0090] S11, determine the key parameters for building the PBPK model, such as solubility, particle size, log P, pKa and other physicochemical properties, Papp, plasma protein binding rate, and P of carbocysteine. app They are 5.97×10 -6 cm / s (A→B direction) and 7.34×10 -7 cm / s (B→A direction), the efflux rate of carbocysteine ​​is 0.12; the plasma protein binding rate of carbocysteine ​​is 65.48%.

[0091] In this step, the solubility is determined by:

[0092] Weigh 100 mg of carbocysteine ​​raw material and place it in a headspace bottle. Add 2 mL of 11 solvents with different pH values ​​(refer to the general rules of Part IV of the 2020 edition of the Chinese Pharmacopoeia) in triplicate, seal it, shake it at 37°C for 24 hours, take the supernatant after centrifugation, and dilute it 10 times for determination. The solubility of carbocysteine ​​raw material in 11 different media, including hydrochloric acid solution (pH 1.0, 2.0), citrate buffer (pH 3.0), acetate buffer (pH 4.0, 5.0), and phosphate buffer (pH 6.0, 7.0, 8.0, 9.0, 10.0, 11.0), was investigated.

[0093] The solubility of carbocysteine ​​in different pH media is shown in Table 1, and the particle size of carbocysteine ​​API is shown in Table 2.

[0094] S12, obtain the in vivo drug-dose curve data of 750 mg oral carbocysteine ​​tablets (by consulting relevant literature).

[0095] S13, optimize the first-pass effect value so that its predicted value matches the measured value.

[0096] S2, with GastroPlus TM The software built the PBPK model of carbocysteine ​​and obtained the simulated drug-time curve.

[0097] S3, compare the simulated drug-time curve with the drug-time curve of S12, the results are as follows Figure 2 , Figure 2 The results showed that the matching degree between the drug-time curve simulated by the software and the measured drug-time curve was significantly improved.

[0098] S4, the established model was validated using the in vivo drug-dose curve data (obtained by consulting relevant literature) of oral 1000 mg carbocysteine ​​tablets, oral 750 mg carbocysteine ​​capsules, oral 1500 mg carbocysteine ​​capsules, oral 750 mg carbocysteine ​​syrup, and oral 1500 mg carbocysteine ​​syrup. The results are as follows Figure 3-Figure 7 ,The results showed that the predicted drug-time curve was basically consistent with the ,measured drug-time curve.

[0099] Figure 2-Figure 7 In the figure, the curve is the drug-time curve simulated by the software, and □ is the actual drug-time curve data.

[0100] The modeling parameters established in this embodiment are shown in Table 3.

[0101] Table 3 Carbocisteine ​​PBPK modeling parameters of Example 2

[0102]

[0103] Example 3

[0104] A method for establishing an IVIVC model of carbocysteine ​​tablets comprises the following steps:

[0105] Q1. Obtain PBPK modeling parameters by establishing the PBPK model of Example 2 (such as the modeling parameters in Table 3 obtained in Example 2).

[0106] Q2, obtain the dissolution curves of different carbocysteine ​​tablets in different dissolution media.

[0107] The dissolution test was used to obtain the disintegration and release process of carbocysteine ​​tablets in vitro. The dissolution curves of carbocysteine ​​tablets in water, 0.1 mol / L HCl solution, pH 4.5 acetate buffer, and pH 6.6 phosphate buffer were measured. Figure 8-Figure 11 .

[0108] Figure 8-Figure 11 The results showed that the reference preparation and generic drug could achieve dissolution of more than 85% in the four dissolution media within 15 minutes.

[0109] In this step, the dissolution curve method is: the second paddle method of Part IV General Rules 0931 of the 2020 edition of the Chinese Pharmacopoeia, temperature 37°C, speed 75r / min, sampling at 5, 10, 15, 30, 45, and 60 minutes, and replenishing the solution at the same time, filtering with a 0.45μm filter membrane, and taking the filtrate.

