CN103018414A - Individual in-vitro dissolving and detecting method and dissolving device of active ingredient of pharmaceutic preparation - Google Patents
Individual in-vitro dissolving and detecting method and dissolving device of active ingredient of pharmaceutic preparation Download PDFInfo
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Abstract
The invention discloses an individual in-vitro dissolution detecting method and a dissolving device of active ingredients of a pharmaceutic preparation. The dissolving method comprises the following steps of: simulating the in-vivo dissolution behavior of the active ingredients of the pharmaceutic preparation in living bodies, wherein the in-vitro dissolution speed of the active ingredients of the pharmaceutic preparation is required to be not smaller than the medicine critical absorption speed; and detecting the dissolved medicine active ingredients on line. The micro dissolving device comprises a medicine dissolving pond, wherein a flow-in pipeline of the medicine dissolving pond is connected with a pressure pump I; a flow-out pipeline of the dissolving pond is connected with a pressure pump II and an on-line detector respectively; a filtering groove is installed at the port of the flow-out pipeline in the medicine dissolving pond; constant temperature heaters are arranged at the medicine dissolving pond and outside the flow-in pipeline of the medicine dissolving pond; and a device which shakes the medicine dissolving pond is further arranged outside the medicine dissolving pond. The in-vitro dissolving method of the active ingredients of the pharmaceutic preparation simulates the in-vivo dissolution behavior, and individual standards are made according to characteristics of the active ingredients, so that in-vivo and in-vitro dissolution relevance is realized.
Description
Technical field
The present invention relates to a kind of pharmaceutical preparation active component In Vitro Dissolution method and vitro Drug dissolving device.Be mainly used in evaluation of bioequivalence between the In Vitro Dissolution control, stripping standard formulation, preparation of pharmaceutical preparation active component; Belong to drug world.
Background technology
Guarantee medicine safe and effective be Social Events concerning the people's livelihood, for original new drug, can pass through pharmacology, toxicity, clinical testing, medicine quality standard etc. and guarantee that safety of medicine is effective, between criticizing after the medicine listing, then can only guarantee that safety of medicine is effective by quality standard and the GMP of medicine between the imitated medicine producer.The quality standard of medicine material is mainly examined the control on screening matter basis, and the quality standard of preparation also will be controlled in the body of medicine by In Vitro Dissolution and exposes except the control of examining screening matter basis, and is effective to guaranteeing safety of medicine.In theory, can come stripping in the control volume by the In Vitro Dissolution of control medicine, and then absorb and drug exposure in the body of control medicine, but the In Vitro Dissolution method of existing pharmacopoeia of each country is owing to the defective that exists on the pattern, can't come stripping in the control volume by In Vitro Dissolution, the stripping of medicine inside and outside is uncorrelated.The defective of the present leaching condition of defect body of this pattern and the defective of standard.Existing official method adopts different leaching conditions to satisfy this pattern of the identical universal standard, at first the leaching condition of leaching condition and body physiological state is finished inconsistent, the current methods In Vitro Dissolution can adopt the dissolution medium of variety classes and volume, the different leaching conditions such as stir speed (S.S.), and under the body physiological state, dissolution fluid in the intestines and stomach is gastric juice and intestinal juice, volume is also relatively fixing, and GI motion is also basically identical; Secondly actual conditions are fully inconsistent in stripping standard and the body, do not consider whether can reflect this key factor of drug exposure yet, act.std is general standard, and actual conditions are that different pharmaceutical is because dissolubility is different, stripping in vivo some faster than the universal standard, some is slower than the universal standard, and the critical absorption rate (NADECAR) that proposes from the inventor is theoretical considers, guarantee that drug exposure is identical between pharmaceutical preparation, the absorption rate of its requirement, dissolution rate are also different.
Based on above situation, be badly in need of wanting a kind of new model of pharmaceutical preparation In Vitro Dissolution, go out the drug-eluting new method based on this Model Design, and formulate personalized stripping standard.Reach relevant in vitro Drug stripping and the body, accurately reflect actual exposed amount in the body of medicine with individualized criteria.
Summary of the invention
The objective of the invention is to provide a kind of and can realize individualized criteria and realize inside and outside stripping related drugs preparation active component In Vitro Dissolution new method in order to address the above problem.
The present invention also provides the external differential dissolving device of realizing the interior stripping of the relevant aids drug active component body of stripping in the body in a kind of said method.
The personalized In Vitro Dissolution detection method of a kind of pharmaceutical preparation active component of the present invention, specifically amount of simulated drug formulation active component stripping behavior in the biosome body, preparation active component dissolution rate in vitro is not less than the critical absorption rate of active constituents of medicine; The online active constituents of medicine that detects stripping;
Described critical absorption rate refer to when the absorption rate of active constituents of medicine under the prerequisite of eliminating speed, when the size of absorption rate on the exposed amount of the active constituents of medicine absorption rate critical value when affecting;
Described critical absorption rate is calculated by the following steps simulation and is obtained:
Press the outer administration vivo medicine concentration of one compartment model blood vessel and the relation formula of time:
Wherein, C is vivo medicine concentration; K is elimination rate constant; Ka is absorption rate constant; F is bioavilability; V is apparent volume of distribution; T is the time, X
0Be dosage;
In the above-mentioned formula, for a kind of medicine, K, V and preparation are irrelevant, and for high-permeability medicine in the biopharmacy classification, preparation is ignored the impact of F, as K, V, F and X
0Be definite value, under different K a, make the C-t curve; Calculate C
Max, draw C
MaxIncrease with Ka, and Ka " during K, C
MaxThe amplitude that increases with Ka diminishes; When the Ka value is Ka
0, Ka
0Increase to Ka
1, and satisfy (Ka
1-Ka
0) * 100%/Ka
0In the time of 〉=50%, corresponding Cmax
0Increase to C
Max 1, and satisfy (C
Max 1-Cmax
0) * 100%/Cmax
0≤ 5%, the Ka of this moment
0It is exactly critical absorption rate constant; According to the proportional relation of absorption rate constant and absorption rate, i.e. the critical absorption rate of speed during critical absorption rate constant.
