CN115684514A - Method for evaluating bioavailability of imitation drug and original drug and application thereof - Google Patents
Method for evaluating bioavailability of imitation drug and original drug and application thereof Download PDFInfo
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- CN115684514A CN115684514A CN202211478677.7A CN202211478677A CN115684514A CN 115684514 A CN115684514 A CN 115684514A CN 202211478677 A CN202211478677 A CN 202211478677A CN 115684514 A CN115684514 A CN 115684514A
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- AYXYPKUFHZROOJ-ZETCQYMHSA-N pregabalin Chemical compound CC(C)C[C@H](CN)CC(O)=O AYXYPKUFHZROOJ-ZETCQYMHSA-N 0.000 claims description 11
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Abstract
The invention provides a method for evaluating bioavailability of a simulated pharmaceutical drug and a primary drug and application thereof, relating to the technical field of pharmacy. The method comprises the following steps: a. obtaining a control imitation drug with equivalent bioavailability to the original drug; b. placing the control imitation drug and the imitation drug to be tested on the adhesion material, adding simulated gastric juice to enable the simulated gastric juice to flow through the control imitation drug and the imitation drug to be tested at the same flow rate along the adhesion material, measuring the moving distance of the control imitation drug and the imitation drug to be tested in the same time or measuring the time for the control imitation drug and the imitation drug to be tested to move the same distance, and evaluating the bioavailability of the imitation drug and the original grinding drug according to the difference of the measurement results; wherein the imitation drug is stomach adhesion type drug, the original research drug is stomach floating type drug, the adhesion material is inclined or vertically placed, and the dissolution rate similarity factor f2 of the imitation drug and the original research drug is not less than 50. The method can accurately evaluate the bioavailability of the simulated medicament and the original medicament.
Description
Technical Field
The invention relates to the technical field of pharmacy, in particular to a method for evaluating bioavailability of a simulated medicament and an original medicament and application thereof.
Background
In the prior art, the bioavailability of the imitation drug and the original drug is evaluated before human testing by using a dissolution curve comparison mode, so that the imitation drug shows similar PK characteristics (comprising four processes of absorption, distribution, metabolism and excretion) with the original drug in a formal human test.
However, the above-mentioned techniques have drawbacks: sustained release time and bioavailability of gastric retentive formulations in vivo cannot be evaluated by dissolution profile alone.
In view of the above, the present invention is particularly proposed.
Disclosure of Invention
It is a first object of the present invention to provide a method for evaluating the bioavailability of a mimetic or a primary drug that solves at least one of the above problems.
The first purpose of the invention is to provide the application of the method in the development of the imitation drugs.
In a first aspect, the present invention provides a method for evaluating the bioavailability of a simulated or original drug, comprising a bioadhesive test;
the bioadhesive test comprises: a. obtaining a control imitation drug with equivalent bioavailability to the original drug;
b. placing the control imitation drug and the imitation drug to be tested on the adhesion material, adding simulated gastric juice to enable the simulated gastric juice to flow through the control imitation drug and the imitation drug to be tested at the same flow rate along the adhesion material, measuring the moving distance of the control imitation drug and the imitation drug to be tested in the same time or measuring the time for the control imitation drug and the imitation drug to be tested to move the same distance, and evaluating the bioavailability of the imitation drug and the original grinding drug according to the difference of the measurement results;
the contrast imitation drug and the imitation drug to be detected are stomach adhesion type drugs; the original medicine is a gastric floating type medicine.
The adhesive material is placed obliquely or vertically;
the dissolution rate similarity factor f2 of the reference imitation drug and the to-be-tested imitation drug and the original research drug is not less than 50.
As a further technical solution, the method further comprises a de-adhesion test, wherein the de-adhesion test comprises: the control imitation drug and the imitation drug to be tested are placed on the adherent material, the force separating the control imitation drug and the imitation drug to be tested from the adherent material is measured, respectively, and the bioavailability of the imitation drug and the original drug is evaluated based on the difference in the measurement results.
As a further technical scheme, a biological equivalence test is adopted to judge whether the bioavailability of the original medicine and the bioavailability of the reference imitation medicine are equivalent.
As a further technical solution, the adhesive material comprises an agar plate or mammalian gastric mucosa.
