CN115684514B - Method for evaluating bioavailability of simulated medicine and original ground medicine and application thereof - Google Patents
Method for evaluating bioavailability of simulated medicine and original ground medicine and application thereof Download PDFInfo
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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 simulated pharmacy and original grinding medicaments and application thereof, and relates to the technical field of pharmacy. The method comprises the following steps: a. obtaining a control simulated drug equivalent to the bioavailability of the original drug; b. placing the control imitation pharmacy and the imitation pharmacy to be tested on an adhesive material, then adding simulated gastric juice, enabling the simulated gastric juice to flow through the control imitation pharmacy and the imitation pharmacy to be tested along the adhesive material at the same flow rate, measuring the moving distance of the control imitation pharmacy and the imitation pharmacy to be tested in the same time or measuring the time taken by the control imitation pharmacy and the imitation pharmacy to be tested to move the same distance, and evaluating the bioavailability of the imitation pharmacy and the original grinding medicament according to the difference of measurement results; wherein the simulated medicine is gastric adhesion medicine, the original grinding medicine is gastric floating medicine, the adhesion material is obliquely or vertically placed, and the dissolution factor similarity factor f2 of the simulated medicine and the original grinding medicine is not less than 50. The method can accurately evaluate the bioavailability of the simulated medicine and the original medicine.
Description
Technical Field
The invention relates to the technical field of pharmacy, in particular to a method for evaluating bioavailability of simulated pharmacy and original grinding medicament and application thereof.
Background
In the prior art, the bioavailability of the simulated drug and the original drug is evaluated before the human body test by using a dissolution curve comparison mode, so that the simulated drug shows PK characteristics (comprising four processes of absorption, distribution, metabolism and excretion) similar to those of the original drug in the formal human body test.
However, the above-mentioned technique has drawbacks: sustained release time and bioavailability in the gastroretentive formulation cannot be assessed by dissolution profile alone.
In view of this, the present invention has been made.
Disclosure of Invention
A first object of the present invention is to provide a method for evaluating the bioavailability of simulated and as-ground drugs, which solves at least one of the above problems.
A first object of the present invention is to provide the use of the above method in imitation drug development.
In a first aspect, the present invention provides a method for evaluating the bioavailability of simulated and as-ground pharmaceuticals comprising a bioadhesion test;
the bioadhesion test comprises: a. obtaining a control simulated drug equivalent to the bioavailability of the original drug;
b. Placing the control imitation pharmacy and the imitation pharmacy to be tested on an adhesive material, then adding simulated gastric juice, enabling the simulated gastric juice to flow through the control imitation pharmacy and the imitation pharmacy to be tested along the adhesive material at the same flow rate, measuring the moving distance of the control imitation pharmacy and the imitation pharmacy to be tested in the same time or measuring the time taken by the control imitation pharmacy and the imitation pharmacy to be tested to move the same distance, and evaluating the bioavailability of the imitation pharmacy and the original grinding medicament according to the difference of measurement results;
The control simulated medicament and the simulated medicament to be detected are gastric adhesion medicaments; the original grinding medicine is a gastric floating medicine.
The adhesive material is placed obliquely or vertically;
the dissolution similarity factor f2 of the control simulated pharmacy and the simulated pharmacy to be detected and the original grinding medicament is not less than 50.
As a further technical solution, the method further comprises a de-adhesion test, wherein the de-adhesion test comprises: and placing the control imitation drug and the imitation drug to be detected on an adhesive material, respectively measuring the separation force of the control imitation drug and the imitation drug to be detected from the adhesive material, and evaluating the bioavailability of the imitation drug and the original grinding drug according to the difference of measurement results.
As a further technical scheme, a bioequivalence test is adopted to judge whether the bioavailability of the original ground drug and the control imitation drug is equivalent.
As a further technical solution, the adhesive material comprises an agar plate or a mammalian gastric mucosa.
As a further technical scheme, the original grinding medicine, the control imitation medicine and the imitation medicine to be tested comprise pregabalin sustained release tablets.
As a further technical solution, 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 barrel 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 measurement results;
The reciprocating barrel 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 simulated drug.
