CN102253173A - Single-tank bionic system device and medicine dissolving solution as well as evaluation method using device and solution - Google Patents
Single-tank bionic system device and medicine dissolving solution as well as evaluation method using device and solution Download PDFInfo
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- CN102253173A CN102253173A CN2011100985419A CN201110098541A CN102253173A CN 102253173 A CN102253173 A CN 102253173A CN 2011100985419 A CN2011100985419 A CN 2011100985419A CN 201110098541 A CN201110098541 A CN 201110098541A CN 102253173 A CN102253173 A CN 102253173A
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Abstract
The invention provides a single-tank bionic system device and medicine dissolving solution as well as an evaluation method using the device and the solution. The device mainly consists of a medicine dissolving chamber, a pH adjuster, a microporous filter and a medicine diffusion cell; each 1000ml of a medicine dissolving solution A contains 7.8894g of NaCl, 9.008g of D-Glucose, 0.2797g of CaCl2, 0.0975g of MgSO4, 1.9524g of MES (fatty acid methyl ester sulfonate), 5.0mL of HCL (1mM) and the balance of water; and each 1000ml of a medicine dissolving solution B contains 0.7977g of KCl, 0.1198g of KH2PO4, 7.8894g of NaCl, 0.0965g of NaH2PO4, 9.762g of MES the Tris pH value of which is adjusted at 6.8-7.8 and the balance of water. By utilizing the device and the evaluation method, the release and absorption law of a delayed-release preparation can be evaluated.
Description
Technical field
The present invention relates to a kind ofly be used to estimate pharmaceutical preparation and discharge and stride device and medicine dissolution liquid and the drug evaluation method that film sees through feature, especially a kind of single pond bionic system device and medicine dissolution liquid and evaluation method that is used to estimate the slowbreak preparation.
Background technology
The dynamic bionic system of existing medicine stripping/absorb (license number: ZL 200920098448.6) is adjusted the chamber and the drug diffusion pond is formed by medicine dissolution chamber, pH, is used for interior dissolution rate of aids drug body and Premeabilisation of cells Evaluation on effect.Yet along with going deep into of research, adopt and to estimate the slowbreak preparation by existing medicine stripping/dynamic bionic system of absorption: on the one hand, the slowbreak preparation rests on not easy disintegrating of medicine dissolution chamber, can not simulate preparation and travel to the process of intestines disintegration, release from stomach, so just is difficult to predict its physiological disposition; On the other hand, pH adjusts the chamber and has hold-up volume, causes stripping side in drug diffusion pond to detect on time of medicine to be detained to some extent, decreases on the apparent concentration, is not easy to microdetermination; In addition, a large amount of auxiliary materials also can be piled up in silicone tube and be caused line clogging along with dissolution fluid enters pipeline, makes test not proceed.
Summary of the invention
Technical matters to be solved by this invention is to provide a kind of single pond bionic system device that is used to estimate the slowbreak preparation.
Another technical matters to be solved by this invention is to provide a kind of above-mentioned medicine dissolution liquid that is used to estimate single pond bionic system device of slowbreak preparation that is applied to.
Another technical matters to be solved by this invention is to provide a kind of use above-mentioned be used to estimate single pond bionic system device of slowbreak preparation and the method that medicine dissolution liquid is estimated release of slowbreak preparation and absorbing rule.
For solving the problems of the technologies described above, technical scheme of the present invention is:
A kind of single pond bionic system device that is used to estimate the slowbreak preparation, mainly form by medicine dissolution chamber, pH adjuster, millipore filter and drug diffusion pond, wherein bottom, medicine dissolution chamber is provided with magnetic stir bar, medicine dissolution is indoor to be provided with a medicine carrying device, leave distance between the magnetic stir bar of described medicine carrying device and bottom, medicine dissolution chamber, stainless steel mesh places this medicine carrying device top; Filling material is non-adsorbability filler in the described pH adjuster; The drug diffusion pond is made up of supply chamber, receiving chamber and the biological membrane tissue that is entrenched between the two; Described medicine dissolution chamber, pH adjuster, millipore filter and the silicone tube of drug diffusion pond by internal diameter 1.0mm-2.0mm are connected successively, be respectively equipped with sample holes in addition at described medicine dissolution chamber, pH adjuster and receiving chamber, also be provided with air admission hole and thief hole at described supply chamber and receiving chamber.
Preferably, the above-mentioned single pond bionic system device that is used to estimate the slowbreak preparation, described medicine carrying device are medicine carrying basket or the sheet metal folders that is made by anti-strong acid, anti-highly basic, resistant to elevated temperatures stainless steel material.
Preferably, the above-mentioned single pond bionic system device that is used to estimate the slowbreak preparation, described non-adsorbability filler is sea sand or glass microsphere.
Preferably, the above-mentioned single pond bionic system device that is used to estimate the slowbreak preparation, described millipore filter is replaceable device.
Preferably, the above-mentioned single pond bionic system device that is used to estimate the slowbreak preparation, described millipore filter aperture is 0.22 μ m-0.8 μ m.
Preferably, the above-mentioned single pond bionic system device that is used to estimate the slowbreak preparation, described millipore filter is synthon filter membrane, quartz fibre filter membrane or glass fiber filter.
Preferably, the above-mentioned single pond bionic system device that is used to estimate the slowbreak preparation, described biological membrane is organized as Caco-2 and transgenic cell monofilm, MDCK and transgenic cell monofilm thereof or animal intestine in vitro.
Preferably, the above-mentioned single pond bionic system device that is used to estimate the slowbreak preparation, described Caco-2 transgenic cell comprises Caco-2/CYP3A4 transgenic cell, Caco-2/CYP2D6 transgenic cell, Caco-2/CYP2C9 transgenic cell, Caco-2/CYP2C19 transgenic cell or Caco-2/CYP1A2 transgenic cell.
Preferably, the above-mentioned single pond bionic system device that is used to estimate the slowbreak preparation, described Caco-2 transgenic cell is the Caco-2/CYP3A4 transgenic cell.