As a further technical scheme, the original research medicine, the reference imitation medicine and the imitation medicine to be tested comprise pregabalin sustained release tablets.
As a further aspect, the simulated gastric fluid comprises FeSSGF.
As a further aspect, the mammalian gastric mucosa comprises porcine gastric mucosa.
As a further technical solution, the method further comprises a skeleton wear test, the skeleton wear test comprising: placing the control imitation drug and the imitation drug to be tested in a reciprocating cylinder dissolution instrument, performing reciprocating motion in simulated gastric fluid, measuring the skeleton size of the control imitation drug and the imitation drug to be tested after the same time, and evaluating the bioavailability of the imitation drug and the original grinding drug according to the difference of the measurement results;
the reciprocating cylinder dissolution instrument contains plastic beads and is used for simulating food abrasion.
As a further technical scheme, the particle size of the plastic beads is 7-9mm, and the density is 1-1.2g/cm 3 。
In a second aspect, the invention provides the use of the above method in the development of a mimetic.
Compared with the prior art, the invention has the following beneficial effects:
the inventor researches and discovers that when the former research drug is a gastric floating drug, the imitation drug is a gastric adhesion drug, and the dissolution rate similarity factor f2 of the imitation drug and the former research drug is not less than 50, whether the bioavailability of the two drugs is equivalent or not is mainly influenced by the adhesion of the imitation drug on gastric mucosa.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, and it is obvious that the drawings in the following description are some embodiments of the present invention, and other drawings can be obtained by those skilled in the art without creative efforts.
Fig. 1 is a linear mean concentration-time curve of pregabalin sustained release tablet test and reference formulations after a single oral administration to a subject before a meal;
FIG. 2 is a linear mean concentration-time curve of a postprandial subject after a single oral administration of a test formulation and a reference formulation of a pregabalin sustained release tablet;
FIG. 3 is a curve of fasting in vivo absorption;
FIG. 4 is a graph of the amount of absorption in the fasting body versus time;
FIG. 5 is a postprandial in vivo absorption curve;
FIG. 6 is a postprandial in vivo absorption vs. time curve;
fig. 7 shows the results of the bioadhesion test.
Detailed Description
Embodiments of the present invention will be described in detail below with reference to embodiments and examples, but it will be understood by those skilled in the art that the following embodiments and examples are only illustrative of the present invention and should not be construed as limiting the scope of the present invention. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention. Those who do not specify the specific conditions are performed according to the conventional conditions or the conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.
The term "bioavailability" refers to the rate and extent to which a drug in a formulation is absorbed into the human circulation. Bioavailability is the proportion of drug administered into the human circulation that reflects the amount of drug absorbed from the gastrointestinal tract and transported through the liver to the systemic circulation as a percentage of the oral dose. Including the degree of bioavailability and the rate of bioavailability.
The term "equivalence test", the BE test, refers to a human test in which the extent and rate of absorption of the active ingredient are statistically different under the same test conditions, using the method of bioavailability studies, comparing formulations of the same or different dosage forms of the same drug, using pharmacokinetic parameters as indices.
In a first aspect, the present invention provides a method for evaluating the bioavailability of a simulated or primary drug, comprising a bioadhesive test;
the bioadhesive test comprises: a. obtaining a control imitation drug with equivalent bioavailability to the original drug;
b. placing the reference imitation drug and the imitation drug to be tested on the adhesion material, adding the simulated gastric juice to enable the simulated gastric juice to flow through the reference imitation drug and the imitation drug to be tested at the same flow rate along the adhesion material, measuring the moving distance of the reference imitation drug and the imitation drug to be tested in the same time or measuring the time for the reference imitation drug and the imitation drug to be tested to move for the same distance, and evaluating the bioavailability of the imitation drug and the original research drug according to the difference of the measurement results;
the contrast imitation drug and the imitation drug to be detected are stomach adhesion type drugs, and the contrast imitation drug and the imitation drug to be detected can adhere to the adhesion material after being placed on the adhesion material; the original grinding medicine is a floating medicine for stomach stagnation;
the adhesive material is inclined or vertically placed so that the imitation drug slides on the adhesive material under the action of gravity. The inclination angle of the adhesion material is not particularly limited, and the imitation drugs can slide relative to the adhesion material in the test process;
the dissolution rate similarity factor f2 of the control imitation drug and the imitation drug to be tested and the original research drug is not less than 50.