The behavior of stripping described in the said method is to realize in comprising the leaching condition of simulating gastro-intestinal Fluid volume, gastrointestinal movement and drug absorption in in-vivo medium, the stomach and intestine; Wherein said medium is simulated gastric fluid or simulated intestinal fluid.
Preparation described in the said method comprises capsule, sustained release preparation or dressing.
The on-line detector device comprises in UV-detector, fluorescence detector, electrochemical detector or the evaporative light-scattering detector one or more in the said method.
The present invention also provides a kind of external differential dissolving device for stripping in the claim 1 aids drug body body, this device comprises the drug-eluting pond, the flow ipe in drug-eluting pond is connected with the forcing pump I, and the drug-eluting pond flows out that pipeline is connected with respectively the forcing pump II and at thread detector; Flow out the pipeline port in the described drug-eluting pond filter pocket is housed; Described drug-eluting pond and flow ipe peripheral hardware thereof have constent temperature heater, and also being provided with outside the drug-eluting pond can be so that the device that the drug-eluting pond is shaken.
The pool volume of stripping described in the said apparatus is 0.5 ~ 10mL.
Comprise in UV-detector, fluorescence detector, electrochemical detector or the evaporative light-scattering detector one or more at thread detector in the said apparatus; Describedly be connected with the on-line monitoring device at thread detector; Described on-line monitoring device comprises registering instrument, digital treating meter and controller.
Said apparatus Chinese traditional medicine stripping pond flow ipe caliber is less than flowing out pipeline, and stretches in the drug-eluting pond.
Outflow pipeline described in the said apparatus is provided with that a three-way pipe is connected with respectively the forcing pump II and at thread detector.
Outer dissolving-out method of the present invention is realized by the differential dissolving device, is referred to dissolving-out method and differential dissolving device according to principle design shown in Figure 1.Its core position is drug-eluting pond 3, and the drug-eluting pool volume is 0.5 ~ 50mL, gastro-intestinal Fluid volume in the intestines and stomach in the analogue body; The stripping medicine flows out after filtration in the drug-eluting pond 3, and the simulation drug disposition is absorbed situation; Drug-eluting pond 3 and inflow pipeline 2 outsides are provided with constent temperature heater (comprise well heater and be set in the drug-eluting pond and inflow pipeline external insulation cover), guarantee that the dissolution medium temperature is 37 ℃; The device 11 that the 3 outer designs of drug-eluting pond can be shaken, the simulated gastrointestinal tract motion.The related medium in this device stripping pond comprises water, simulated gastric fluid, simulated intestinal fluid; Add in case of necessity solubilizer in the preparation prescription and cholate, cholic acid.Drug-eluting pond 3 flow ipe ports are connected with forcing pump I 1, and drug-eluting pond 3 flows out that pipelines 4 are connected with respectively forcing pump II 12 and at thread detector 5; Online prison detecting device also is connected with on-line monitoring device 6(registering instrument, digital treating meter and controller) dissolving device of the present invention can realize stripping, detection, curve simulation, automatic integratedization of calculation of parameter.
The stripping standard that the present invention formulates refers to the individualized criteria different from the universal standard of existing official method.The core of personalized stripping standard is that the dissolution rate of standard code should be able to reflect medicine actual speed rate in vivo, namely according to the critical absorption rate that does not affect drug exposure (the Non Affection Drug Exposure Critical AbsorptionRate of medicine, NADECAR) formulate the stripping standard, require dissolution rate to approach or greater than critical absorption rate.NADECAR is the inventor by the outer administration of one compartment model blood vessel, by the C-t relational expression, calculates different absorption rates to the impact of drug exposure, and analog computation gets.Medicine exposed amount in vivo depends on drug absorption speed and eliminates speed, when absorption rate when eliminating the speed certain multiple, the change of absorption rate is very little on the impact of drug exposure, and absorption rate at this moment is not for affecting the critical absorption rate of drug exposure.
