CN112924632A - In-vitro bionic evaluation method and evaluation equipment for gastrointestinal tracts of medicines - Google Patents
In-vitro bionic evaluation method and evaluation equipment for gastrointestinal tracts of medicines Download PDFInfo
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/15—Medicinal preparations ; Physical properties thereof, e.g. dissolubility
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N35/00—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
- G01N35/10—Devices for transferring samples or any liquids to, in, or from, the analysis apparatus, e.g. suction devices, injection devices
- G01N35/1009—Characterised by arrangements for controlling the aspiration or dispense of liquids
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Abstract
The invention discloses a method and equipment for evaluating the in-vitro bionics of a medicine gastrointestinal tract, which realize accurate in-vitro bionics evaluation by reasonably selecting sampling time nodes, adjusting the pH value of physiological liquid of the gastrointestinal tract and selecting an adaptive osmotic membrane through the combined action of a dynamic dissolution instrument, a sampling device and an osmotic device, and comprise the evaluation of the environment disintegration and the release of the medicine gastrointestinal tract and the evaluation of the dissolution and the infiltration of the medicine gastrointestinal tract, thereby forming a complete and reliable overall evaluation process.
Description
Technical Field
The invention relates to the technical field of drug bionic evaluation, in particular to a drug gastrointestinal tract in-vitro bionic evaluation method and evaluation equipment.
Background
Oral drugs are the most common types of drugs at present, and for general oral drugs, drugs after being swallowed need to enter a blood system through intestinal absorption to exert corresponding drug curative effects, so that the absorption amount of the drugs in the intestinal directly influences the therapeutic effects of the drugs, and clinical curative effects cannot be realized if the absorption amount is too large or too small. In the development of oral drugs, the absorption of the drug in the gastrointestinal tract involves the following steps: 1. oral pharmaceutical formulations (oral preparations such as tablets, pills, capsules and the like) disintegrate in the gastrointestinal environment and release the active ingredients of the drugs; 2. the effective components of the medicine in the prescription are dissolved in the liquid environment of the gastrointestinal tract and enter the blood through the permeation of the intestinal mucosa, thus realizing the curative effect of the medicine.
In the development of oral drug prescriptions, real human experiments are often required to determine that the drug is clearly absorbed in the intestinal tract, and an effective technical means for complete gastrointestinal absorption evaluation of the drug prescription is lacking at present in vitro. The technical means at the present stage can perform biomimetic simulation on the first step of gastrointestinal absorption of the medicament, but the biomimetic simulation of the second step is lacked, the gastrointestinal dissolution and the blood infiltration of the medicament are evaluated, and the biomimetic evaluation is difficult to achieve in vitro, so that the in vitro biomimetic simulation evaluation technology of the gastrointestinal absorption of the whole medicament is also lacked; meanwhile, when the first step is bionic, the existing bionic dynamic digestion instrument can generate a large amount of bubbles when the pH value bionic simulation is carried out, so that bionic physiological digestion liquid cannot be used, and the bionic degree of the physiological environment of the gastrointestinal tract is reduced.
Disclosure of Invention
The invention aims to provide a multi-dimensional bionic detection device and a detection method for gastrointestinal absorption of a medicine, which can realize accurate in-vitro bionic evaluation through the combined action of a dynamic dissolution instrument, a sampling device and a penetration device, comprise the environmental disintegration and release of the gastrointestinal tract of the medicine (a first step) and the evaluation of the gastrointestinal tract of the medicine by dissolution and penetration (a second step), and can form a complete and reliable integral evaluation flow.
In order to achieve the purpose, the invention adopts the technical scheme that: a bionic evaluation method of medicine gastrointestinal tract in vitro comprises the following steps,
s1) preparing physiological liquid of gastrointestinal tract;
s2) adding the gastrointestinal physiological fluid into a dynamic dissolution instrument, and performing biomimetic simulation on gastrointestinal absorption of the medicine through the dynamic dissolution instrument after the medicine is added;
s3) sampling the physiological liquid of the gastrointestinal tract in the dynamic dissolution instrument at different time nodes, and introducing the physiological liquid into a Eusis perfusion chamber to perform osmotic simulation through a permeable membrane.