Preferably, the above-mentioned single pond bionic system device that is used to estimate the slowbreak preparation, described MDCK transgenic cell comprises MDCK-CYP3A4 transgenic cell, MDCK-CYP2D6 transgenic cell, MDCK-CYP2C9 transgenic cell, MDCK-CYP2C19 transgenic cell, MDCK-CYP1A2 transgenic cell, MDCK-MDR1-CYP3A4 transgenic cell, MDCK-MDR1-CYP2D6 transgenic cell, MDCK-MDR1-CYP2C9 transgenic cell, MDCK-MDR1-CYP2C19 transgenic cell or MDCK-MDR1-CYP1A2 transgenic cell.
Preferably, the above-mentioned single pond bionic system device that is used to estimate the slowbreak preparation, described MDCK transgenic cell is MDCK-CYP3A4 transgenic cell or MDCK-MDR1-CYP3A4 transgenic cell.
Preferably, the above-mentioned single pond bionic system device that is used to estimate the slowbreak preparation, described medicine dissolution chamber, pH adjuster and drug diffusion pond are made by the transparent organic glass material.
A kind ofly be applied to the above-mentioned medicine dissolution liquid that is used to estimate single pond bionic system device of slowbreak preparation, comprise medicine dissolution liquid A and medicine dissolution liquid B, wherein:
Medicine dissolution liquid A is mainly by NaCl, D-Glucose, CaCl
2, MgSO
4, MES and HCl (1mM) form, and contains NaCl 7.8894g, D-Glucose 9.008g, CaCl in wherein every 1000ml solution
20.2797g, MgSO
40.0975g, MES 1.9524g, HCl (1mM) 5.0mL, all the other are water;
Medicine dissolution liquid B is mainly by KCl, KH
2PO
4, NaCl, NaH
2PO
4, MES and Tris form, and contains KCl 0.7977g, KH in wherein every 1000ml solution
2PO
40.1198g, NaCl 7.8894g, NaH
2PO
40.0965g, MES 9.762g, Tris regulates pH value to 6.8-7.8, all the other are water.
Be that following table 1 is described:
Table 1 medicine dissolution liquid A, medicine dissolution liquid B component and proportioning
* medicine dissolution liquid B transfers to 6.8 with Tris; Medicine dissolution liquid A and medicine dissolution liquid B add water to 1000mL.
A kind of above-mentioned single pond bionic system device that is used to estimate the slowbreak preparation and medicine dissolution liquid used estimates that the slowbreak preparation discharges and the method for absorbing rule, concrete steps are: during mensuration preparation is joined in the medicine carrying device of medicine dissolution chamber, feed medicine dissolution liquid A earlier, switch to medicine dissolution liquid B through behind the certain hour; By the constant current peristaltic pump dissolved drug is transferred to the pH adjuster and mixes, further be transferred to the supply chamber in drug diffusion pond then, and constantly enter the medicine receiving chamber, respectively from supply chamber and receiving chamber sampling and measuring through the biological membrane tissue with pH adjustment liquid.
Preferably, be used to estimate single pond bionic system device of slowbreak preparation and the method that medicine dissolution liquid is estimated release of slowbreak preparation and absorbing rule, be 15-30min the switching time of described medicine dissolution liquid A and medicine dissolution liquid B.
The invention has the beneficial effects as follows:
The stainless steel mesh of the medicine dissolution chamber of the above-mentioned single pond bionic system device that is used for estimating the slowbreak preparation, as the one-level millipore filter, make auxiliary material and not fully the preparation granule of disintegration can not flow out, thereby having prevented that undissolved granule enters the pH adjuster in the test causes the test deviation; The pH adjuster is used for regulating the above-mentioned pH value that is used to estimate single pond bionic system device of slowbreak preparation, fill non-adsorbability filler in it, pH adjustment liquid and medicine dissolution liquid were fully mixed, again can be as the secondary millipore filter, make the preparation granule of auxiliary material and not complete disintegration can not flow out the pH adjuster, thereby obstruction and the short grained loss of preparation avoiding excipient substance in silicone tube, to pile up and cause, the serious problems that the test that causes because of obstruction must be ended have been solved like this, in addition, reduced the existence of hold-up volume in the past installing, solve diffusion cell stripping side and detected the time delay of medicine and the problem that apparent concentration reduces, be convenient to microdetermination; Described millipore filter makes the medicine that has only dissolving fully to discharge just can enter the supply chamber in drug diffusion pond as three grades of millipore filters, prevents from not discharge the loss of medicine, and the settled solution that obtains can be directly as analytic liquid; Even if a small amount of auxiliary material is arranged to be piled up and the phenomenon that results in blockage at millipore filter, also can change the new millipore filter of another one very easily, test can be proceeded, simultaneously, according to different pharmaceutical dosage forms, millipore filter can be changed as required, for example, when pharmaceutical preparation is an opaque capsule, can adopt the synthon film is filter membrane; When pharmaceutical preparation toughness composition, can adopt a spot of quartz fibre as filter membrane; When pharmaceutical preparation is the disintegration-type pharmaceutical preparation, for avoiding absorption, can adopt glass fiber filter, and glass fiber filter can reuse, get final product the saving cost with finishing to rinse well at every turn.
The technical scheme that is provided by above invention as seen, compared with prior art, a kind of single pond bionic system device that is used to estimate the slowbreak preparation provided by the invention is a kind of continuous dynamic apparatus, can simulate preparation travels to intestines from stomach process, overcome the deficiency that existing bionic system can not be used for estimating the slowbreak preparation, it has been generalized to solid pharmaceutical preparation widely; Reduce pH and adjusted the hold-up volume that the chamber exists, solved diffusion cell stripping side and detected the time delay of medicine and the problem that apparent concentration reduces, be convenient to microdetermination.Simultaneously, solved again and remove pH and adjust the blockage problem that excipient substance causes behind the chamber; This device has fully taken into account the dynamic process in the human body, intestines and stomach situation in the body of real simulation people's normal physiological, and can reflect slowbreak preparation dissolving and absorption process in vivo, can estimate the release and the absorbing rule of slowbreak preparation.