The inventor proves through simulation test repeatedly, and for a kind of medicine, K, V and preparation are irrelevant, and for high-permeability medicine in the biopharmacy classification, then preparation also can be ignored the impact of F, gives above and the incoherent parameter of preparation and X
0Give a fixed value, and satisfy Ka " during K, under the different K a, calculate the C of a time point, make the C-t curve, calculate C
Max, find C
MaxIncrease with Ka, when the relative K of Ka greatly to a certain extent after, C
MaxThe amplitude that increases with Ka diminishes, and the inventor sets a Ka in all Ka values be Ka
0, Ka
0Increase to Ka
1, and satisfy (Ka
1-Ka
0) * 100%/Ka
0In the time of 〉=50%, and corresponding Cmax
0Increase to C
Max 1, and satisfy (C
Max 1-Cmax
0) * 100%/Cmax
0≤ 5%(thinks to change clinically has clinical meaning less than 15%), the Ka of this moment
0It is exactly critical absorption rate constant; According to the proportional relation of absorption rate constant and absorption rate, i.e. the critical absorption rate of speed during critical absorption rate constant.For the high-permeability medicine, stripping is the rate-limiting step that absorbs in the body of active constituents of medicine, namely as long as guarantee dissolution rate greater than critical absorption rate, can guarantee then that active component exposes in vivo not to be subjected to the preparation factor affecting.For low permeability medicine, then can use this leaching to guarantee the In Vitro Dissolution behavior consistence, reach and expose conforming purpose in the body.When formulating personalized stripping standard, be precondition with reference to NADECAR, consider that dissolution rate can guarantee that greater than NADECAR absorption rate is not subjected to the restriction of dissolution rate, drug absorption is very little on the drug exposure impact, bioequivalence between preparation.
It is the half life period that non-compartment model calculates that Chinese traditional medicine of the present invention is eliminated the half life period, and sustained release preparation is external to be measured by dissolving-out method of the present invention, and the stripping standard is considered the In Vitro Dissolution curve, but not the accumulation stripping percent of stipulated time.
Effect of the present invention: the dissolving device of the present invention by oneself assembling, condition in the analogue body has realized relevant with stripping in the body; Next has broken the limitation of general stripping standard, extrapolates critical absorption rate, formulates individualized criteria and has realized that the stripping standard is consistent with actual conditions in the body.
Description of drawings
[Fig. 1] is external differential dissolving device structural representation of the present invention:
1-forcing pump I; 2-flows into pipeline; 3-drug-eluting pond; 4-flows out pipeline; 5-is at thread detector; 6-on-line monitoring device; The 7-filter pocket; The 8-well heater; The 9-muff; The 10-three-way pipe; 11-can be so that the device that the drug-eluting pond is shaken; 12-forcing pump II; L is the flow direction of pharmaceutical preparation.
[Fig. 2] is the embodiment of the invention 1 C under the different half life period
Max-Ka curve.
[Fig. 3] is the embodiment of the invention 1 AUC-Ka curve under the different half life period.
[Fig. 4] is the linear regression of the embodiment of the invention 1 levamlodipine series solution.
[Fig. 5] is the embodiment of the invention 1 different manufacturers amlodipine besylate tablets differential Determination by Stripping curve; The 1st, Liansheng Pharmaceutical Co., Ltd., Guizhou produces; The 2nd, Nanchang Hongyi Drug Industry Co., Ltd produces; The 3rd, Levamlodipine pharmaceutical Co. Ltd produces; The 4th, Anhui Healstar Pharmaceutical Co., Ltd. produces.
[Fig. 6] is the average drug-time curve of Levamlodipine besylate in the embodiment of the invention 1 reference preparation and the test preparation healthy volunteer blood plasma.
[Fig. 7] is absorption curve in the embodiment of the invention 1 company limited of Levamlodipine medicine company group (Jilin) the Levamlodipine beaylate tablets body.
[Fig. 8] is absorption curve in the embodiment of the invention 1 Anhui Healstar Pharmaceutical Co., Ltd.'s Levamlodipine beaylate tablets body.
[Fig. 9] is the embodiment of the invention 2 Hainan Xinshitong Pharmaceutical Co., Ltd's Lamy stationary slice differential stripping curves.
[Figure 10] is the embodiment of the invention 2 GlaxoSmithKline PLCs (Suzhou) company limited Lamy stationary slice differential stripping curve.
[Figure 11] is the average drug-time curve of Lamivudine in the embodiment of the invention 2 reference preparations and the test preparation healthy volunteer blood plasma.
[Figure 12] is absorption curve in the embodiment of the invention 2 GlaxoSmithKline PLC pharmacy (Suzhou) the company limited Lamivudine lamellar bodies.
[Figure 13] is absorption curve in the embodiment of the invention 2 Hainan Xinshitong Pharmaceutical Co., Ltd's Lamivudine lamellar bodies.
Embodiment
Embodiments of the invention are to further specify of the present invention, rather than limitation of the present invention.
This invention is main to be implemented by following research: 1. the In Vitro Dissolution method that the external differential dissolving device of design and assembly, design can the interior stripping behaviors of analogue body; 2. according to BCS feature and the personalized stripping standard of the theoretical formulation of NADECAR; 3. the correlativity of inside and outside stripping is studied in checking; 4. Slope map of pixels reflects the efficient of drug exposure; 5. apply new drug-eluting device, dissolving-out method and stripping standard.
Embodiment one:
The new method research of Levamlodipine beaylate tablets In Vitro Dissolution and inside and outside correlation research
(1) In Vitro Dissolution method research
1 medicine, reagent and instrument
1.1 medicine
Levamlodipine beaylate tablets: Anhui Healstar Pharmaceutical Co., Ltd. (lot number 1112132.5mg), company limited of Levamlodipine medicine company group (Jilin) (lot number 120102 25mg), Liansheng Pharmaceutical Co., Ltd., Guizhou (lot number 1112012.5mg), Nanchang Hongyi Drug Industry Co., Ltd (lot number 111205 2.5mg).