As a further optimization, the time nodes are 15min, 30min, 50min, 70min, 90min, 110min, 120min, 150min and 180min after the medicine is added into the physiological fluid of the gastrointestinal tract; and adjusting the pH value of the physiological liquid of the gastrointestinal tract to be 1.2, 1.3, 6.8, 7.4, 6.5 and 6.5 by the ventilation structure according to the time node.
As a further optimization, the permeable membranes used corresponding to the time nodes are sequentially rat gastric mucosa, rat jejunal mucosa, rat ileum mucosa, rat large intestine mucosa and rat large intestine mucosa.
The invention also provides a device for evaluating the bionics of the gastrointestinal tract in vitro by using the medicine, which comprises a dynamic dissolution instrument, a sampling device and a penetration device, wherein the dynamic dissolution instrument is used for containing the physiological liquid of the gastrointestinal tract and is used for simulating the environment of the gastrointestinal tract, and the sampling device is communicated with the dynamic dissolution instrument and the penetration device and is used for conveying the physiological liquid of the gastrointestinal tract.
As a further optimization, the dynamic dissolution instrument comprises a water bath box, a lifting mechanism, a stirring mechanism and a ventilation mechanism for adjusting the pH value of the physiological liquid of the gastrointestinal tract, wherein a plurality of dissolution cups for containing the physiological liquid of the gastrointestinal tract are arranged in the water bath box, the top ends of the dissolution cups are covered with sealing covers, the lifting mechanism is arranged on one side of the water bath box through a support, the lifting mechanism is provided with the stirring mechanism which penetrates through the sealing covers and then can extend into the dissolution cups, and the sampling device is communicated with the dissolution cups.
As a further optimization, the lower end of the sealing cover is provided with a plurality of pricks in a matrix shape, and the pricks are not abutted with the bottom of the dissolution cup and are positioned above the gastrointestinal tract physiological liquid.
As a further optimization, the stirring mechanism comprises a mounting frame, a driving component, a stirring rod and stirring blades, the mounting frame can slide up and down and is fixed on the lifting mechanism, the driving component is arranged on the mounting frame and is in transmission connection with the stirring rod, and the stirring blades are installed at one end of the stirring rod extending into the dissolution cup.
As a further optimization, the sampling device comprises a plurality of first guide pipes and a first pump body which are matched with the dissolution cup, one end of each first guide pipe extends into gastrointestinal tract physiological liquid of the dissolution cup and is communicated with a second guide pipe through the first pump body, and the second guide pipe extends into the permeation device.
As a further optimization, the sampling device further comprises an auxiliary conduit, an auxiliary pump body and a fluid infusion cup, wherein the auxiliary conduit is communicated with the fluid infusion cup and the dissolution cup, and the gastrointestinal tract physiological fluid infusion is carried out on the dissolution cup through the auxiliary pump body.
As a further optimization, the infiltration apparatus is a uss perfusion chamber.
Compared with the prior art, the invention has the following beneficial effects:
by using the bionic dynamic dissolution instrument, a sampling time node is set according to the change of the dynamic dissolution instrument and the condition of the real gastrointestinal tract, the disintegration and release parts of the real gastrointestinal tract of the medicine are corresponded, and then the medicine liquid sampled from the dissolution instrument is guided into the Eustachian perfusion chamber through automatic sampling, so that the bionic medicine gastrointestinal tract permeation evaluation is realized, and a complete and reliable overall evaluation flow can be formed.
Drawings
FIG. 1 is a schematic structural diagram of the present invention.
FIG. 2 is a schematic diagram of the dynamic dissolution apparatus of the present invention.