Description of drawings
Fig. 1 is a kind of structural representation that is used to estimate single pond bionic system device of slowbreak preparation provided by the invention;
Among the figure: the 2-pH adjuster 3-supply chamber 4-receiving chamber of 1-medicine dissolution chamber
5-silicone tube 6-medicine carrying basket 7-magnetic stir bar 8-stainless steel mesh
The non-adsorbability filler of 9-10-millipore filter 11-biological membrane tissue
Fig. 2 is a kind of another structural representation that is used to estimate single pond bionic system device of slowbreak preparation provided by the invention;
Among the figure: the 2-pH adjuster 3-supply chamber 4-receiving chamber of 1-medicine dissolution chamber
5-silicone tube 6 '-sheet metal folder 7-magnetic stir bar 8-stainless steel mesh
The non-adsorbability filler of 9-10-millipore filter 11-biological membrane tissue
Fig. 3 is that C14H10Cl2NNaO2 solubleness is with the pH variation diagram;
Fig. 4 is that the Diclofenac sodium enteric tablet is being used for estimating the release-time curve (n=3) of single pond bionic system device of slowbreak preparation with the pH variation;
Fig. 5 is that the Diclofenac sodium enteric tablet is in the comparison (n=3) that is used for estimating single pond bionic system device of slowbreak preparation and the cumulative release degree-time curve in the oar method;
Fig. 6 is the Diclofenac sodium enteric tablet at the transmitance-time curve (n=3) of the single pond bionic system device that is used for estimating the slowbreak preparation;
Fig. 7 is the Diclofenac sodium enteric tablet at the accumulation transmitance-time curve (n=3) of the single pond bionic system device that is used for estimating the slowbreak preparation;
Fig. 8 is Diclofenac sodium enteric tablet F
aAnd F
dBetween relation curve (n=10);
Fig. 9 is that magnesium omeprazole solubleness is with the pH variation diagram;
Figure 10 is that the magnesium omeprazole enteric coatel tablets are being used for estimating the release-time curve (n=3) of single pond bionic system device of slowbreak preparation with the pH variation;
Figure 11 is that the magnesium omeprazole enteric coatel tablets are in the comparison (n=3) that is used for estimating single pond bionic system device of slowbreak preparation and is changeing the cumulative release degree-time curve in the basket method;
Figure 12 is the magnesium omeprazole enteric coatel tablets at the transmitance-time curve (n=3) of the single pond bionic system device that is used for estimating the slowbreak preparation;
Figure 13 is the magnesium omeprazole enteric coatel tablets at the accumulation transmitance-time curve (n=3) of the single pond bionic system device that is used for estimating the slowbreak preparation;
Figure 14 is magnesium omeprazole enteric coatel tablets F
aAnd F
dBetween relation curve (n=10);
Figure 15 is the blood concentration-time curves (n=6) of magnesium omeprazole enteric coatel tablets in Beagle dog body;
The correlativity curve of Figure 16 to be the magnesium omeprazole enteric coatel tablets absorb in the body of the accumulation transmitance of the single pond bionic system device that is used for estimating the slowbreak preparation and Beagle percentage.
Embodiment
In order to make those skilled in the art better understand technical scheme of the present invention, technical scheme of the present invention is described in further detail below in conjunction with the drawings and the specific embodiments.
As shown in Figure 1, a kind of single pond bionic system device that is used to estimate the slowbreak preparation, mainly form by medicine dissolution chamber 1, pH adjuster 2, removable millipore filter 10 and drug diffusion pond, described medicine dissolution chamber 1, pH adjuster 2 and drug diffusion pond are made by the transparent organic glass material, wherein 1 bottom, medicine dissolution chamber is provided with magnetic stir bar 7, be provided with a medicine carrying device in the medicine dissolution chamber 1, leave distance between the magnetic stir bar 7 of described medicine carrying device and 1 bottom, medicine dissolution chamber, stainless steel mesh 8 places this medicine carrying device top; Filling material is non-adsorbability filler 9 in the described pH adjuster 2; The drug diffusion pond is made up of supply chamber 3, receiving chamber 4 and the biological membrane tissue 11 that is entrenched between the two; Described medicine dissolution chamber 1, pH adjuster 2, millipore filter 10 is connected successively with the silicone tube 5 of drug diffusion pond by internal diameter 1.0mm, in described medicine dissolution chamber 1, pH adjuster 2 and receiving chamber 4 are respectively equipped with sample holes in addition, also be provided with air admission hole and thief hole at described supply chamber 3 and receiving chamber 4, wherein said medicine carrying device is by anti-strong acid, anti-highly basic, the medicine carrying basket 6 that resistant to elevated temperatures stainless steel material is made, described non-adsorbability filler 9 is a sea sand, described millipore filter 10 is the synthon filter membrane, its aperture is 0.22 μ m, and described biological membrane tissue 11 is a Caco-2 cell monolayer film.
As shown in Figure 1, a kind of single pond bionic system device that is used to estimate the slowbreak preparation, have with the described single pond bionic system device that is used to estimate the slowbreak preparation of embodiment 1 and similarly construct, wherein said medicine dissolution chamber 1, pH adjuster 2, millipore filter 10 is connected successively with the silicone tube 5 of drug diffusion pond by internal diameter 2.0mm, in described medicine dissolution chamber 1, pH adjuster 2 and receiving chamber 4 are respectively equipped with sample holes in addition, also be provided with air admission hole and thief hole at described supply chamber 3 and receiving chamber 4, wherein said medicine carrying device is by anti-strong acid, anti-highly basic, the medicine carrying basket 6 that resistant to elevated temperatures stainless steel material is made, described non-adsorbability filler 9 is a glass microsphere, described millipore filter 10 is a glass fiber filter, its aperture is 0.8 μ m, and described biological membrane tissue 11 is a MDCK-CYP3A4 transgenic cell monofilm.