1.2 reagent
Self-control deionization ultrapure water, Levamlodipine besylate chemical reference substance (middle inspection institute), other reagent are pure for analyzing.
1.3 instrument
DZG-303A type Laboratory Pure Water system (Ai Ke. auspicious Development Co., Ltd is nourished in Chongqing); Ultraviolet-visible spectrophotometer (SHIMAZU); METTLER TOLEDO AB135-S type 100,000/balance (METTLER, Switzerland); Full-automatic fast preparative chromatography system (the sharp fringe science and technology of Ez Purifier (Suzhou) company limited).
2 research methods
2.1 the structure of differential dissolving device
Adopt full-automatic fast preparative chromatography system (such as Fig. 2) to make up the differential dissolving device, this device is comprised of transfusion system, digestion series and detection system three parts.Transfusion system is pressed certain flow rate with dissolution medium by the medium lift pump of computer control and is imported digestion series, and tablet dissolves in digestion series and discharges medicine, and the medicine after the dissolving is taken digestion series out of by medium rapidly, enters on-line detecting system.On-line monitoring system converts light signal to electric signal, by software analysis, the uv absorption signal-time curve of medicine is presented on the display.The uv absorption signal converted to just obtain drug-eluting liquid concentration time curve (full-automatic fast preparative chromatography system and device schematic diagram is seen Fig. 2) behind the drug concentration.
2.2 the NADECAR analog computation of different half life period medicines
Take one compartment model as example, suppose the bioavilability F=1 of medicine, dosage is 100mg, apparent volume of distribution V=50L, when the elimination half life period is 1～36 hour scope, medicine exposure under the different absorption rate constants of analog computation, the preliminary NADECAR that seeks under the different half life period.
2.3 Levamlodipine beaylate tablets differential dissolution determination
Take the self-control ultrapure water as dissolution medium, room temperature, stripping pond volume is 2ml, the dissolution fluid assay method is UV-VIS spectrophotometry, the uv absorption signal of monitor record different time efflux, collect drug-eluting solution in per 0.5 minute, be diluted to the absorbance of measuring each sample after the certain multiple at ultraviolet-visible spectrophotometer, detect wavelength 238nm.Draw the differential stripping curve after converting solution concentration to.
3 results of study
3.1 the differential dissolving device makes up
Successfully make up the differential dissolving device, and with the differential stripping curve of having studied amlodipine besylate tablets and Lamy stationary slice, obtained expected result.Test unit can meet the demands substantially, but must further improve.
3.2 the NADECAR analog computation of different half life period medicines
According to one compartment model extravascular administration vivo medicine concentration-time relationship formula:
The different half life period, the C that different absorption rate constant Imitatings calculate
MaxSee Table 1, the different half life period, the AUC that different absorption rate constant Imitatings calculate sees Table 2..Take the drug absorption rate constant as horizontal ordinate, C
MaxBe map to get C under the different half life period of ordinate with AUC
MaxWith the curve (Fig. 3, Fig. 4) of AUC to Ka.Estimation NADECAR sees Table 3, table 4.Can find out from table and figure, absorption rate major effect Cmax is not on AUC impact little (simulation process is considered the hold-up time, if consider the hold-up time, is influential to AUC).The medicine NADECAR of different half life period is different, for the half life period short medicine, NADECAR is very large, then requires in vivo Fast Stripping of medicine.Be 1 hour medicine such as the half life period, absorption halftime on not impact of drug exposure, then requires in vivo faster stripping of medicine less than the variation of 5min guarantee absorption rate.Although it is less that absorption rate changes the AUC impact, if because dissolution rate causes absorption rate slow slowly, then may cause medicine to miss GI optimal absorption position, and cause bioavilability to reduce.The present universal standard obviously can not satisfy this requirement, formulates individuation stripping standard very important.
The different half life period medicines of table 1., the lower C of the different ka values of analog computation
Max(μ g/ml)
The different half life period medicines of table 2., AUC(μ g.h/ml under the different ka of analog computation)
Table 3. is with C
MaxC during with ka=11.2
MaxCompare different half life period, different ka value C
MaxNumber percent.
Table 4 is changed to greater than 50% the time with ka, and it is standard estimation gained NADECAR value and calculating absorption halftime that Cmax changes the NADECAR that Ka less than 5% correspondence is decided to be this eliminations half life period medicine
3.3 the stripping of Levamlodipine beaylate tablets differential is measured
3.3.1 dissolution fluid assay method
Precision takes by weighing Levamlodipine besylate chemical reference substance 10mg and places the brown volumetric flask of 10ml, and constant volume after the pure water dissolving gets the 1mg/ml stock solution.The preparation of series standard solution: get respectively stock solution 0.1,0.12,0.14,0.16,0.18,0.20,0.40ml places the 10ml volumetric flask, and the pure water constant volume gets 0.01,0.012,0.014,0.016,0.018,0.020,0.040mg/ml standard solution.Measure absorbance at the 238nm place, drawing standard curve (such as Fig. 5) is in 0.001 ~ 0.1mg/ml scope, and concentration and absorbance are good linear relationship, regression equation: A=37.409C+0.0361; R=0.998.With this typical curve Preliminary Determination stripping liquid concentration.