Compared with the prior art, the invention has the following beneficial effects:
The inventor researches find that when the original grinding medicine is a gastric floating medicine and the simulated medicine is a gastric adhesion medicine, and the dissolution similarity factor f2 of the simulated medicine and the original grinding medicine is not less than 50, whether the bioavailability of the simulated medicine and the original grinding medicine is equivalent or not is mainly influenced by the adhesion of the simulated medicine 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 that are needed in the description of the embodiments or the prior art will be briefly described, and it is obvious that the drawings in the description below are some embodiments of the present invention, and other drawings can be obtained according to the drawings without inventive effort for a person skilled in the art.
FIG. 1 is a graph of linear mean concentration versus time for a pre-meal subject after a single oral administration of a pregabalin sustained release tablet test formulation and a reference formulation;
FIG. 2 is a graph of linear mean concentration versus time for a postprandial subject after a single oral administration of a pregabalin sustained release tablet test formulation and a reference formulation;
FIG. 3 is an absorption curve in the fasting body;
FIG. 4 is a graph of absorption capacity versus time in an empty stomach;
FIG. 5 is a graph of postprandial in vivo absorption;
FIG. 6 is a graph showing the absorption amount in the body after meal versus time;
FIG. 7 is a biological adhesion test result.
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 for illustrating the present invention and should not be construed as limiting the scope of the present invention. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention. The specific conditions are not specified, and the process is carried out according to conventional conditions or conditions suggested by manufacturers. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention.
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 and describes the percentage of oral drug absorbed from the gastrointestinal tract and delivered to the systemic blood circulation via the liver. Including the degree of bioavailability and the rate of bioavailability.
The term "equivalence test", i.e., BE test, refers to a human body test using a method of bioavailability research, comparing formulations of the same drug in the same or different dosage forms with pharmacokinetic parameters as indicators, and under the same test conditions, whether the absorption degree and the absorption speed of the active ingredients are statistically different.
In a first aspect, the present invention provides a method for evaluating the bioavailability of simulated and as-ground pharmaceuticals comprising a bioadhesion test;
the bioadhesion test comprises: a. obtaining a control simulated drug equivalent to the bioavailability of the original drug;
b. Placing the control imitation pharmacy and the imitation pharmacy to be tested on an adhesive material, then adding simulated gastric juice, enabling the simulated gastric juice to flow through the control imitation pharmacy and the imitation pharmacy to be tested along the adhesive material at the same flow rate, measuring the moving distance of the control imitation pharmacy and the imitation pharmacy to be tested in the same time or measuring the time taken by the control imitation pharmacy and the imitation pharmacy to be tested to move the same distance, and evaluating the bioavailability of the imitation pharmacy and the original grinding medicament according to the difference of measurement results;
the control simulated pharmacy and the simulated pharmacy to be tested are gastric adhesion type medicines, and the gastric adhesion type medicines are adhered to an adhesion material after being placed on the adhesion material; the original grinding medicine is a gastric stagnation floating medicine;
the adhesive material is placed obliquely or vertically so that the simulated medicine slides on the adhesive material under the action of gravity. The invention does not limit the inclination angle of the adhesive material, and can enable the imitated medicine to slide relative to the adhesive material in the test process;
the dissolution similarity factor f2 of the control simulated pharmacy and the simulated pharmacy to be detected and the original grinding medicament is not less than 50.
The simulated pharmacy is the same as the original grinding medicine, but the original grinding medicine is gastric floating type preparation, the simulated pharmacy is gastric adhesion type preparation, and how to evaluate that the simulated pharmacy and the stomach adhesion type preparation have the same bioavailability can not be predicted only by in vitro dissolution curve comparison. The inventor researches find that when the original ground medicament is a gastric floating medicament and the simulated medicament is a gastric adhesion medicament, and the dissolution similarity factor f2 of the simulated medicament and the original ground medicament is not less than 50, whether the bioavailability of the simulated medicament and the original ground medicament is equivalent or not is mainly influenced by the adhesion of the simulated medicament on gastric mucosa.
In some preferred embodiments, the method further comprises a de-adhesion test comprising: and placing the control imitation drug and the imitation drug to be detected on an adhesive material, respectively measuring the separation force of the control imitation drug and the imitation drug to be detected from the adhesive material, and evaluating the bioavailability of the imitation drug and the original grinding drug according to the difference of measurement results.
The method for the adhesion test is not particularly limited in the present invention, and for example, a fresh gastric mucosa of a pig is used as an adhesion material, placed horizontally, a control imitation drug and a to-be-tested imitation drug are placed on the adhesion material, and the force of separating the tablet from the adhesion material in the vertical direction is examined.