As shown in Figure 1, a kind of single pond bionic system device that is used to estimate the slowbreak preparation, have with the described single pond bionic system device that is used to estimate the slowbreak preparation of embodiment 1 and similarly construct, wherein said medicine dissolution chamber 1, pH adjuster 2, millipore filter 10 is connected successively with the silicone tube 5 of drug diffusion pond by internal diameter 1.5mm, in described medicine dissolution chamber 1, pH adjuster 2 and receiving chamber 4 are respectively equipped with sample holes in addition, also be provided with air admission hole and thief hole at described supply chamber 3 and receiving chamber 4, wherein said medicine carrying device is by anti-strong acid, anti-highly basic, the medicine carrying basket 6 that resistant to elevated temperatures stainless steel material is made, described non-adsorbability filler 9 is a sea sand, described millipore filter 10 is the quartz fibre filter membrane, its aperture is 0.57 μ m, and described biological membrane tissue 11 is the mdck cell monofilm.
As shown in Figure 2, a kind of single pond bionic system device that is used to estimate the slowbreak preparation, have with the described single pond bionic system device that is used to estimate the slowbreak preparation of embodiment 1 and similarly construct, wherein said medicine dissolution chamber 1, pH adjuster 2, millipore filter 10 is connected successively with the silicone tube 5 of drug diffusion pond by internal diameter 1.0mm, in described medicine dissolution chamber 1, pH adjuster 2 and receiving chamber 4 are respectively equipped with sample holes in addition, also be provided with air admission hole and thief hole at described supply chamber 3 and receiving chamber 4, wherein said medicine carrying device is by anti-strong acid, anti-highly basic, the sheet metal folder 6 ' that resistant to elevated temperatures stainless steel material is made, described non-adsorbability filler 9 is a glass microsphere, described millipore filter 10 is a glass fiber filter, its aperture is 0.65 μ m, and described biological membrane tissue 11 is a Caco-2/CYP3A4 transgenic cell monofilm.
As shown in Figure 1, a kind of single pond bionic system device that is used to estimate the slowbreak preparation, have with the described single pond bionic system device that is used to estimate the slowbreak preparation of embodiment 1 and similarly construct, wherein said medicine dissolution chamber 1, pH adjuster 2, millipore filter 10 is connected successively with the silicone tube 5 of drug diffusion pond by internal diameter 2.0mm, in described medicine dissolution chamber 1, pH adjuster 2 and receiving chamber 4 are respectively equipped with sample holes in addition, also be provided with air admission hole and thief hole at described supply chamber 3 and receiving chamber 4, wherein said medicine carrying device is by anti-strong acid, anti-highly basic, the medicine carrying basket 6 that resistant to elevated temperatures stainless steel material is made, described non-adsorbability filler 9 is a glass microsphere, described millipore filter 10 is the quartz fibre filter membrane, its aperture is 0.35 μ m, and described biological membrane tissue 11 is the animal intestine in vitro.
In addition, the used biological membrane tissue 11 of embodiment 1-5 can arbitrarily be changed as required, for example: the Caco-2/CYP2D6 transgenic cell, the Caco-2/CYP2C9 transgenic cell, Caco-2/CYP2C19 transgenic cell or Caco-2/CYP1A2 transgenic cell, the MDCK-CYP2D6 transgenic cell, the MDCK-CYP2C9 transgenic cell, the MDCK-CYP2C19 transgenic cell, the MDCK-CYP1A2 transgenic cell, the MDCK-MDR1-CYP3A4 transgenic cell, the MDCK-MDR1-CYP2D6 transgenic cell, the MDCK-MDR1-CYP2C9 transgenic cell, MDCK-MDR1-CYP2C19 transgenic cell or MDCK-MDR1-CYP1A2 transgenic cell.
A kind of medicine dissolution liquid that is applied to above-mentioned single pond bionic system device comprises medicine dissolution liquid A and medicine dissolution liquid B, in wherein every 1000ml solution:
Table 2 medicine dissolution liquid A, medicine dissolution liquid B component and proportioning
* medicine dissolution liquid B transfers to 6.8 with Tris.Medicine dissolution liquid A and medicine dissolution liquid B add water to 1000mL.
Compound method gets final product according to conventional means weighing, mixing.
Embodiment 7
A kind of medicine dissolution liquid that is applied to above-mentioned single pond bionic system device comprises medicine dissolution liquid A and medicine dissolution liquid B, in wherein every 1000ml solution:
Table 3 medicine dissolution liquid A, medicine dissolution liquid B component and proportioning
* medicine dissolution liquid B transfers to 7.4 with Tris.Medicine dissolution liquid A and medicine dissolution liquid B add water to 1000mL.
Compound method gets final product according to conventional means weighing, mixing.
A kind of medicine dissolution liquid that is applied to above-mentioned single pond bionic system device comprises medicine dissolution liquid A and medicine dissolution liquid B, in wherein every 1000ml solution:
Table 4 medicine dissolution liquid A, medicine dissolution liquid B component and proportioning
* medicine dissolution liquid B transfers to 7.8 with Tris.Medicine dissolution liquid A and medicine dissolution liquid B add water to 1000mL.
Compound method gets final product according to conventional means weighing, mixing.
Embodiment 9
Be example now, sketch the concrete course of work that is used to estimate single pond bionic system device of slowbreak preparation of the present invention with embodiment 5, embodiment 6:
(1) debugging thermostatic water-circulator bath, constant current peristaltic pump, magnetic stirring apparatus and program control sample automatic collector;
(2) treat system stability work after, solid pharmaceutical preparation is joined the medicine carrying device of medicine dissolution chamber 1, feed medicine dissolution liquid A (pH 2.0) earlier, behind 15-30min, switch to medicine dissolution liquid B (pH 6.8-7.8).Each solution remains on 37 ℃ ± 0.2 ℃ in whole stripping of medicine and the absorption process;
(3) medicine constantly discharges under magnetic stir bar 7 beating actions, the medicine that discharges is transferred to pH adjuster 2 by the constant current peristaltic pump to be mixed with pH adjustment liquid (pH 6.8), further be transferred to supply chamber 3 then, and constantly enter medicine receiving chamber 4 through biological membrane tissue 11.