The former drug is a gastric-retention type preparation, but the former drug is a gastric-floating type and the latter drug is a gastric-adhesion type, so how to evaluate the two drugs have the same bioavailability, which cannot be predicted only by comparing in vitro dissolution curves. The inventor researches and discovers that when the former research drug is a gastric floating drug, the imitation drug is a gastric adhesion drug, and the dissolution rate similarity factor f2 of the imitation drug and the former research drug is not less than 50, whether the bioavailability of the two drugs is equivalent or not is mainly influenced by the adhesion of the imitation drug on gastric mucosa.
In some preferred embodiments, further comprising a peel adhesion test, the peel adhesion test comprising: the control imitation drug and the imitation drug to be tested are placed on the adherent material, the force separating the control imitation drug and the imitation drug to be tested from the adherent material is measured, respectively, and the bioavailability of the imitation drug and the original drug is evaluated based on the difference in the measurement results.
The method of the adhesion-removal test in the present invention is not particularly limited, and for example, fresh mucous membrane of pig stomach as an adhesive material may be horizontally placed, a control mimetic and a mimetic to be tested may be placed on the adhesive material, and the force of separating the tablet from the adhesive material in the vertical direction may be examined.
In some preferred embodiments, a bioequivalence test is used to determine whether the bioavailability of the primary and control mimetics is equivalent.
In some preferred embodiments, the adhesive material includes, but is not limited to, agar plates or mammalian gastric mucosa, preferably porcine gastric mucosa, to better simulate the human gastric environment;
in some preferred embodiments, the primary drug, the control drug and the test drug include but are not limited to pregabalin sustained release tablets, or other sustained release drugs known to those skilled in the art.
In some preferred embodiments, the simulated gastric fluid includes, but is not limited to, feSSGF (USP simulated gastric fluid).
In some preferred embodiments, the method further comprises a skeletal wear test comprising: placing the reference imitation drug and the imitation drug to be tested in a reciprocating cylinder dissolution instrument, performing reciprocating motion in simulated gastric fluid, measuring the skeleton size of the reference imitation drug and the imitation drug to be tested after the same time, and evaluating the bioavailability of the imitation drug and the original drug according to the difference of the measurement results;
the reciprocating cylinder dissolution instrument contains plastic beads and is used for simulating food abrasion.
Wherein the simulated gastric fluid includes, but is not limited to, feSSGF.
By combining a reciprocating cylinder with plastic beads, the abrasion effect of food after meals is simulated, the abrasion of tablets is inspected, the abrasion is less, the time of passing through pylorus can be prolonged, and the bioavailability is improved.
As a further technical proposal, the material of the plastic beads can be PA66, the grain diameter can be 7mm, 8mm or 9mm, and the density can be 1g/cm 3 、1.1g/cm 3 Or 1.2g/cm 3 。
It should be noted that, in the above experiment, it is preferable to keep the sizes and shapes of the control imitation drug and the imitation drug to be tested consistent, which contributes to the improvement of the accuracy of the test.
In a second aspect, the invention provides the use of the above method in the development of a counterfeit drug.
The method for evaluating the bioavailability of the imitation drugs and the original drugs provided by the invention is simple and convenient, can accurately evaluate the bioavailability of the imitation drugs and the original drugs, and has guiding significance for the development of the imitation drugs.
The present invention is further illustrated by the following specific examples and comparative examples, but it should be understood that these examples are for illustrative purposes only and are not to be construed as limiting the invention in any way.
It should be noted that in the following examples or experiments, the self-developed formulation and the control (reference) formulation are both pregabalin sustained release tablets, wherein the self-developed formulation is from ningbo double city pharmaceutical industry, and the control formulation is from the pfeiri pharmaceutical industry.
Example 1
The method comprises the following steps: determination of in vitro dissolution curves: the dissolution profiles of the self-developed formulation (formula one) and the reference formulation in ph5.0 medium were determined and compared for f2, with the results shown in table 1.
TABLE 1
Step two: human body preliminary experiments: the simplified human bioequivalence test (subject less than formal human bioequivalence test) was performed with the original drug to look for differences in the in vivo absorption of the imitation drug (prescription one) and the original drug.
1. Pre-meal test
1) Test protocol
TABLE 2 dosing regimen
Administration dose: t:330mg; r:330mg.