In some preferred embodiments, bioequivalence tests are used to determine whether the bioavailability of the original and control imitations are equivalent.
In some preferred embodiments, the adhesive material includes, but is not limited to, agar plates or mammalian gastric mucosa, wherein the mammalian gastric mucosa is preferably porcine gastric mucosa, which is advantageous for better simulating the human gastric environment;
in some preferred embodiments, the primary, control and test simulated drugs 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 skeleton wear test comprising: placing the control imitation drug and the imitation drug to be tested in a reciprocating barrel 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 measurement results;
The reciprocating barrel dissolution instrument contains plastic beads and is used for simulating food abrasion.
Wherein simulated gastric fluid includes, but is not limited to FeSSGF.
The method of combining the reciprocating cylinder with the plastic beads simulates the abrasion action of food after eating, inspects the abrasion to tablets, reduces the abrasion, prolongs the time of passing through the pylorus and improves the bioavailability.
As a further technical scheme, the plastic beads can be made of PA66, the particle size can be 7mm, 8mm or 9mm, and the density can be 1g/cm 3、1.1g/cm3 or 1.2g/cm 3.
In the experimental process, the sizes and shapes of the control simulated medicament and the simulated medicament to be detected are preferably kept consistent, which is beneficial to improving the detection accuracy.
In a second aspect, the invention provides the use of the above method in the development of a simulated drug.
The method for evaluating the bioavailability of the simulated pharmacy and the original grinding medicine is simple and convenient, can accurately evaluate the bioavailability of the simulated pharmacy and the original grinding medicine, and has guiding significance for the development of the simulated pharmacy.
The invention is further illustrated by the following specific examples and comparative examples, but it should be understood that these examples are for the purpose of illustration only and are not to be construed as limiting the invention in any way.
In the following examples or experiments, the self-grinding preparation and the control (reference) preparation are pregabalin sustained-release tablets, wherein the self-grinding preparation is derived from Ningbo Shuangcheng pharmaceutical industry, and the control preparation is derived from the gabbroil pharmaceutical industry.
Example 1
Step one: determination of in vitro dissolution profile: the dissolution profile of the self-developing agent (formula one) and the reference formulation in pH5.0 medium was measured and f2 comparison was performed and the results are shown in Table 1.
TABLE 1
Step two: human body pre-experiment: simplified human bioequivalence tests (fewer subjects than formal human bioequivalence tests) were performed with the original drug to find the difference between the simulated drug (prescription one) and the original drug absorbed in vivo.
1. Pre-meal test
1) Test protocol
Study inclusion 8 healthy subjects. The sequences were randomized into 2 sequence groups of 4 subjects each according to the order of administration of both T-R and R-T. The study was performed in two cycles, with subjects receiving either the test formulation T or the reference formulation R in a first cycle on an empty stomach, after an elution period, into a second cycle, and either the reference formulation R or the test formulation T in the same state, with an elution period of at least 3 days between cycles. The subjects uniformly eat light diet at night 1 day before administration in each period, and then forbid for more than 10 hours, and take study medicines with 240mL of water in the fasting state on the test day. Drinking water is forbidden within 1 hour before taking and 1 hour after taking, 200ml drinking water is uniformly given every 2 hours (+10 min) after taking, and drinking water can be freely given 14 hours after taking; the upper body is kept in an upright state within 4 hours after the administration; the lunch and dinner are taken about 4 hours and 10 hours after administration, respectively. The specific dosing regimen is shown in table 2:
Table 2 dosing regimen
Dosage of administration: t:330mg; r:330mg.
2) Experimental results
Results of pharmacokinetic parameter analysis of the test and reference formulations of the single fasting oral pregabalin sustained release tablet of the subject are shown in table 3, and linear mean concentration-time curves of pregabalin in plasma after the single fasting oral pregabalin sustained release tablet of the subject and the reference formulation are shown in fig. 1.