(4) testing sample is pumped by the constant current peristaltic pump respectively in the supply chamber 3 in drug diffusion pond and the receiving chamber 4, and the while collects the stripping side respectively by program control sample automatic collector and sees through the sample of side;
(5) come analytic sample with suitable analytical instrument such as UV spectrophotometer, HPLC or LC-MS.
The concrete course of work and test result are referring to following embodiment.
Being used to described in the Application Example 5 estimated single pond bionic system device of slowbreak preparation and estimates the release of Diclofenac sodium enteric tablet and stride the film absorption.
(1) debugging of external single pond bionic system
The preparation that medicine dissolution liquid A, medicine dissolution liquid B, pH adjust liquid, reception liquid sees Table 5.
Table 5 solution preparation program
*Medicine dissolution liquid B, pH adjust liquid and transfer to 6.8 with Tris.Medicine dissolution liquid A, medicine dissolution liquid B, pH adjust liquid and add water to 1000mL.
Medicine dissolution liquid A, medicine dissolution liquid B, pH adjust liquid and are put in the thermostatic water-circulator bath case and make temperature remain on 37 ℃ ± 0.5 ℃; Constant current peristaltic pump flow velocity transfers to 0.5ml/min; Magnetic stirring apparatus transfers to " 5 " shelves.
(2), dispensing
Behind the connecting line, add medicine dissolution liquid A in the medicine dissolution chamber, supply chamber adds medicine dissolution liquid A and pH adjusts liquid, and receiving chamber adds reception liquid.Single pond bionic system brings into operation, and treats the dispensing of stable back; Diclofenac sodium enteric tablet dispensing a slice (25mg/ sheet), parallel doing 3 times.The medicine dissolution chamber feeds medicine dissolution liquid A earlier, switches to medicine dissolution liquid B after 0.5 hour.
(3), collect sample
After the dispensing, pick up counting immediately, start program control sample automatic collector, the every 10min of stripping side sample collects once.
(4), sample determination
The content of C14H10Cl2NNaO2 in the HPLC method working sample.
Chromatographic condition: Waters600E (automatic sampler, the online degassing, the quaternary gradient pump, 2487 detecting devices), chromatographic column: Agilent TC-C18 (5 μ m, 4.6 * 150mm), moving phase: 0.5% glacial acetic acid-methyl alcohol (20-80), flow velocity: 1ml/min detects wavelength: 276nm, column temperature: 25 ℃, sample size: 10 μ l.
(5), data processing
Be used to estimate single pond bionic system stripping side (supply chamber) of slowbreak preparation and see through side (receiving chamber) data according to this, draw drug release rate-time curve, drug accumulation release-time curve, medicine transmitance-time curve, drug accumulation transmitance-time curve, and relatively use the stripping result of the Pharmacopoeia of the People's Republic of China (hereinafter to be referred as " pharmacopeia ") (2010 editions two ones) described oar method and this list pond bionic system.With the different release model of corresponding software match.
(6), result and conclusion
C14H10Cl2NNaO2, pKa=4.0, micro dissolution in pure water dissolves in methyl alcohol, ethanol, is slightly soluble in acetone, is insoluble to chloroform, ether, and the dissolving situation in buffer salt solution is seen Fig. 3.
From accompanying drawing 4 as can be known, the Diclofenac sodium enteric tablet does not discharge at sour environment, and with the rising of pH value, medicine begins to discharge, and shows that the single pond bionic system device that is used to estimate the slowbreak preparation of the present invention can reflect the influence of pH value variation to the preparation dispose procedure.
Compare with the result that " pharmacopeia " described oar method draws in the result who is used to estimate single pond bionic system device stripping side gained of slowbreak preparation of the present invention with the Diclofenac sodium enteric tablet.See accompanying drawing 5.
As can be seen from the results, the Diclofenac sodium enteric tablet is after " pharmacopeia " described oar method release medium switches to simulated intestinal fluid by simulated gastric fluid, and medicine discharges rapidly.And medicine discharges the continuous dynamic process that embodies the gradual change from stomach (pH 1-2) to intestines (pH 6-8) at the single pond bionic system device that is used for estimating the slowbreak preparation of the present invention, approaches the physiological status of human gastrointestinal tract pH variation more.In addition, the oar method can only the cumulative release amount of response preparation in single dissolution medium, and the cumulative release amount that this single pond bionic system device that is used to estimate the slowbreak preparation can response preparation also can reflect its transient change result, and this also is that the oar method is incomparable.
The Diclofenac sodium enteric tablet through the mathematical model match, the results are shown in Table 6 in the cumulative release degree result of single pond bionic system device that is used for estimating the slowbreak preparation of the present invention and oar method.
Table 6 Diclofenac sodium enteric tablet is through the mathematical model fitting result
From degree of fitting, the r value is represented goodness of fit maximum more near " 1 ".The Diclofenac sodium enteric tablet, all meets one-level and discharges model equation through the mathematical model match at the drug release process of single pond bionic system device that is used for estimating the slowbreak preparation of the present invention and oar method, and promptly this medicine is the one-level drug release process of non-constant speed.Show that this single pond bionic system device that is used to estimate the slowbreak preparation can be used to estimate the release dynamic characteristic of Diclofenac sodium enteric tablet.
The Diclofenac sodium enteric tablet transmitance-time curve, the accumulation transmitance-time curve that obtain by the single pond bionic system device that is used to estimate the slowbreak preparation of the present invention.See accompanying drawing 6,7.