3.3.2 Levamlodipine beaylate tablets dissolution rate in vitro constant measuring
The stripping of differential Determination by Stripping different manufacturers amlodipine besylate tablets the results are shown in Table 5, and the differential stripping curve is seen Fig. 6.By reaching behind the peak logarithm value of concentration the time is done curve, the dissolution rate constant K that obtains each producer's Levamlodipine beaylate tablets is respectively: 0.1384min
-1(Liansheng Pharmaceutical Co., Ltd., Guizhou); 0.1068min
-1(Nanchang Hongyi Drug Industry Co., Ltd); 0.109min
-1(Levamlodipine pharmaceutical Co. Ltd); 0.2044min
-1(Anhui Healstar Pharmaceutical Co., Ltd.).
The differential stripping curve of each producer's Levamlodipine beaylate tablets conforms to the expectation result, proves that full-automatic fast preparative chromatography system can be can be used as the differential dissolving device carries out follow-up study.
Table 5 different manufacturers amlodipine besylate tablets differential stripping data
Continuous upper table
(2), bioequivalence Journal of Sex Research in the body
1. test objective
Research healthy male volunteers single oral is carried out Study on relative bioavailability by the Levamlodipine beaylate tablets of Anhui Healstar Pharmaceutical Co., Ltd.'s production and the Levamlodipine beaylate tablets of company limited of Levamlodipine medicine company group (Jilin) production, estimate the bioequivalence between two kinds of preparations, estimate stripping in the body by absorption curve.
2. trial
This research is finished jointly by refined three hospital's I phase clinical research chambers, Central South University Hunan and the refined Remedy Research Limited in Tag Hunan, Hunan.Clinical sampling is carried out in refined three hospital national drug institution of clinical trial I phase wards in Central South University Hunan, is finished by doctor and nurse through the GCP training.Analytical test carries out in the refined Remedy Research Limited in Tag Hunan, Hunan, is operated by the technician through the GCP training.The test overall process is all carried out according to the relevant regulations of GCP.
3. trial drug
3.1 test preparation (T)
Common name: Levamlodipine beaylate tablets
Principal ingredient: Levamlodipine besylate
Specification: 2.5mg/ sheet
Storage: shading, sealing, shady and cool place preserves
Manufacturer: Anhui Healstar Pharmaceutical Co., Ltd.
Product batch number: 111213
Verification result: up to specification
Content: 102.6%
3.2 reference preparation (R)
Common name: Levamlodipine beaylate tablets
Trade name: Levamlodipine
Principal ingredient: Levamlodipine besylate
Specification: 2.5mg/ sheet
Storage: shading, sealing, shady and cool place preserves
Manufacturer: company limited of Levamlodipine medicine company group (Jilin)
Product batch number: 110903
Verification result: up to specification
Content: 103.2%
4. the experimenter selects
20 examples participate in the Chinese healthy volunteers of research voluntarily, the male sex, and the age is 19 years old ~ 29 years old, and body weight is 53kg ~ 75kg, and height is 164cm ~ 179cm.The experimenter is healthy, and without history of disease such as cardiovascular, liver, kidney, alimentary canal, spirit, nerves, without this class drug allergy history, test is front through disease history inquire, physical examination and laboratory examination no abnormal (table 6).AIDS and HIV virus infections person, the drug abuser, donate blood in nearest three months or as the experimenter person of being sampled, and have a liking for and once took various medicine persons in cigarette, wine-head and two weeks and all get rid of beyond screening conditions, concrete subject enrollment and exclusion standard are referring to " clinical research scheme ".The duration of test experimenter need unify bland diet.The experimenter all need sign Informed Consent Form before the test.Test is the approval of the refined three Medical Ethics councils of hospital through Central South University Hunan.
5 test design
5.1 overall design
Development test preparation and the reference preparation relative bioavailability behind single-dose is estimated the bioequivalence between two kinds of preparations.Adopt random, opening, two preparations, two cycles, trial design, the wash-out phase during week is 14 days.20 routine healthy male subjects are divided into 2 groups at random, and every group of 10 people specifically see random table 7.
The experimenter screens the inspection of phase 1 week before test.Inspection item comprises disease history inquire, vital sign inspection, cardiogram, HIV, HBsAg, HCV and RPR inspection, routine blood test, routine urinalysis, liver function, renal function etc., and every Index for examination eligible receives group.
The experimenter takes medicine in per cycle and moves in I phase ward last evening, morning on the same day was taken respectively the test preparation Levamlodipine beaylate tablets 5mg(2 sheet of being produced by Anhui Healstar Pharmaceutical Co., Ltd. according to dosage regimen in test in different cycles) or the reference preparation Levamlodipine beaylate tablets 5mg(2 sheet produced by company limited of Levamlodipine medicine company group (Jilin)), and before administration after (0h) and the administration fixed time point accept 15 ulnar veins blood samplings, extract ulnar vein blood 5mL at every turn.