Table 3 pharmacokinetic parameter analysis of single fasting oral pregabalin sustained release tablet test formulation and reference formulation for subjects
2. Postprandial test
1) Test protocol
Study inclusion was performed on 12 healthy subjects. The sequences were randomized into 2 sequence groups of 6 subjects each according to the order of administration of both T-R and R-T. The study was performed in two cycles, with subjects receiving either the test formulation T or the reference formulation R in the postprandial state of the first cycle, after an elution period, entering the second cycle, and either the reference formulation R or the test formulation T in the same state, with an elution period of at least 3 days between cycles. The subjects uniformly had a light diet 1 day night before dosing, followed by a fasting for more than 10 hours, and on the post-trial day, the study medication was taken with 240mL of water. Drinking water was prohibited for 1 hour before and 1 hour after administration, and 200ml drinking water was uniformly administered every 2 hours (+10 min) after administration, and 14 hours after administration.
Can drink water freely; the upper body is kept in an upright state within 4 hours after the administration; the lunch and dinner are taken about 4 hours and 10 hours after administration, respectively.
The specific dosing regimen is shown in table 4:
Table 4 dosing regimen
Dosage of administration: t:330mg; r:330mg.
2) Experimental results
The results are shown in Table 5 and FIG. 2.
TABLE 5 pharmacokinetic parameter analysis of single postprandial oral pregabalin sustained release tablet test formulation and reference formulation for subjects
The results indicated that the test formulation was not bioequivalent to the reference formulation.
Step three: and (3) developing a biological correlation method and establishing a model: analyzing the in vivo absorption sites of two preparations (original drug and prescription one), developing an analysis method with biological relevance, including but not limited to dissolution curve, bioadhesion test, skeleton abrasion test and the like;
1. Analysis of human body test results
Step one: deconvolution of the in-vivo drug concentration-time curve into a drug accumulated absorption concentration-time curve through an atrioventricular model;
Step two: the cumulative drug absorption concentration-time curve, and thus the cumulative concentration at each time point divided by the cumulative concentration at the final time point, yields the drug absorption, i.e., the in vivo absorption curve.
Step three: and calculating the absorption difference between two time points according to the accumulated absorption concentration-time curve of the medicine, and obtaining the in-vivo absorption-time relationship.
1) The absorption curve in the fasting body is shown in fig. 3, and the absorption curve in the fasting body is shown in fig. 4. The two preparations are absorbed basically in the same way, are absorbed rapidly in vivo, and gradually reduce the absorption amount. The absorption trend of the T preparation is basically consistent with that of the meal, and the T preparation is proved to have no obvious gastric retention process. The R formulation had no significant floating retention or a shorter retention time after the stomach.
2) The in-vivo postprandial absorption curve is shown in FIG. 5, and the in-vivo postprandial absorption curve is shown in FIG. 6. Both formulations showed faster absorption before 4 hours, with faster self-grinding absorption; the absorption of the T preparation reaches the maximum value within the beginning 2 hours, the subsequent absorption gradually decreases, and the absorption quantity of the R preparation shows wave crests and wave troughs; through data analysis, the T formulation failed to exhibit a significant gastric retention effect, but resulted in delayed absorption with the effect of food gastric emptying; the absorption of the R preparation is bimodal, namely in vivo release occurs at two positions, and the R preparation can be proved to have obvious gastric retention process under the condition of postprandial, and the time is longer.
Based on the above analysis, the main difference between the T-formulation and the R-formulation is the difference in gastric retention time, and it is speculated that extending the gastric retention time of the T-formulation helps to achieve a bioavailability more similar to that of the R-formulation.
2. In vivo and in vitro correlation evaluation
After development, a second formulation was obtained, the dissolution profile of the self-developed formulation (second formulation) and the reference formulation in pH5.0 medium was measured, and f2 comparison was performed, and the results are shown in Table 1.
1) Bioadhesion investigation
Fresh porcine gastric mucosa is selected as an adhesive material, fixed on a flat plate, and then tablets (prescription one and prescription two) are placed on the adhesive material, and the flat plate is vertically placed.
(1) FeSSGF was added to the plate using FeSSGF as a medium to allow simulated gastric fluid to flow through the reference and test simulated pharmaceuticals at the same flow rate along the adherent material, and after 25min, the displacement distance of the tablet on the plate was examined and the results are shown in fig. 7.
Results: recipe 2 moved 2.1cm and recipe 1 moved 4.2cm.
(2) Fresh pig gastric mucosa is used as an adhesive material, the adhesion removal force is examined (the tablet is placed on the adhesive material, and the force for separating the tablet from the adhesive material is examined):
TABLE 6 adhesion results
| Prescription 2 | Prescription 1 |
| 22 N | 16 N |
Furthermore, the inventors have repeatedly conducted the above experiments using agar instead of gastric mucosa as an adhesive material, and as a result, found that the trend of the results of both experiments is the same.