Fig. 3 is a block diagram of the closure and spike of the present invention.
Fig. 4 is a block diagram of a closure according to another embodiment of the present invention.
FIG. 5 is a block diagram of an adjustment portion and awl according to another embodiment of the invention.
FIG. 6 is a structural view of the stirring mechanism of the present invention.
In the figure, 100. dynamic dissolution instrument; 200. a sampling device; 300. a permeation device; 1. a base; 2. a water bath tank; 3. a dissolution cup; 41. sealing the cover; 411. a central bore; 4111. an internal thread; 412. a side hole; 413. a limiting ring; 431. mounting a plate; 432. a guide cylinder; 4321. an external thread; 4322. perforating; 42. e, stabbing; 5. a lifting mechanism; 6. a stirring mechanism; 61. a mounting frame; 62. a rotating electric machine; 63. a rotating shaft; 64. a bevel gear is vertically arranged; 65. a stirring rod; 66. a horizontal bevel gear; 67. a stirring blade; 68. a pH meter socket; 69. a touch screen; 71. a first conduit; 72. a first pump body; 73. a second conduit; 74. a test tube; 75. an auxiliary conduit; 76. an auxiliary pump body; 77. and a liquid replenishing cup.
Detailed Description
The following are specific embodiments of the present invention and are further described with reference to the drawings, but the present invention is not limited to these embodiments.
As shown in fig. 1 to 6, an in vitro bionic evaluation device for gastrointestinal tract of a drug comprises a dynamic dissolution instrument 100, a sampling device 200 and a permeation device 300, wherein the dynamic dissolution instrument contains a physiological solution of gastrointestinal tract for simulating the gastrointestinal tract environment, the sampling device 200 is communicated with the dynamic dissolution instrument 100 and the permeation device 300 for delivering the physiological solution of gastrointestinal tract, and the permeation device can be a uss perfusion chamber.
The dynamic dissolution instrument comprises a water bath box 2, a lifting mechanism 5, a stirring mechanism 6 and a ventilation mechanism (not shown) for adjusting the pH value of gastrointestinal tract physiological liquid, wherein the water bath box 2 is arranged on a base 1, a plurality of dissolution cups 3 for containing the gastrointestinal tract physiological liquid are arranged in the water bath box, the top ends of the dissolution cups 3 are covered with a sealing cover 41, the lifting mechanism 5 is arranged on one side of the water bath box 2 through a bracket, the lifting mechanism 5 is provided with the stirring mechanism 6 which penetrates through the sealing cover 41 and then can extend into the dissolution cups 3, and a sampling device is communicated with the dissolution cups 3; the lower end of the sealing cover 41 is provided with a plurality of pricks 42 in a matrix shape, and the pricks 42 are not contacted with the bottom of the dissolution cup 3 and are positioned above the physiological liquid of the gastrointestinal tract.
The gastrointestinal tract physiological liquid is added into the dissolution cup to realize the simulation of the gastrointestinal tract liquid, and during the pH value simulation, the gastrointestinal tract liquid in the dissolution cup is aerated through an aeration mechanism to realize the change of the pH value, and the basic principle is that the pH value of the liquid in the dissolution cup is adjusted by introducing carbon dioxide or mixed gas of carbon dioxide and oxygen (95% of carbon dioxide and 5% of oxygen) and helium into the liquid in the dissolution cup. Increasing the ventilation volume of liquid carbon dioxide, dissolving the carbon dioxide in water, reducing the pH value of the liquid, reducing the ventilation volume of the carbon dioxide, increasing the ventilation volume of helium, decreasing the dissolution of the carbon dioxide in water, and increasing the pH value of the liquid (see Merchant, H., Frost, J., & Basit, A. (2014). IPC number GB2509286. Apparatus and method for testing the details of the production (Patent number 2509286)), but the conventional device can generate a large number of bubbles in the ventilation process, so that the bionic degree of the gastrointestinal tract physiological environment can be reduced because bionic physiological dissolution liquid cannot be used in the state, and therefore, in order to prevent a large number of bubbles generated by shearing action, the bubbles in the dissolution cup can be punctured by conical pricked on the sealing cover, so that the drug dissolution environment is closer to the gastrointestinal tract physiological environment; the stirring and shearing of the stirring mechanism to the gastrointestinal tract liquid are controlled by a built-in program to simulate the peristalsis of the gastrointestinal tract, and in conclusion, the bionic degree of the gastrointestinal tract physiological environment can be improved through the synergistic effect of the gastrointestinal tract physiological environment, the pH value change and the stirring and shearing change.