All experimenters of duration of test need carry out a series of O﹠E, and be the observing time of regulation: take medicine front (0h) and take medicine rear 8h, 24h, 48h, 72h, 96h and 120h of the 1st day per cycle checks vital sign; And in second round the rear 120h that takes medicine carry out the Laboratory project inspection.As have the unusual of clinical meaning, continue to follow up a case by regular visits to normal or stable.
Finish the wash-out phase after the sampling, the experimenter does not require and must move in clinicalⅰstage test ward, but the testing requirements that needs to observe researcher's regulation.
Any bad reaction no matter whether duration of test caused by trial drug is by medical personnel's record, report and in time process.Experimenter's duration of test need keep daily light activity, avoids carrying out strenuous exercise.
5.2 method of administration and dosage regimen
Method of administration: oral.
Dosage regimen: test 8:00 in the 1st day morning, the experimenter is (fasting is more than 10 hours) oral test preparation or reference preparation on an empty stomach, and 250mL warm water takes.Take medicine front and the control drinking-water in rear 2 hours of taking medicine, rear 4 hours, the 10 hours feed standard lunches of taking medicine, dinner, duration of test is unified bland diet.And 14 days wash-out after dates of Nikkei from then on, beginning test second round, the experimenter accepts cross processing, the same period 1 of administering mode.
5.3 dosage and definite foundation
Levamlodipine beaylate tablets is produced by Anhui Healstar Pharmaceutical Co., Ltd., answer producer's requirement, existing P-TOLUENE SULFO ACID 99's levo-amlodipine carries out Bioequivalence research, and used reference preparation is the Levamlodipine beaylate tablets that company limited of Levamlodipine medicine company group (Jilin) produces.
Clinical usage with reference to the Levamlodipine besylate oral formulations that has gone on the market: treatment hypertension and anginal predose are 2.5mg, 1 time on the one; According to patient's clinical response, dosage can be increased, maximum can increase to 5mg, 1 time on the one.This product and thiazide diuretic, beta-blocker and angiotensin converting enzyme inhibitor share Shi Buxu adjustment amount.The dosage of the existing health volunteer's clinical testing of bibliographical information is 5mg/ time, every day 1 time, and have no adverse reaction.
Consider above-mentioned data and in conjunction with the feasibility of security and the sample test of clinical application, this test intended order time dosage is the 5mg(2 sheet).
5.4 blood specimen collection scheme
According to the literature, the oral rear absorption of this product is rapid, and bioavilability is 64% ~ 80%, and peak time is 6 ~ 12h, and the end elimination half life period is about 35 ~ 50h to blood plasma eventually.It is as follows that blood sampling time point is drafted in this research: 1h, 2h, 3h, 4h, 5h, 6h, 8h, 10h, 12h, 24h, 48h, 72h, 96h, 120h gather ulnar vein blood 5mL after (0h) and the administration before administration.
5.5 sample preparation and preservation
Blood specimen collection is placed in the liquaemin anti-freezing negative tube of prior numbering, centrifugal (3000rpm, 10min) separated plasma in 15 minutes, and blood plasma is transferred in the EP pipe that posts corresponding label, in-20 ℃ of refrigerator storage, to be measured.Need be placed in the ice chest during sample transportation, transport under 2 ~ 8 ℃ of conditions, the transhipment time is no more than 20min.
6. Determination of Biological Samples method
According to the pertinent literature report, intend adopting the HPLC-MS-/MS method to measure the drug concentration of Levamlodipine besylate in the blood plasma.The analytical test of biological sample is specifically responsible for by the refined Remedy Research Limited in Tag Hunan, Hunan.
7. the experimenter enters group and test performance
This research enters group 20 routine experimenters altogether, and all experimenters have all finished sample collection and the follow-up observation in two cycles according to testing requirements.
8. safety results
The every laboratory checking index of 20 routine experimenters after screening phase and off-test of finishing test sees table 5 and table 6 for details.
The test period 1 has 4 routine experimenters-(No. 03, No. 05, No. 08, No. 12) to occur respectively after administration " abdominal distension ", " Sleep hyperhidrosis ", " dizziness " and " swelling and aching of gum " and the adverse events symptom, degree is slightly; , above-mentioned adverse events is unprocessed all to be recovered voluntarily, through the clinical monitoring doctor evaluation, thinks " and dizziness " certainly relevant with medicine, " abdominal distension " with " Sleep hyperhidrosis " relevant with the medicine possibility, " swelling and aching of gum " impossible relevant with medicine; Test 3 routine experimenters-(No. 05 are arranged second round, No. 08, No. 04) after administration, occur respectively " Sleep hyperhidrosis ", " dizziness " and " abscess of throat " and the adverse events symptom, 3 routine experimenters-(No. 10, No. 16, No. 17) after administration, occur " infection of the upper respiratory tract " and the adverse events symptom, degree is slightly., process all voluntarily recovery without other, through the clinical monitoring doctor evaluation, think " dizziness " certainly relevant with medicine, " Sleep hyperhidrosis " relevant with the medicine possibility, " abscess of throat " with " infection of the upper respiratory tract " impossible relevant with medicine.Above-mentioned adverse events is processed all without other and is recovered voluntarily, through the clinical monitoring doctor evaluation, think that " dizziness " is certainly relevant with medicine; " abdominal distension " may be relevant with " Sleep hyperhidrosis " and medicine, " abscess of throat ", " swelling and aching of gum " can not be relevant with " infection of the upper respiratory tract " and medicine.Have 1 routine experimenter-(No. 14) to occur in the laboratory examination project after test administration second round " AST " raise, the result recovers normal after check, through the clinical monitoring doctor evaluation, think " AST " raising may have nothing to do with medicine, and all the other experimenter's duration of test occur without any adverse events.The test overall process is followed the use other drug without the experimenter.