2) Skeleton wear test
Dissolution device: a reciprocating cartridge dissolution instrument;
Medium: feSSGF, volume 250ml;
temperature: 37 ℃;
Reciprocation rate: 15dpm (15 reciprocations per minute);
food wear simulation: simulating by adding plastic beads, wherein the density is 1.1g/cm 3, the diameter is 8mm, and the adding amount is 40;
and (3) screening: the lower part is 40mesh, and the upper part is free of a screen;
Duration of investigation: 4 hours;
Evaluation mode: the dimensions of the skeleton vary.
The results are shown in Table 7.
TABLE 7 self-developing agent size variation
Conclusion: after the second prescription is finished, the skeleton size is obviously larger than that of the first prescription, which means that gastric retention is easier to achieve, and thus, the bioavailability is higher.
Step four: prescription selection: based on the above-described method for analyzing the biological correlation, a second prescription with a stronger adhesion was selected for the BE test, and the results are shown in Table 8.
Table 8 results of two-test-in-one BE
Example 2
A method of evaluating the bioavailability of a drug mimetic and a drug of prime grinding comprising: including bioadhesion tests;
The bioadhesion test included: a. obtaining a control simulated drug equivalent to the bioavailability of the original drug;
b. Placing the control imitation drug and the imitation drug to be tested on a flat plate of a fresh pig gastric mucosa, placing the flat plate vertically, then adding FeSSGF to enable FeSSGF to flow through the control imitation drug and the imitation drug to be tested along an adhesive material at the same flow rate, measuring the moving distance of the control imitation drug and the imitation drug to be tested within 25 minutes, and evaluating the bioavailability of the imitation drug and the original grinding drug according to the difference of the measuring results;
Wherein the control simulated medicament and the simulated medicament to be detected are gastric adhesion medicaments; the original grinding medicine is gastric floating medicine; the dissolution similarity factor f2 of the control simulated medicine and the simulated medicine to be detected and the original grinding medicine is not less than 50.
Example 3
A method of evaluating the bioavailability of a drug mimetic and a drug of prime grinding comprising: the method comprises a biological adhesion test, a de-adhesion test and a skeleton abrasion test;
The bioadhesion test included: a. obtaining a control simulated drug equivalent to the bioavailability of the original drug;
b. The control imitation drug and the imitation drug to be tested are placed on a flat plate of a fresh pig gastric mucosa, the flat plate is vertically placed, then FeSSGF is added, so that FeSSGF flows through the control imitation drug and the imitation drug to be tested along an adhesion material at the same flow rate, the moving distance of the control imitation drug and the imitation drug to be tested within 25 minutes is measured, and the bioavailability of the imitation drug and the original grinding drug is evaluated according to the difference of the measured results.
Adhesion removal test: fresh pig gastric mucosa is used as an adhesion material, the adhesion material is horizontally placed, a control imitation drug and a imitation drug to be tested are placed on the adhesion material, and the separation force of the tablet from the adhesion material in the vertical direction is examined.
Skeleton abrasion test:
dissolution device: a reciprocating cartridge dissolution instrument;
Medium: feSSGF, volume 250ml;
temperature: 37 ℃;
Reciprocation rate: 15dpm (15 reciprocations per minute);
food wear simulation: simulating by adding plastic beads, wherein the density is 1.1g/cm 3, the diameter is 8mm, and the adding amount is 40;
and (3) screening: the lower part is 40mesh, and the upper part is free of a screen;
Duration of investigation: 4 hours;
Evaluation mode: the dimensions of the skeleton vary.
Wherein the control simulated medicament and the simulated medicament to be detected are gastric adhesion medicaments; the original grinding medicine is gastric floating medicine; the dissolution similarity factor f2 of the control simulated medicine and the simulated medicine to be detected and the original grinding medicine is not less than 50.
Test example 1
Prescription three and prescription four were provided, and the bioavailability of the prescription three and prescription four and the original drug was evaluated using the method provided in example 3, with prescription two in example 1 as a control drug imitation. Bioadhesive tests are shown in table 9 and skeletal wear tests are shown in table 10.