The height of the prick at the middle position of the sealing cover 41 is greater than that of the prick at the side position, and the liquid level in the dissolving cup is generally lower than that of the liquid level at the side part in the gastrointestinal tract liquid stirring and shearing process, so that the height of the prick is set correspondingly, and the air bubbles generated in the puncturing and ventilating process and the stirring process are facilitated.
The sealing cover 41 is provided with a central hole 411, the stirring rod passes through the central hole and then extends into the dissolution cup, the sealing cover is also provided with one or more side holes 412 which penetrate through the body of the sealing cover and can be used for sampling or/and fluid infusion or ventilation of a ventilation structure for pH value adjustment after the guide pipe extends into the sealing cover.
As shown in fig. 4 to 5, in another embodiment, the sealing cap further includes a mounting portion, the mounting portion includes a mounting plate 431 and a guide cylinder 432, the awl is disposed on the lower end surface of the mounting plate, the guide cylinder is disposed at the center of the mounting plate and has a through hole 4322 penetrating through the body and the mounting plate, the guide cylinder is provided with an external thread 4321 around and adapted to the internal thread, the central hole 411 of the sealing cap is provided with an internal thread 4111 around, the guide cylinder is mounted in the central hole of the sealing plate in a screwing manner, and the adjustment of the height of the lower end surface of the awl can be realized through the matching of the external thread and the internal thread, so that the air bubbles punctured. At this point, the stir bar extends through the central hole into the dissolution cup, and the side holes 412 are located on the opposite outer side of the mounting plate and do not impede sampling or fluid replacement. In addition, a stopper ring 413 may be provided on the peripheral side of the sealing plate so as to be fitted over the dissolution cup for stopping, thereby preventing positional deviation when the mounting portion is adjusted.
Elevating system 5 includes elevator motor, lead screw and slide rail, and lead screw and slide rail are fixed in on the support, but the setting that rabbling mechanism vertical slided on the slide rail, and link to each other through lead screw and elevator motor transmission, and elevating system is conventional setting, and its concrete part is not shown, also can choose for use the mechanism that has the same raising and lowering functions to replace, like lift electric jar etc..
The stirring mechanism 6 comprises a mounting frame 61, a driving component, a stirring rod 65 and stirring blades 67, the mounting frame 61 can be fixed on the lifting mechanism 5 in a vertically sliding manner, the driving component is arranged on the mounting frame 61 and is in transmission connection with the stirring rod 65, and the stirring blades 67 are arranged at one end of the stirring rod 65 extending into the dissolution cup 3; the driving component comprises a rotating motor 62, a rotating shaft 63, a vertical bevel gear 64 and a horizontal bevel gear 66, a stirring rod 65 is rotatably arranged on the mounting rack 61, the horizontal bevel gear 66 is arranged on the stirring rod 65, the rotating shaft 63 is arranged at the output end of the rotating motor 62, the vertical bevel gear 64 is arranged on the rotating shaft 63, and the vertical bevel gear 64 is meshed with the horizontal bevel gear 66; the conversion of two rotation forms is realized; the conversion of the rotation form can also be realized by other mechanisms, such as a synchronous belt and the like.