The routine number of concrete generation of adverse events and description situation see Table 8 and table 9.
9. pharmacokinetic parameters result
Use WinNonlin 6.1 softwares, adopt non-compartment parameter computation (NCA module), the Pharmacokinetic parameter of calculating Levamlodipine besylate is asked calculation.After finishing the oral reference preparation of 20 routine experimenters and test preparation of research, each experimenter's pharmacokinetic parameters is seen
Annex 3, average pharmacokinetic parameters is referring to table 12, and the average drug-time curve of Amlodipine Besylate Tablet is seen Fig. 8.
10. stripping evaluation in bioequivalence and the body
Use SPSS 1317.0 softwares that the test preparation of calculating gained and the pharmacokinetic parameters of reference preparation Levamlodipine besylate are carried out statistical study.Adopt multifactor multivariate analysis of variance (ANOVA) to carry out significance test between individuality, between preparation, during week; Adopting two one-side t checks and calculate 90%(1-2 α, get α=0.05) statistical analysis technique of fiducial interval compares the degree of absorption of medicine between different preparations.Adopt Mann-Whitney U non-parametric test to T
MaxCarry out statistical study, estimate the difference of drug absorption speed between preparation.
Variance analysis and Mann-WhitneyU check all think that with p＜0.05 difference between group has statistical significance.
According to the statistic of two one side test, try to achieve simultaneously (1-2 α) % fiducial interval, such as the AUC of test preparation after to number conversion
LastAnd AUC
InfAt 80% ~ 125% scope of reference preparation, C
MaxIn 75% ~ 133% scope, i.e. explanation can have the probabilistic determination two preparation bioequivalences of 1-2 α; If AUC
Last, AUC
InfAnd C
MaxExceed above-mentioned scope, then think the biological inequivalence of two preparations.
This medicine is biopharmacy 1 class of classifying, and stripping is rate-limiting step, and absorption curve is stripping curve in the body.
Main pharmacokinetic parameters statistic analysis result is referring to table 14 ~ table 15.The interior stripping curve of absorption curve and body is seen Fig. 9, Figure 10 in the body that calculates.The analysis-by-synthesis the above results,---commercially available reference preparation that Levamlodipine beaylate tablets (2.5mg/ sheet) and company limited of Levamlodipine medicine company group (Jilin) produce---Levamlodipine beaylate tablets of thinking the test preparation of being produced by Anhui Healstar Pharmaceutical Co., Ltd.
Table 6 experimenter basic condition table
Table 7 experimenter random packet table
Annotate: total routine number N:20, random seed: 20111220, T is test preparation, R is reference preparation.
Table 8 adverse events title and routine number occurs
Specifically a situation arises for table 9 adverse events
Table 10 experimenter screens phase Laboratory project check result (continued)
Continuous upper table
Annotate: "
#" represent unusually without clinical meaning
120h Laboratory project check result after table 11 experimenter administration second round
Continuous upper table
Annotate: "
#" represent unusually without clinical meaning; " * " expression has clinical meaning unusually; " No. 14 " experimenter, the AST abnormal index is afterwards check recovery normal (" 27 ") in 7 days
The average pharmacokinetic parameters of table 12 Levamlodipine besylate reference preparation and test preparation
The multivariate analysis of variance result of the main pharmacokinetic parameters of table 13 Levamlodipine besylate
Table 14T
MaxThe Mann-Whitney assay
Table 15 LnC
MaxWith the two one-side t of LnAUC-check and 90% credibility interval
16. every laboratory examination reference value
(3) inside and outside stripping correlation research and personalized stripping standard formulation
It is 38.6h that the Levamlodipine beaylate tablets of company limited of Levamlodipine medicine company group (Jilin) is eliminated the half life period, and its absorption rate constant Ka is 0.356min
-1The elimination half life period of the Levamlodipine beaylate tablets that Anhui Healstar Pharmaceutical Co., Ltd. produces is 38.8h, and absorption rate constant Ka is 0.358min
-1Theoretical according to NADECAR, the half life period, NADECAR was greater than 0.266min greater than 36 hours medicine
-1The time, the variation of absorption rate is very little on the drug exposure impact.The absorption rate constant Ka of two preparations is greater than 0.266h
-1, infer bioequivalence.Verified the two bioequivalence of equivalence trial conforms to estimation result.