TABLE 9 bioadhesive test results
| Adhesion test | Prescription two | Prescription III | Prescription IV |
| Distance of displacement/25 min | 2.1 cm | 3.9 cm | 1.8 cm |
| Adhesion removal force | 2 2 N | 16 N | 31 N |
TABLE 10 results of skeleton wear test
And (3) performing a simplified BE test on the prescription III and the prescription IV, and verifying the accuracy of the result, wherein the result shows that the prescription III is not equivalent to the original grinding, and the prescription IV is equivalent to the original grinding.
Finally, it should be noted that: the above embodiments are only for illustrating the technical solution of the present invention, and not for limiting the same; although the invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical scheme described in the foregoing embodiments can be modified or some or all of the technical features thereof can be replaced by equivalents; such modifications and substitutions do not depart from the spirit of the invention.
Claims (7)
1. A method for evaluating the bioavailability of a simulated pharmaceutical and an as-ground pharmaceutical comprising a bioadhesion test; the bioadhesion test comprises:
a. obtaining a control simulated drug equivalent to the bioavailability of the original drug;
b. Placing the control imitation pharmacy and the imitation pharmacy to be tested on an adhesive material, then adding simulated gastric juice, enabling the simulated gastric juice to flow through the control imitation pharmacy and the imitation pharmacy to be tested along the adhesive material at the same flow rate, measuring the moving distance of the control imitation pharmacy and the imitation pharmacy to be tested in the same time or measuring the time taken by the control imitation pharmacy and the imitation pharmacy to be tested to move the same distance, and evaluating the bioavailability of the imitation pharmacy and the original grinding medicament according to the difference of measurement results;
the control simulated medicament and the simulated medicament to be detected are gastric adhesion medicaments; the original grinding medicine is a gastric floating medicine;
The adhesive material is placed obliquely or vertically; the adhesive material comprises an agar plate or a mammalian gastric mucosa;
the dissolution similarity factor f2 of the control simulated pharmacy and the simulated pharmacy to be detected and the original grinding medicament is not less than 50;
also included is a debonding test comprising:
Placing the control imitation drug and the imitation drug to be detected on an adhesive material, respectively measuring the separation force of the control imitation drug and the imitation drug to be detected from the adhesive material, and evaluating the bioavailability of the imitation drug and the original grinding drug according to the difference of measurement results;
also included is a skeleton wear test, the skeleton wear test comprising:
placing the control imitation drug and the imitation drug to be tested in a reciprocating barrel 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 measurement results;
The reciprocating barrel dissolution instrument contains plastic beads and is used for simulating food abrasion.
2. The method of claim 1, wherein the bioequivalence test is used to determine whether the bioavailability of the original and control mimetic is equivalent.
3. The method of claim 1, wherein the mammalian gastric mucosa comprises porcine gastric mucosa.
4. The method of claim 1, wherein the raw, control and test simulated pharmaceuticals comprise pregabalin sustained release tablets.
5. The method of claim 1, wherein the simulated gastric fluid comprises FeSSGF.