2) Results of the experiment
The pharmacokinetic parameter analysis results of the test preparation and the reference preparation of the pregabalin sustained release tablet taken by the subject on an empty stomach are shown in table 3, and the linear mean concentration-time curve of pregabalin in blood plasma after the test preparation and the reference preparation of the pregabalin sustained release tablet taken by the subject on an empty stomach is shown in fig. 1.
TABLE 3 pharmacokinetic parameter analysis of Single fasting oral administration of Pregabalin extended Release tablet test and reference formulations in Subjects
2. Postprandial testing
1) Test protocol
12 healthy subjects were enrolled in the study. The two administration orders of T-R and R-T were randomly divided into 2 sequence groups of 6 subjects per sequence group. The study was conducted in two cycles, with the subject receiving test formulation T or reference formulation R in the first cycle post-prandial state and entering the second cycle after an elution period, and reference formulation R or test formulation T in the same state, with an elution period of at least 3 days between cycles. Subjects were uniformly on a light diet 1 day night before dosing, and then fasted for over 10 hours per cycle, using 240mL of water to take study medication in the postprandial state of the day of the trial. Drinking water was prohibited 1 hour before and 1 hour after administration, and 200ml of drinking water was given every 2h (+ 10 min) after administration, 14h after administration.
Water can be freely drunk; keeping the upper body in an upright state within 4 hours after the medicine is taken; lunch and dinner were taken about 4h and 10h after dosing, respectively.
Specific dosing regimens are shown in table 4:
TABLE 4 dosing regimen
Administration dose: t:330mg; r:330mg.
2) Results of the experiment
The results are shown in table 5 and fig. 2.
TABLE 5 pharmacokinetic parameter analysis of Single postprandial oral administration of Pregabalin extended Release tablet test and reference formulations by Subjects
The results indicate that the test formulation is not bioequivalent to the reference formulation.
Step three: biological correlation method development and model establishment: analyzing the absorption sites in vivo of the two preparations (original medicine and prescription I) to develop an analysis method with biological correlation, including but not limited to dissolution curve, biological adhesion test, skeleton abrasion test, etc.;
1. analysis of human test results
The method comprises the following steps: deconvoluting the in-vivo drug concentration-time curve into a drug accumulated absorption concentration-time curve through an atrioventricular model;
step two: the cumulative concentration absorbed by the drug versus time curve, and the cumulative concentration at each time point divided by the cumulative concentration at the final time point, to obtain the drug absorption%, i.e., the in vivo absorption curve.
Step three: and calculating the difference of the absorption amount between the two time points by using the cumulative absorption concentration-time curve of the medicine to obtain the relation of the in vivo absorption amount-time.
1) The curve of the absorption in the fasting state is shown in FIG. 3, and the curve of the absorption in the fasting state is shown in FIG. 4. The two preparations have basically consistent absorption, are quickly absorbed in vivo, and gradually decrease the absorption amount. The absorption trend of the T preparation is basically consistent with that of the T preparation after meal, and the T preparation is proved to have no obvious gastric retention process. The R formulation had no apparent floating retention or a shorter retention time after a shorter stomach meal.
2) The postprandial internal absorption curve is shown in FIG. 5, and the postprandial internal absorption curve is shown in FIG. 6. Both preparations showed faster absorption before 4 hours, and were absorbed faster by self-research; the absorption of the preparation T reaches the maximum value in the beginning 2h, the subsequent absorption gradually decreases, and the absorption amount of the preparation R appears in wave crests and wave troughs; through data analysis, the T preparation fails to show obvious gastric retention effect, but causes delayed absorption along with the influence of food gastric emptying; the R preparation has double peaks in absorption, namely in vivo release occurs at two parts, and the R preparation can be proved to have an obvious gastric retention process under the postprandial condition for a long time.
Based on the above analysis, the T preparation is different from the R preparation mainly in gastric retention time, and it is presumed that extending the gastric retention time of the T preparation contributes to achieving more similar bioavailability to the R preparation.
2. Evaluation of in vivo and in vitro correlation
Through research and development, a formula II is obtained, the dissolution curve of the self-developing preparation (formula II) and a reference preparation under the medium of pH5.0 is measured, and f2 comparison is carried out, and the result is shown in Table 1.