Carry out non-linear dependencies at the cumulative release degree that is used to estimate single pond bionic system device stripping side gained of slowbreak preparation of the present invention with the accumulation transmitance that sees through the side gained with the Diclofenac sodium enteric tablet and investigate, the results are shown in Figure 8.
Suppose that the external stripping feature of medicine is equal to stripping feature in the body, and present under sink conditions that first order kinetics discharges and first order kinetics sees through, can draw following relation:
α=k wherein
a/ k
d, promptly one-level transmission rates constant is than one-level dissolution rate constant; f
aBe that t absorbs percentage in the body when infinity.
Use software MATLAB (version4.0) to come matched curve.Stripping speed limit type medicine (α is greater than 1) will produce " linear pattern " correlogram.See through speed limit type medicine (α is less than 1) and will produce " inverted L shape " correlogram.See through with stripping mixing speed limit type medicine (α approximates 1) and will produce " hockey stick type " correlogram.
Find out easily from the correlativity evaluation result of Fig. 8: correlativity r value is 0.9305, and greater than critical value 0.8721, correlativity is good.And α=0.3438＜1 is " inverted L shape " correlogram, and one-level transmission rates constant is less than one-level dissolution rate constant.Therefore the evaluation information that the single pond bionic system device that is used to estimate the slowbreak preparation of the present invention provides is more objective reliable, is better than the oar method.
Being used to described in the Application Example 5 estimated single pond bionic system device of slowbreak preparation and estimates the release of magnesium omeprazole enteric coatel tablets and stride the film absorption.
(1), the debugging of external single pond bionic system
The preparation that medicine dissolution liquid A medicine dissolution liquid B, pH adjust liquid, reception liquid sees Table 7.
Table 7 solution preparation program
*Medicine dissolution liquid B, pH adjust liquid and transfer to 6.8 with Tris, receive liquid and transfer to 7.4 with Tris.Medicine dissolution liquid A, medicine dissolution liquid B, pH adjust liquid, reception liquid adds water to 1000mL.
Medicine dissolution liquid A medicine dissolution liquid B, pH adjust liquid, reception liquid is put in the thermostatic water-circulator bath case makes temperature remain on 37 ℃ ± 0.5 ℃; Constant current peristaltic pump flow velocity transfers to 0.5ml/min; The every passage flow velocity of constant current peristaltic pump that links with receiving chamber transfers to 1.0ml/min; Magnetic stirring apparatus transfers to " 5 " shelves.
(2), dispensing
Chimeric isolated rat intestinal tube between supply chamber, the receiving chamber behind the connecting line, adds medicine dissolution liquid A in the medicine dissolution chamber, supply chamber adds medicine dissolution liquid A and pH adjusts liquid, and receiving chamber adds reception liquid.Single pond bionic system brings into operation, and treats the dispensing of stable back; Magnesium omeprazole enteric coatel tablets dispensing a slice (20mg/ sheet), parallel doing 3 times.The medicine dissolution chamber feeds medicine dissolution liquid A earlier, switches to medicine dissolution liquid B after 0.5 hour.
(3), collect sample
After the dispensing, pick up counting immediately, start program control sample automatic collector, see through the every 10min of side sample and collect once.
(4), sample determination
The content of Omeprazole in the HPLC method working sample.
Chromatographic condition: Waters600E (automatic sampler, the online degassing, the quaternary gradient pump, 2487 detecting devices), chromatographic column Agilent TC-C18 (5 μ m, 4.6 * 150mm), moving phase is water: methyl alcohol (47: 53), flow velocity are 1ml/min, detect wavelength: 302nm, 25 ℃ of column temperatures, sample size: 10 μ l
(5), data processing
Be used to estimate single pond bionic system stripping side (supply chamber) of slowbreak preparation and see through side (receiving chamber) data according to this, draw drug release rate-time curve, drug accumulation release-time curve, medicine transmitance-time curve, drug accumulation transmitance-time curve, and relatively use the stripping result of " pharmacopeia " described commentaries on classics basket method and this list pond bionic system, with the different release model of corresponding software match; According to experimental data in the Beagle dog body, draw blood concentration-time curve, and return principle with linear least square, calculating the medicine absorption percentage that the pharmacokinetics experiment draws in each time point Beagle dog body with chamber dependence method accumulates transmitance with it accordingly at this list pond bionic system and carries out linear regression and investigate evaluation inside and outside correlativity.
(6), result and conclusion
Magnesium omeprazole, pKa=4.0, easily molten in methylene chloride, molten at methyl alcohol or ethanol part omitted, slightly soluble in acetone, insoluble in water; In the 0.1mol/L sodium hydroxide solution, dissolve.Dissolving situation in buffer salt solution is seen Fig. 9.
From accompanying drawing 10 as can be known, the magnesium omeprazole enteric coatel tablets do not discharge at sour environment, and with the rising of pH value, medicine begins to discharge, and show that the single pond bionic system device that is used to estimate the slowbreak preparation of the present invention can reflect the influence of pH value variation to the preparation dispose procedure.
Compare with the result that " pharmacopeia " described commentaries on classics basket method draws in the result who is used to estimate single pond bionic system device stripping side gained of slowbreak preparation of the present invention with the magnesium omeprazole enteric coatel tablets.See accompanying drawing 11.
As can be seen from the results, the magnesium omeprazole enteric coatel tablets are after " pharmacopeia " described commentaries on classics basket method release medium switches to simulated intestinal fluid by simulated gastric fluid, and medicine discharges rapidly.And medicine discharges the continuous dynamic process that embodies the gradual change from stomach (pH 1-2) to intestines (pH 6-8) at the single pond bionic system device that is used for estimating the slowbreak preparation of the present invention, approaches the physiological status of human gastrointestinal tract pH variation more.In addition, changeing the basket method can only the cumulative release amount of response preparation in single dissolution medium, and this single pond bionic system device that is used to estimate the slowbreak preparation can response preparation the cumulative release amount also can reflect its transient change result, this also is that to change the basket method incomparable.