6. The method of claim 1, wherein the plastic beads have a particle size of 7-9mm and a density of 1-1.2g/cm 3.
7. Use of the method of any one of claims 1-6 in imitation drug development.
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Citations (17)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6197346B1 (en) * | 1992-04-24 | 2001-03-06 | Brown Universtiy Research Foundation | Bioadhesive microspheres and their use as drug delivery and imaging systems |
| CN1668283A (en) * | 2002-06-21 | 2005-09-14 | 转化医药公司 | Pharmaceutical compositions with improved dissolution |
| WO2010041279A2 (en) * | 2008-10-08 | 2010-04-15 | V.B. Medicare Pvt. Ltd. | Sustained release drug delivery system |
| CN103191048A (en) * | 2012-01-06 | 2013-07-10 | 贵阳医学院 | Preparation method of oleanolic acid bioadhesive preparation |
| CN203132976U (en) * | 2013-02-07 | 2013-08-14 | 东华大学 | Sample bearing table for testing adhesive power of biological tissue adhesion material |
| CN103399129A (en) * | 2013-07-24 | 2013-11-20 | 西安交通大学 | Method for measuring in-vitro release degree and adhering time/corrosion time of bioadhesive preparation |
| CN203414458U (en) * | 2013-07-24 | 2014-01-29 | 西安交通大学 | Device for measuring in-vitro release degree and adhesion time/corrosion time of bioadhesive preparation |
| CN204903365U (en) * | 2015-08-12 | 2015-12-23 | 成都医学院 | Grab determining instrument |
| CN105343162A (en) * | 2015-12-01 | 2016-02-24 | 徐斌 | Preparation method and detection method of lamiophlomis rotata kudo oral slow-release adhesive film |
| CN106822007A (en) * | 2015-09-11 | 2017-06-13 | 西姆莱斯股份公司 | Oral formulations |
| US9989519B1 (en) * | 2017-05-04 | 2018-06-05 | Clayton Pharmaceuticals, LLC | Method for determining in vitro bioequivalence of a sucralfate suspension sample to a sucralfate suspension reference listed drug (RLD) |
| WO2019042247A1 (en) * | 2017-08-28 | 2019-03-07 | 江苏恒瑞医药股份有限公司 | Pharmaceutical composition of cyp17 inhibitor and preparation method therefor |
| CN109432057A (en) * | 2018-12-24 | 2019-03-08 | 兰州大学 | A kind of stomach is interior to position site-specific drug delivery mini-pill and preparation method thereof |
| CN110865026A (en) * | 2019-10-22 | 2020-03-06 | 杭州电子科技大学 | Adhesion testing device and adhesion testing method thereof |
| WO2021233461A1 (en) * | 2020-05-22 | 2021-11-25 | 苏州晶云药物科技股份有限公司 | Novel crystal form of benzothiazole compound and preparation method therefor |
| CN113777207A (en) * | 2021-09-09 | 2021-12-10 | 安徽省食品药品检验研究院(安徽国家农副加工食品质量监督检验中心) | Determination method of gliclazide sustained release tablet dissolution curve, similarity evaluation method and application thereof |
| WO2022200971A1 (en) * | 2021-03-22 | 2022-09-29 | Università Degli Studi Di Genova | A method for the production of gastroretentive compact matrices for the controlled release of active substances and compact matrices thus obtained |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU2003278564A1 (en) * | 2002-10-23 | 2004-05-13 | Yissum Research Development Company Of The Hebrew University Of Jerusalem | In vitro test for studying compound predicting pharmacologic and/or pharmacokinetic and/or pharmacodynamic parameters of a compound |
| EP1730516A1 (en) * | 2004-03-30 | 2006-12-13 | Pfizer Products Incorporated | Method and device for evaluation of pharmaceutical compositions |
| KR101882820B1 (en) * | 2015-12-30 | 2018-07-30 | 주식회사 삼양바이오팜 | Mucoadhesive pharmaceutical composition and preparation method thereof |
| GB201904757D0 (en) * | 2019-04-04 | 2019-05-22 | Biorelevant Com Ltd | Biorelevant composition |
-
2022
- 2022-11-24 CN CN202211478677.7A patent/CN115684514B/en active Active