A heater for water bath heat preservation is arranged in the water bath tank 2, so that the water bath temperature is kept at 37 +/-0.5 ℃, and the temperature of gastrointestinal tract liquid in the dissolution cup is ensured to be more consistent with the temperature of a human body; a pH meter is arranged in the dissolution cup 3, the pH meter is connected with a host through a pH meter socket 68, and man-machine interaction is carried out through a touch screen 69.
The sampling device 200 comprises a plurality of first guide pipes 71 and a plurality of first pump bodies 72 which are matched with the dissolution cup 3, one end of each first guide pipe 71 extends into gastrointestinal physiological fluid of the dissolution cup 3 and is communicated with the corresponding second guide pipe 73 through the corresponding first pump body 72, the corresponding second guide pipe 73 extends into the Euler perfusion chamber, and through program control, sampling can be carried out on a sampling time node through the first pump bodies and is conveyed into the Euler perfusion chamber, and sampling can also be carried out in the test tubes 74 and is manually transferred to the Euler perfusion chamber.
The sampling device 200 further comprises an auxiliary conduit 75, an auxiliary pump body 76 and a fluid infusion cup 77, wherein the auxiliary conduit 75 is communicated with the fluid infusion cup 77 and the dissolution cup 3, the gastrointestinal tract physiological fluid infusion is carried out on the dissolution cup 3 through the auxiliary pump body 76, and the gastrointestinal tract environment can be simulated more bionically by supplementing the bionic gastrointestinal tract physiological fluid to the bionic gastrointestinal tract environment.
The method for evaluating the bionics of the gastrointestinal tract of the medicine comprises the following steps:
s1) preparing a gastrointestinal physiological fluid (the specific formula of the gastrointestinal physiological fluid can be seen in Manual Ibarra, Cristian Valiane, Patricia Sope ñ a, Alejatra Schiiavo, Marianela Lorie, Marta V-zquez, Pietro Fagiolino, Integration of in vitro biorievel dispersion and in silico PBPK model of cardiac diology to predict bioequival of organic products, European Journal of pharmaceutical sciences, 10.1016/j. ejps.2018.03.032, 118, (176-) 2018));
s2) adding the gastrointestinal tract physiological solution into a dynamic dissolution instrument, performing biomimetic simulation on gastrointestinal tract absorption of the medicine through the dynamic dissolution instrument after the medicine is added, and adjusting the pH value of the gastrointestinal tract physiological solution through a ventilation mechanism;
s3) sampling the physiological liquid of the gastrointestinal tract in the dynamic dissolution instrument at different time nodes, and introducing the physiological liquid into a Eusis perfusion chamber to perform osmotic simulation through a permeable membrane.
The method specifically comprises the following steps: the bionic dynamic dissolution instrument is used, the bionic of the first step of gastrointestinal absorption of the medicine can be realized, sampling time nodes are set according to the change of the dynamic dissolution instrument and the condition of the real gastrointestinal tract, the disintegration and release positions of the real gastrointestinal tract of the medicine correspond to the sampling time nodes, and then the medicine liquid sampled from the dissolution instrument is guided into the Eusis perfusion chamber through automatic sampling, so that the bionic medicine gastrointestinal tract permeation evaluation is realized. For example, the drug liquid sampled from the stomach represents the amount of drug released from the stomach, and then the permeation test in the ews perfusion chamber can evaluate how much of the drug can be absorbed into the blood through the gastric mucosa after the drug is released from the stomach in a certain amount.
The sampling time node (dissolution duration), dissolution environment, and corresponding physiological site are shown in the following table.
The specific embodiments described herein are merely illustrative of the spirit of the invention. Various modifications or additions may be made to the described embodiments or alternatives may be employed by those skilled in the art without departing from the spirit or ambit of the invention as defined in the appended claims.