The magnesium omeprazole enteric coatel tablets through the mathematical model match, the results are shown in Table 8 in the cumulative release degree result who is used for estimating single pond bionic system device of slowbreak preparation and changes the basket method of the present invention.
Table 8 magnesium omeprazole enteric coatel tablets are through the mathematical model fitting result
From degree of fitting, the r value is represented goodness of fit maximum more near " 1 ".The magnesium omeprazole enteric coatel tablets, all meet one-level and discharge model equation through the mathematical model match at the drug release process that is used for estimating single pond bionic system device of slowbreak preparation and changes the basket method of the present invention, and promptly this medicine is the one-level drug release process of non-constant speed.Show that this single pond bionic system device that is used to estimate the slowbreak preparation can be used to estimate the release dynamic characteristic of magnesium omeprazole enteric coatel tablets.
The magnesium omeprazole enteric coatel tablets transmitance-time curve, the accumulation transmitance-time curve that obtain by the single pond bionic system device that is used to estimate the slowbreak preparation of the present invention.See accompanying drawing 12,13.
Carry out non-linear dependencies at the cumulative release degree that is used to estimate single pond bionic system device stripping side gained of slowbreak preparation of the present invention with the accumulation transmitance that sees through the side gained with the magnesium omeprazole enteric coatel tablets and investigate, the results are shown in Figure 14.
Suppose that the external stripping feature of medicine is equal to stripping feature in the body, and present under sink conditions that first order kinetics discharges and first order kinetics sees through, can draw following relation:
α=k wherein
p/ k
d, promptly one-level transmission rates constant is than one-level dissolution rate constant; f
aBe that t absorbs percentage in the body when infinity.
Use software MATLAB (version4.0) to come matched curve.Stripping speed limit type medicine (α is greater than 1) will produce " linear pattern " correlogram.See through speed limit type medicine (α is less than 1) and will produce " inverted L shape " correlogram.See through with stripping mixing speed limit type medicine (α approximates 1) and will produce " hockey stick type " correlogram.
Find out easily from the correlativity evaluation result of Figure 14: correlativity r value is 0.9738, and greater than critical value 0.8721, correlativity is good.And α=2.158＞1 are " linear pattern " correlogram, and one-level transmission rates constant is greater than one-level dissolution rate constant.Therefore the evaluation information that the single pond bionic system device that is used to estimate the slowbreak preparation of the present invention provides is more objective reliable, is better than changeing the basket method.
Obtain the blood concentration-time curve of magnesium omeprazole enteric coatel tablets by pharmacokinetics experiment in the Beagle dog body.See accompanying drawing 15.
The result that pharmacokinetics experiment in Beagle dog body draws to the magnesium omeprazole enteric coatel tablets carries out the correlativity evaluation with the single pond bionic system device that is used for estimating the slowbreak preparation of the present invention through the result that side draws, select medicine to absorb percentage in the corresponding respectively body respectively and do the correlativity investigation with the accumulation transmitance at 1,1.5,2,2.5,3,3.5,4,5 hour, check level of significance a=0.001, the r critical value of tabling look-up is 0.9249.See accompanying drawing 16.
Find out easily from the correlativity evaluation result of Figure 16: correlativity r value is 0.9313, and greater than critical value 0.9249, correlativity is good.Show and see through the fit internal procedure of side character symbol.Illustrated that the described single pond bionic system device that is used to estimate the slowbreak preparation can more approach the absorption process of the evaluation medicine of human body.
Above data representation, " pharmacopeia " described oar method/commentaries on classics basket method be only with the process in leaching of reflection medicine, can not reflect medicine in vivo stride the film feature.And the single pond bionic system device that is used to estimate the slowbreak preparation of the present invention not only can provide the stripping information of medicine, also can investigate the process of striding film, promptly can be used as a kind of technology platform of estimating the slowbreak preparation and describes the slowbreak preparation and discharge and absorbing rule.
In sum, the single pond bionic system device that is used to estimate the slowbreak preparation of the present invention has not only been simulated the human body physiological state stomach, enteron aisle pH changes, and dynamic similation preparation from stomach, travel to enteron aisle disintegration, release, stride the process that film absorbs at enteron aisle then.Successfully estimated the enteric coatel tablets release rule in vitro by embodiment 10, to Diclofenac sodium enteric tablet and magnesium omeprazole enteric coatel tablets at the drug release process of the single pond bionic system device that is used for estimating the slowbreak preparation of the present invention and " pharmacopeia " described oar method/commentaries on classics basket method through the mathematical model match, all meet one-level and discharge model equation, promptly two preparations are one-level drug release process of non-constant speed, show that this single pond bionic system device that is used to estimate the slowbreak preparation is the same with oar method/commentaries on classics basket method, can be used to estimate the release dynamic characteristic of two preparations, be used to estimate the result of single pond bionic system device stripping side gained of slowbreak preparation and the result that the oar method/commentaries on classics basket method draws compares with two preparations at this, show that this system obviously is better than oar method/commentaries on classics basket method; Secondly, successfully estimated the enteric coatel tablets absorbing rule by embodiment 11, the magnesium omeprazole enteric coatel tablets are carried out the correlativity evaluation in the side gained result that sees through that this is used to estimate single pond bionic system device of slowbreak preparation with the result that the experiment of pharmacokinetics in Beagle dog body draws, as can be seen, this system sees through the fit internal procedure of side character symbol, has illustrated that the described single pond bionic system device that is used to estimate the slowbreak preparation can more approach the absorption process of the evaluation medicine of human body.
In addition, but release and the absorption process that is used to estimate single pond bionic system device on-line evaluation preparation of slowbreak preparation of the present invention, also be easy to describe different release and the absorption features constantly of preparation, obtain each release constantly of preparation continuously, cumulative release degree and transmembrane transport situation, can accurately monitor the dispose procedure of preparation, the cumulative release of the match preparation line of writing music, observe the release behavior of medicine, compare with traditional dissolution determination method in " pharmacopeia ", but the disintegration of continuous analog preparation in intestines and stomach, discharge, absorption process, be better than the dissolution rate test method that existing " pharmacopeia " recorded, this single pond bionic system device that is used to estimate the slowbreak preparation has accurately been simulated gastrointestinal tract environment in the human body, truly reflect stripping and the absorption process of medicine in human body, thereby can predict release and the absorption feature of slowbreak preparation in human body.