1) Bioadhesion investigation
Fresh pig stomach mucosa is selected as an adhesive material and fixed on a flat plate, then tablets (formula one and formula two) are placed on the adhesive material, and the flat plate is vertically placed.
(1) FeSSGF is added to the plate using FeSSGF as a medium so that the simulated gastric fluid flows through the reference drug mimic and the drug mimic to be tested at the same flow rate along the adhesive material, and after 25min, the displacement distance of the tablet on the plate is examined, and the result is shown in FIG. 7.
As a result: recipe 2 moves 2.1cm and recipe 1 moves 4.2cm.
(2) The fresh mucous membrane of the pig stomach was used as the adhesive material, and the adhesion-removing force was examined (the force of separating the tablet from the adhesive material by placing the tablet on the adhesive material):
table 6 adhesion results
| |
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| 22 N | 16 N |
Further, the inventors repeated the above-described experiments also with agar as an adhesive material instead of the gastric mucosa, and found that the results of the two experiments tended to be the same.
2) Skeleton wear test
The dissolution device comprises: a reciprocating barrel dissolution instrument;
medium: feSSGF with the volume of 250ml;
temperature: 37 ℃;
reciprocating speed: 15dpm (15 reciprocations per minute);
food wear simulation: the density is 1.1g/cm by adding plastic beads for simulation 3 The diameter is 8mm, and the adding amount is 40 particles;
screening: the lower part is 40mesh, and the upper part is not provided with a screen mesh;
investigation duration: 4 hours;
evaluation method: the size of the skeleton changes.
The results are shown in Table 7.
Table 7 self-development agent size change
And (4) conclusion: at the end of the second study, the size of the matrix is significantly larger than that of the first study, indicating that gastric retention is more easily achieved, and thus, bioavailability is higher.
Step four: prescription selection: the results of the BE test performed by selecting the second formulation having a stronger adhesive force according to the above-described method for analyzing bio-correlation are shown in Table 8.
TABLE 8 results of the second-prescription BE test
Example 2
A method for evaluating the bioavailability of a simulated drug and a primary drug comprising: including bioadhesive testing;
the bioadhesive test included: a. obtaining a control imitation drug with equivalent bioavailability to the original drug;
b. placing the control imitation drug and the imitation drug to be tested on a flat plate of the fresh pig gastric mucosa, vertically placing the flat plate, then adding FeSSGF, enabling the FeSSGF to flow through the control imitation drug and the imitation drug to be tested at the same flow rate along an adhesive material, measuring the moving distance of the control imitation drug and the imitation drug to be tested within 25min, and evaluating the bioavailability of the imitation drug and the original grinding drug according to the difference of the measurement results;
wherein the reference imitation drug and the imitation drug to be tested are stomach adhesion type drugs; the former medicine is gastric floating type medicine; the dissolution rate similarity factor f2 of the reference imitation drug and the to-be-tested imitation drug and the original research drug is not less than 50.
Example 3
A method for evaluating the bioavailability of a simulated drug and a primary drug comprising: the method comprises a biological adhesion test, a de-adhesion test and a skeleton abrasion test;
the bioadhesive test included: a. obtaining a reference imitation drug with equivalent bioavailability to the original drug;
b. and placing the reference imitation drug and the imitation drug to be tested on a flat plate of the fresh pig gastric mucosa, vertically placing the flat plate, adding FeSSGF so that the FeSSGF flows through the reference imitation drug and the imitation drug to be tested at the same flow rate along the adhesion material, measuring the moving distance of the reference imitation drug and the imitation drug to be tested within 25min, and evaluating the bioavailability of the imitation drug and the original research drug according to the difference of the measurement results.
And (3) adhesion removal testing: the mucous membrane of the fresh pig stomach was used as an adhesive material, placed horizontally, the control imitation drug and the imitation drug to be tested were placed on the adhesive material, and the force separating the tablet from the adhesive material in the vertical direction was examined.
And (3) testing framework abrasion:
the dissolution device comprises: a reciprocating barrel dissolution instrument;
medium: feSSGF with the volume of 250ml;
temperature: at 37 ℃;
reciprocating speed: 15dpm (15 reciprocations per minute);
food wear simulation: the density of the mixture is 1.1g/cm by adding plastic beads for simulation 3 The diameter is 8mm, and the adding amount is 40 particles;
screening: the lower part is 40mesh, and the upper part is not provided with a screen;
investigation duration: 4 hours;
evaluation method: the size of the skeleton changes.