Claims (10)
1. A bionic evaluation method of medicine gastrointestinal tract in vitro is characterized by comprising the following steps,
s1) preparing physiological liquid of gastrointestinal tract;
s2) adding the gastrointestinal physiological fluid into a dynamic dissolution instrument, and performing biomimetic simulation on the gastrointestinal dissolution of the medicine through the dynamic dissolution instrument after the medicine is added;
s3) sampling the physiological liquid of the gastrointestinal tract in the dynamic dissolution instrument at different time nodes, and introducing the physiological liquid into a Eusis perfusion chamber to perform osmotic simulation through a permeable membrane.
2. The method for the in vitro biomimetic assessment of the gastrointestinal tract by using the drug according to claim 1, wherein the time nodes are 15min, 30min, 50min, 70min, 90min, 110min, 120min, 150min and 180min after the drug is added into the physiological fluid of the gastrointestinal tract.
3. The in vitro biomimetic evaluation method for gastrointestinal tract of medicine according to claim 2, wherein the permeable membranes used corresponding to the time nodes are rat gastric mucosa, rat jejunal mucosa, rat ileum mucosa, rat large intestinal mucosa, and rat large intestinal mucosa in sequence.
4. The in-vitro bionic evaluation equipment for the gastrointestinal tract of the medicine is characterized by comprising a dynamic dissolution instrument, a sampling device and a penetration device, wherein the dynamic dissolution instrument is used for containing the gastrointestinal tract physiological liquid and is used for simulating the gastrointestinal tract environment, and the sampling device is communicated with the dynamic dissolution instrument and the penetration device and is used for conveying the gastrointestinal tract physiological liquid.
5. The in vitro bionics assessment device of a drug gastrointestinal tract of claim 4, wherein the dynamic dissolution apparatus comprises a water bath, a lifting mechanism, a stirring mechanism and a ventilation mechanism for adjusting the pH value of the physiological fluid of the gastrointestinal tract, a plurality of dissolution cups for containing the physiological fluid of the gastrointestinal tract are arranged in the water bath, a sealing cover is covered on the top end of each dissolution cup, the lifting mechanism is arranged on one side of the water bath through a bracket, the lifting mechanism is provided with the stirring mechanism which penetrates through the sealing cover and then can extend into the dissolution cup, and the sampling device is communicated with the dissolution cups.
6. The device for the in vitro biomimetic assessment of the gastrointestinal tract as claimed in claim 5, wherein the lower end of the cover is provided with a plurality of pricks in a matrix shape, and the pricks are not abutted with the bottom of the dissolution cup and are located above the physiological fluid of the gastrointestinal tract.
7. The in vitro bionic evaluation device for gastrointestinal tracts according to claim 5, wherein the stirring mechanism comprises a mounting frame, a driving component, a stirring rod and stirring blades, the mounting frame is fixed on the lifting mechanism in a vertically sliding manner, the driving component is arranged on the mounting frame, the driving component is in transmission connection with the stirring rod, and the stirring blades are arranged at one end of the stirring rod extending into the dissolution cup.
8. The apparatus for in vitro biomimetic evaluation of gastrointestinal tract according to claim 5, wherein the sampling device comprises a plurality of first conduits and a first pump body matched with the dissolution cup, one end of the first conduit extends into the gastrointestinal tract physiological fluid of the dissolution cup, and is communicated with the second conduit through the first pump body, and the second conduit extends into the osmotic device.
9. The apparatus for in vitro bionic evaluation of gastrointestinal tract according to claim 5, wherein the sampling device further comprises an auxiliary conduit, an auxiliary pump body and a fluid infusion cup, the auxiliary conduit is communicated with the fluid infusion cup and the dissolution cup, and the auxiliary conduit is used for carrying out fluid infusion of gastrointestinal tract physiological fluid to the dissolution cup through the auxiliary pump body.
10. The apparatus for the in vitro biomimetic assessment of the gastrointestinal tract by drugs according to claim 4, wherein the osmotic device is a ewings perfusion chamber.
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