Above-mentionedly this is used to estimate the detailed description that single pond bionic system device of slowbreak preparation and medicine dissolution liquid and evaluation method carry out with reference to embodiment; be illustrative rather than determinate; can list several embodiment according to institute's limited range; therefore in the variation and the modification that do not break away under the general plotting of the present invention, should belong within protection scope of the present invention.
Claims (10)
1. single pond bionic system device that is used to estimate the slowbreak preparation, it is characterized in that: mainly form by medicine dissolution chamber, pH adjuster, millipore filter and drug diffusion pond, wherein bottom, medicine dissolution chamber is provided with magnetic stir bar, medicine dissolution is indoor to be provided with a medicine carrying device, leave distance between the magnetic stir bar of described medicine carrying device and bottom, medicine dissolution chamber, stainless steel mesh places this medicine carrying device top; Filling material is non-adsorbability filler in the described pH adjuster; The drug diffusion pond is made up of supply chamber, receiving chamber and the biological membrane tissue that is entrenched between the two; Described medicine dissolution chamber, pH adjuster, millipore filter and the silicone tube of drug diffusion pond by internal diameter 1.0mm-2.0mm are connected successively, be respectively equipped with sample holes in addition at described medicine dissolution chamber, pH adjuster and receiving chamber, also be provided with air admission hole and thief hole at described supply chamber and receiving chamber.
2. the single pond bionic system device that is used to estimate the slowbreak preparation according to claim 1 is characterized in that: described medicine carrying device is medicine carrying basket or the sheet metal folder that is made by anti-strong acid, anti-highly basic, resistant to elevated temperatures stainless steel material.
3. the single pond bionic system device that is used to estimate the slowbreak preparation according to claim 1, it is characterized in that: described non-adsorbability filler is sea sand or glass microsphere.
4. the single pond bionic system device that is used to estimate the slowbreak preparation according to claim 1, it is characterized in that: described millipore filter is replaceable device.
5. according to claim 1 or the 4 described single pond bionic system devices that are used to estimate the slowbreak preparation, it is characterized in that: described millipore filter aperture is 0.22 μ m-0.8 μ m.
6. according to claim 1 or the 4 described single pond bionic system devices that are used to estimate the slowbreak preparation, it is characterized in that: described millipore filter is synthon filter membrane, quartz fibre filter membrane or glass fiber filter.
7. the single pond bionic system device that is used to estimate the slowbreak preparation according to claim 1, it is characterized in that: described biological membrane is organized as Caco-2 and transgenic cell monofilm, MDCK and transgenic cell monofilm thereof or animal intestine in vitro.
8. the single pond bionic system device that is used to estimate the slowbreak preparation that is used to estimate the slowbreak preparation according to claim 1, it is characterized in that: described medicine dissolution chamber, pH adjuster and drug diffusion pond are made by the transparent organic glass material.
9. medicine dissolution liquid that is applied to the described single pond of one of claim 1-8 bionic system device is characterized in that: comprise medicine dissolution liquid A and medicine dissolution liquid B, wherein:
Medicine dissolution liquid A is mainly by NaCl, D-Glucose, CaCl
2, MgSO
4, MES and HCl (1mM) form, and contains NaCl 7.8894g, D-Glucose 9.008g, CaCl in wherein every 1000ml solution
20.2797g, MgSO
40.0975g, MES 1.9524g, HCl (1mM) 5.0mL, all the other are water;
Medicine dissolution liquid B is mainly by KCl, KH
2PO
4, NaCl, NaH
2PO
4, MES and Tris form, and contains KCl 0.7977g, KH in wherein every 1000ml solution
2PO
40.1198g, NaCl 7.8894g, NaH
2PO
40.0965g, MES 9.762g, Tri s regulates pH value to 6.8-7.8, all the other are water.
10. an application rights requires one of 1-8 described single pond bionic system device and the described medicine dissolution liquid of claim 9 to estimate the method for release of slowbreak preparation and absorbing rule, it is characterized in that: concrete steps are: during mensuration preparation is joined in the medicine carrying device of medicine dissolution chamber, feed earlier medicine dissolution liquid A, after switch to medicine dissolution liquid B; By the constant current peristaltic pump dissolved drug is transferred to the pH adjuster and mixes, further be transferred to the supply chamber in drug diffusion pond then, and constantly enter the medicine receiving chamber, respectively from supply chamber and receiving chamber sampling and measuring through the biological membrane tissue with pH adjustment liquid.
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| CN104458504A (en) * | 2013-09-16 | 2015-03-25 | 中国科学院大连化学物理研究所 | Diffusion cell membrane module and diffusion cell |
| CN103792327A (en) * | 2014-03-03 | 2014-05-14 | 上海天科化工检测有限公司 | Siphoning balance type heavy metal pollutant dissolving and adsorbing test device |
| CN103792327B (en) * | 2014-03-03 | 2015-09-30 | 上海天科化工检测有限公司 | A kind of siphon balanced type heavy metal contaminants stripping-adsorption test device |
| CN105651822A (en) * | 2014-11-14 | 2016-06-08 | 湘潭大学 | A testing method and a testing device for dissolution properties of an active component of a solid preparation |
| CN110045071A (en) * | 2019-04-19 | 2019-07-23 | 禄根仪器(镇江)有限公司 | A kind of absorption pool structure of drug absorption sampling system |
| WO2021163988A1 (en) * | 2020-02-21 | 2021-08-26 | 南京海维医药科技有限公司 | Dissolution testing auxiliary apparatus |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102253173B (en) | 2016-08-03 |
| CN202033355U (en) | 2011-11-09 |
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