[0110] Q3, using the modeling parameters of Q1 through GastroPlus TM The IVIVC module in the software inputs the oral 750mg carbocysteine ​​tablets and 750mg carbocysteine ​​capsules medication curve data and the corresponding dissolution curve data (obtained by consulting relevant literature) to establish the IVIVC model of carbocysteine.

[0111] Q4, compare the simulated drug-time curve based on the dissolution curve with the measured drug-time curve. The results are as follows Fig.12 and Fig.14 At the same time, the measured in vitro dissolution curve was compared with the predicted in vivo dissolution curve. The results are as follows Fig.13 and Fig.15 . Figure 11-Figure 14 In the figure, the curve is the drug-time curve simulated by the software, and the red ▲ is the actual drug-time curve data.

[0112] Carbocisteine ​​tablets were subjected to in vitro and in vivo correlation analysis. Fig.16 , indicating that the established IVIVC model has a good in vitro and in vivo dissolution correlation (R 2 =0.9466).

[0113] Example 4

[0114] Q1, through the established IVIVC model, the measured dissolution curve data of carbocysteine ​​tablets reference preparation were input to predict its in vivo absorption curve.

[0115] The results are as follows Fig.17 , Fig.19 , Fig.21 and Fig.23 .

[0116] Q2, based on the predicted in vivo absorption curve of the reference preparation of carbocysteine ​​tablets, a virtual BE analysis was performed on the carbocysteine ​​tablets preparation modeled by IVIVC.

[0117] The results are as follows Fig.18 , Fig. 20 , Fig. 22 and Fig.24 .

[0118] The results showed that the prediction results of the dissolution medium of pH 6.6 phosphate buffer were consistent with the carbocysteine ​​tablets modeled by IVIVC.

[0119] Although the in vitro dissolution and release behaviors of the reference formulation of carbocysteine ​​tablets did not show significant differences, the similar dissolution behaviors of the reference formulation of carbocysteine ​​tablets in the four dissolution media can reflect different in vivo release behaviors through the IVIVC model. Among them, the prediction results of the dissolution medium of pH 6.6 phosphate buffer have a virtual BE with the carbocysteine ​​tablets modeled by IVIVC, which can better reflect the in vivo differences of carbocysteine ​​tablets preparations and have the best physiological relevance.

[0120] Example 5

[0121] The PBPK model established in Example 1, the PBPK model established in Example 2, or the IVIVC model established in Example 3 is applied to generic drug development, production process optimization, and virtual bioequivalence evaluation. The above is only a preferred embodiment of the present invention and is not intended to limit the present invention. For those skilled in the art, the present invention may have various changes and variations. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the scope of protection of the present invention.

Claims

1. A method for evaluating the in vitro and in vivo correlation of carbocysteine ​​tablets, characterized in that: This method uses GastroPlus software to establish the PBPK model and IVIVC model of carbocysteine, and predicts the concentration-time curve of carbocysteine ​​tablets based on the measured dissolution curve.

2. The method for evaluating the in vitro and in vivo correlation of carbocysteine ​​tablets according to claim 1, characterized in that: In the PBPK model building of the carbocysteine ​​tablets, solubility testing, particle size testing, in vitro permeability testing, and plasma protein binding rate determination of the carbocysteine ​​raw material were carried out.

3. A method for modeling a PBPK model of carbocysteine ​​tablets, characterized in that: The following steps are involved: S1, obtain modeling parameters, including: S11, determining the key parameters for building a PBPK model, wherein the key parameters include solubility, particle size, log P, pKa, Papp, and plasma protein binding rate of carbocysteine ​​API; S12, in vivo concentration-time curve data and dissolution data of carbocysteine ​​preparation; S2, with GastroPlus TM The software built the PBPK model of carbocysteine ​​and obtained the simulated drug-time curve.