Wherein the reference imitation drug and the imitation drug to be tested are stomach adhesion type drugs; the former medicine is gastric floating type medicine; the dissolution rate similarity factor f2 of the reference imitation drug and the imitation drug to be tested and the original research drug is not less than 50.
Test example 1
Prescription three and prescription four are provided, and bioavailability of the prescription three and prescription four and the original drug is evaluated by the method provided in example 3 with prescription two in example 1 as a reference imitation drug. The bioadhesive force test is shown in table 9 and the skeleton abrasion test is shown in table 10.
TABLE 9 bioadhesive test results
| Adhesion test | Prescription two | Prescription three | Prescription four |
| Displacement distance/25 min | 2.1 cm | 3.9 cm | 1.8 |
| Adhesion removal | |||
| 2 2 N | 16 N | 31 N |
TABLE 10 skeletal wear test results
And (3) carrying out a simplified BE test on the third prescription and the fourth prescription, and verifying the accuracy of the result, wherein the result shows that the third prescription is not equivalent to the original research and the fourth prescription is equivalent to the original research.
Finally, it should be noted that: the above embodiments are only used to illustrate the technical solution of the present invention, and not to limit the same; while the invention has been described in detail and with reference to the foregoing embodiments, it will be understood by those skilled in the art that: the technical solutions described in the foregoing embodiments may still be modified, or some or all of the technical features may be equivalently replaced; and these modifications or substitutions do not depart from the spirit of the corresponding technical solutions of the embodiments of the present invention.
Claims (10)
1. A method for evaluating the bioavailability of a simulated or original drug comprising a bioadhesive test;
the bioadhesive test comprises: a. obtaining a control imitation drug with equivalent bioavailability to the original drug;
b. placing the control imitation drug and the imitation drug to be tested on the adhesion material, adding simulated gastric juice to enable the simulated gastric juice to flow through the control imitation drug and the imitation drug to be tested at the same flow rate along the adhesion material, measuring the moving distance of the control imitation drug and the imitation drug to be tested in the same time or measuring the time for the control imitation drug and the imitation drug to be tested to move the same distance, and evaluating the bioavailability of the imitation drug and the original grinding drug according to the difference of the measurement results;
the contrast imitation drug and the imitation drug to be detected are stomach adhesion type drugs; the original grinding medicine is a gastric floating medicine;
the adhesive material is placed obliquely or vertically;
the dissolution rate similarity factor f2 of the control imitation drug and the imitation drug to be tested and the original research drug is not less than 50.
2. The method of claim 1, further comprising a de-adhesion test, the de-adhesion test comprising: the control imitation drug and the imitation drug to be tested are placed on the adherent material, the force separating the control imitation drug and the imitation drug to be tested from the adherent material is measured, respectively, and the bioavailability of the imitation drug and the original drug is evaluated based on the difference in the measurement results.
3. The method of claim 1, wherein the bioavailability of the primary drug and the control mimetic are determined to be equivalent using a bioequivalence test.
4. The method of claim 1, wherein the adhesive material comprises an agar plate or mammalian gastric mucosa.
5. The method of claim 4, wherein the mammalian gastric mucosa comprises porcine gastric mucosa.
6. The method of claim 1, wherein the primary study, the control study, and the study to be tested comprise extended release tablets of pregabalin.
7. The method of claim 1, wherein the simulated gastric fluid comprises FeSSGF.
8. The method of claim 1, further comprising a skeletal wear test comprising: placing the control imitation drug and the imitation drug to be tested in a reciprocating cylinder dissolution instrument, performing reciprocating motion in simulated gastric fluid, measuring the skeleton size of the control imitation drug and the imitation drug to be tested after the same time, and evaluating the bioavailability of the imitation drug and the original grinding drug according to the difference of the measurement results;
the reciprocating cylinder dissolution instrument contains plastic beads and is used for simulating food abrasion.
9. The method of claim 8, wherein the plastic beads have a particle size of 7-9mm and a density of 1-1.2g/cm 3 。
10. Use of the method of any one of claims 1 to 9 in mimetic development.
Priority Applications (1)
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