Patent Citations (18)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6197346B1 (en) * | 1992-04-24 | 2001-03-06 | Brown Universtiy Research Foundation | Bioadhesive microspheres and their use as drug delivery and imaging systems |
| CN1668283A (en) * | 2002-06-21 | 2005-09-14 | 转化医药公司 | Pharmaceutical compositions with improved dissolution |
| WO2010041279A2 (en) * | 2008-10-08 | 2010-04-15 | V.B. Medicare Pvt. Ltd. | Sustained release drug delivery system |
| CN102307574A (en) * | 2008-10-08 | 2012-01-04 | 鲍斯生命科学Pvt有限公司 | Sustained release drug delivery system |
| CN103191048A (en) * | 2012-01-06 | 2013-07-10 | 贵阳医学院 | Preparation method of oleanolic acid bioadhesive preparation |
| CN203132976U (en) * | 2013-02-07 | 2013-08-14 | 东华大学 | Sample bearing table for testing adhesive power of biological tissue adhesion material |
| CN103399129A (en) * | 2013-07-24 | 2013-11-20 | 西安交通大学 | Method for measuring in-vitro release degree and adhering time/corrosion time of bioadhesive preparation |
| CN203414458U (en) * | 2013-07-24 | 2014-01-29 | 西安交通大学 | Device for measuring in-vitro release degree and adhesion time/corrosion time of bioadhesive preparation |
| CN204903365U (en) * | 2015-08-12 | 2015-12-23 | 成都医学院 | Grab determining instrument |
| CN106822007A (en) * | 2015-09-11 | 2017-06-13 | 西姆莱斯股份公司 | Oral formulations |
| CN105343162A (en) * | 2015-12-01 | 2016-02-24 | 徐斌 | Preparation method and detection method of lamiophlomis rotata kudo oral slow-release adhesive film |
| US9989519B1 (en) * | 2017-05-04 | 2018-06-05 | Clayton Pharmaceuticals, LLC | Method for determining in vitro bioequivalence of a sucralfate suspension sample to a sucralfate suspension reference listed drug (RLD) |
| WO2019042247A1 (en) * | 2017-08-28 | 2019-03-07 | 江苏恒瑞医药股份有限公司 | Pharmaceutical composition of cyp17 inhibitor and preparation method therefor |
| CN109432057A (en) * | 2018-12-24 | 2019-03-08 | 兰州大学 | A kind of stomach is interior to position site-specific drug delivery mini-pill and preparation method thereof |
| CN110865026A (en) * | 2019-10-22 | 2020-03-06 | 杭州电子科技大学 | Adhesion testing device and adhesion testing method thereof |
| WO2021233461A1 (en) * | 2020-05-22 | 2021-11-25 | 苏州晶云药物科技股份有限公司 | Novel crystal form of benzothiazole compound and preparation method therefor |
| WO2022200971A1 (en) * | 2021-03-22 | 2022-09-29 | Università Degli Studi Di Genova | A method for the production of gastroretentive compact matrices for the controlled release of active substances and compact matrices thus obtained |
| CN113777207A (en) * | 2021-09-09 | 2021-12-10 | 安徽省食品药品检验研究院(安徽国家农副加工食品质量监督检验中心) | Determination method of gliclazide sustained release tablet dissolution curve, similarity evaluation method and application thereof |
Non-Patent Citations (16)
| Title |
|---|
| 三七总皂苷胃肠道生物黏附片的体外释药及黏附特性考察;陈卫;朱春燕;;中国药学杂志(第12期);全文 * |
| 以卡波普为黏附材料的三七总皂苷生物黏附片的研制与体外评价;朱春燕;陈卫;;中国药学杂志(第24期);全文 * |
| 利用生物粘附技术提高萘哌地尔的生物利用度(英文);丁劲松, 蒋学华;Journal of Chinese Pharmaceutical Sciences(第01期);第30-32页 * |
| 利用生物粘附技术提高萘哌地尔的生物利用度;丁劲松, 蒋学华, 袁牧;药学学报(第05期);全文 * |
| 卡波姆等6种生物黏附材料体内外黏附性能评价;赵壮;杜守颖;陆洋;王振;白洁;郭懿望;;中国药学杂志(第24期);全文 * |
| 应用生物可降解材料玉米醇溶蛋白制备胃肠道生物黏附控释片;谢俊俊;吴鸿飞;鲁传华;张群卫;鲁涛;;中国组织工程研究与临床康复(第12期);全文 * |
| 格列齐特生物黏附缓释片的研制及体外评价;谭建国, 向大雄, 张毕奎;中南药学(第02期);全文 * |
| 格列齐特生物黏附缓释片的研制及其体内体外评价;张毕奎;苏芬丽;向大雄;朱运贵;谭建国;许飞;李焕德;;中国药学杂志(第12期);全文 * |
| 生物粘附性萘哌地尔缓释胶囊的处方筛选;丁劲松, 蒋学华;中国医院药学杂志(第07期);全文 * |
| 生物黏附性阴道片的研究进展;秦凌浩;关浩彬;;中国医院药学杂志(第19期);全文 * |
| 纳米铁制剂:非生物复合物(NBCD)仿制药的审批要求及临床对比性研究的重要性;李欣宇;邱峰;赵志刚;;药品评价(第14期);全文 * |
| 胃肠道生物粘附制剂的研究进展;郑玲利;高峰;;乐山师范学院学报(第12期);全文 * |
| 萘普生在新型缓释系统中的释药;夏林;胡艾希;谭英;陈慧;;应用化学;20080210(第02期);全文 * |
| 葛根总黄酮生物粘附性缓释片体外组织粘附力及释放度研究;向大雄, 李焕德, 罗杰英, 张杰, 袁红波;中国药房(第08期);全文 * |
| 西地碘口腔黏附片的研制;岳红坤;曹永娟;於娜;;石家庄学院学报(第06期);全文 * |
| 酒石酸美托洛尔片仿制与原研的溶出度比较;李舸远;何华;;海峡药学(第03期);全文 * |
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