4. The method for modeling the PBPK model of carbocysteine ​​tablets according to claim 3, characterized in that: S1 also includes: S13, first-pass effect value; or / and The P of carbocysteine app They are 5.97×10 -6 cm / s (A→B direction) and 7.34×10 -7 cm / s (B→A direction), the efflux rate of carbocysteine ​​is 0.12; the plasma protein binding rate of carbocysteine ​​is 65.48%.

5. The method for modeling the PBPK model of carbocysteine ​​tablets according to claim 3, characterized in that: The solubility determination method is as follows: weigh 100 mg of carbocisteine ​​API and place it in a headspace bottle, add 2 mL of 11 solvents with different pH values ​​respectively, in triplicate, seal tightly, shake at 37°C for 24 hours, take the supernatant after centrifugation, dilute 10 times and perform dissolution content determination; or / and The particle size determination method is: using laser scattering method to analyze the particle size of carbocysteine ​​raw material; wherein, firstly, a methodological investigation is carried out, and the dispersion pressure of 0.5 bar, 1 bar, 2 bar, 3 bar, 4 bar and the vibration injection rate of 20%, 40%, 50%, 70%, 100% are investigated respectively, and the particle size determination method finally determined is the dispersion pressure of 4 bar and the vibration injection rate of 100%; or / and The method for determining the Papp value is: when the drug concentration is 1.00 μM, the permeability of carbocysteine ​​MDCK cells is determined, and the Papp values ​​in the directions of A→B and B→A are calculated; or / and The method for determining the plasma protein binding rate is: when the administration concentration is 10 μM, the binding of the carbocysteine ​​raw material drug and the plasma protein in human plasma is determined.

6. The method for modeling the PBPK model of carbocysteine ​​tablets according to claim 3, characterized in that: The modeling parameters of the PBPK model are: Chemical structure; molecular formula C5H9NO4S; relative molecular mass 179.1900; melting point 185-187℃; log P-4.24; pKa1 1.84; pKa2 4.05; pKa3 9.14; pH 3.0; solubility 1.92mg / mL; average particle size 79.731μm; P app 0.597cm / s×10 5 ; Unbound percentage in plasma 34.52%; Whole blood-plasma distribution ratio 1.23Rbp; Clearance, CL, 8.3059L / h; Renal Clearance, CL, 2.4918L / h; Volume of Distribution 0.343 L / kg; The dosage form is 750mg carbocysteine ​​tablets, 1000mg carbocysteine ​​tablets, 750mg carbocysteine ​​capsules, 1500mg carbocysteine ​​capsules, 750mg carbocysteine ​​syrup or 1500mg carbocysteine ​​syrup.

7. A method for establishing an IVIVC model of carbocysteine ​​tablets, characterized in that: The following steps are involved: Q1, obtaining PBPK modeling parameters by the modeling method described in any one of claims 3-6; Q2, using the modeling parameters of Q1 to model the IVIVC model through the IVIVC module in the GastroPlusTM software; Q3, obtain the dissolution curves of different carbocysteine ​​tablets in different dissolution media; Q4, based on the established IVIVC model, the dissolution curves of Q3 were input respectively to obtain the simulated drug-time curves of different dissolution media.

8. The method for establishing the IVIVC model of carbocysteine ​​tablets according to claim 6, characterized in that: The dissolution medium is a pH 6.6 phosphate buffer; or / and The dissolution curve method is: the second paddle method of Part IV General Rules 0931 of the 2020 edition of the Chinese Pharmacopoeia, temperature 37°C, rotation speed 75r / min, sampling at 5, 10, 15, 30, 45, and 60 minutes, and replenishing the solution at the same time, filtering with a 0.45μm filter membrane, and taking the filtrate.

9. A PBPK model / IVIVC model for carbocysteine ​​tablets, characterized in that: The PBPK model is constructed by the modeling method described in any one of claims 3-6, or the IVIVC model is constructed by the modeling method described in any one of claims 7-8.

10. The PBPK model / IVIVC model of carbocysteine ​​tablets described in claim 9 is used to guide generic drug development and virtual bioequivalence evaluation.

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