The external medicine dissolution rate constant of the Levamlodipine beaylate tablets of Levamlodipine pharmaceutical Co. Ltd is 0.109min
-1, the Levamlodipine beaylate tablets dissolution rate in vitro constant of Anhui Healstar Pharmaceutical Co., Ltd. is 0.2044min
-1The two all can fully stripping in 40 minutes.Dissolution rate is much larger than absorption rate (ka=0.356min
-1), do not consist of rate-limiting step.Analyze in theory, guarantee that dissolution rate constant is greater than 0.356min
-1Namely can reach non-speed limit process.External usually interior relevant with body.When formulating the In Vitro Dissolution standard, should stipulate the new method dissolution rate in vitro greater than NADECAR, namely greater than 0.266min
-1
Embodiment two: the new method research of Lamy stationary slice In Vitro Dissolution and inside and outside correlation research
(1) In Vitro Dissolution method research
Except medicine with reference substance is different, other reagent and method are identical with embodiment one, result of study such as Figure 11 ~ Figure 13 and table 17,18..Lamy stationary slice: GlaxoSmithKline PLC pharmacy (Suzhou) company limited (lot number 11070033100mg)
The Lamy stationary slice differential stripping of table 17 GlaxoSmithKline PLC (Suzhou) company limited
Continuous upper table
Continuous upper table
(2) stripping research in the Lamivudine lamellar body
Except medicine with reference substance is different, other reagent, research method, test design etc. are similar with embodiment one, do not do play-by-play.The result of study selectivity is reported as follows.
The average pharmacokinetic parameters of table 18 Lamivudine reference preparation and test preparation
The multivariate analysis of variance result of the main pharmacokinetic parameters of table 19 Lamivudine
Table 20LnC
MaxWith the two one-side t of LnAUC-check and 90% credibility interval
Table 21T
MaxThe Mann-Whitney assay
(3) inside and outside stripping correlation research and personalized stripping standard formulation
The absorption rate constant Ka=0.07min of the Lamy stationary slice that Hainan Xinshitong Pharmaceutical Co., Ltd produces
-1,The Lamy stationary slice absorption rate constant Ka=0.067minh of GlaxoSmithKline PLC (Suzhou) company limited
-1, the half life period is 3 hours.Theoretical according to NADECAR, the half life period is 3 hours medicine, and NADECAR should be 0.08 ~ 0.1min
-1, experimental result is near guess value, and the two should bioequivalence.In vivo studies confirms the two bioequivalence, and is consistent with estimation result, and the inside and outside is relevant.
The Lamy stationary slice dissolution rate constant K of GlaxoSmithKline PLC (Suzhou) company limited is 0.271min
-1Can guarantee fully stripping in 18 minutes.Dissolution rate is much larger than absorption rate (ka=0.067min
-1), do not consist of rate-limiting step.Analyze in theory, guarantee that dissolution rate constant is greater than NADECAR, namely greater than 0.1min
-1Namely can reach non-speed limit process.When formulating new method In Vitro Dissolution standard, should stipulate that the dissolution rate in vitro constant is greater than 0.1min
-1
Claims (11)
1. the personalized In Vitro Dissolution detection method of pharmaceutical preparation active component is characterized in that, the amount of simulated drug formulation active component is the stripping behavior in the biosome body, and preparation active component dissolution rate in vitro is not less than the critical absorption rate of active constituents of medicine; The online active constituents of medicine that detects stripping;
Described critical absorption rate refer to when the absorption rate of active constituents of medicine under the prerequisite of eliminating speed, when the size of absorption rate on the exposed amount of the active constituents of medicine absorption rate critical value when affecting;
Described critical absorption rate is calculated by the following steps simulation and is obtained:
Press the outer administration vivo medicine concentration of one compartment model blood vessel and the relation formula of time:
Wherein, C is vivo medicine concentration; K is elimination rate constant; Ka is absorption rate constant; F is bioavilability; V is apparent volume of distribution; T is the time, X
0Be dosage;
In the above-mentioned formula, for a kind of medicine, K, V and preparation are irrelevant, and for high-permeability medicine in the biopharmacy classification, preparation is ignored the impact of F, as K, V, F and X
0Be definite value, under different K a, make the C-t curve; Calculate C
Max, draw C
MaxIncrease with Ka, and Ka " during K, C
MaxThe amplitude that increases with Ka diminishes; When the Ka value is Ka
0, Ka
0Increase to Ka
1, and satisfy (Ka
1-Ka
0) * 100%/Ka
0In the time of 〉=50%, corresponding Cmax
0Increase to C
Max 1, and satisfy (C
Max 1-Cmax
0) * 100%/Cmax
0≤ 5%, the Ka of this moment
0Be exactly critical absorption rate constant, the corresponding speed of critical absorption rate constant is critical absorption rate.
2. method according to claim 1 is characterized in that, described stripping behavior is to realize in comprising the leaching condition of simulating gastro-intestinal Fluid volume, gastrointestinal movement and drug absorption in in-vivo medium, the stomach and intestine.
3. method according to claim 2 is characterized in that, described medium is simulated gastric fluid or simulated intestinal fluid.
4. method according to claim 1 is characterized in that, described preparation comprises capsule, sustained release preparation or dressing.
5. method according to claim 1 is characterized in that, the on-line detector device comprises in UV-detector, fluorescence detector, electrochemical detector or the evaporative light-scattering detector one or more.
6. external differential dissolving device that is used for stripping in the claim 1 aids drug body, it is characterized in that, comprise the drug-eluting pond, the flow ipe in drug-eluting pond is connected with the forcing pump I, and the stripping pond flows out that pipeline is connected with respectively the forcing pump II and at thread detector; Flow out the pipeline port in the described drug-eluting pond filter pocket is housed; Described drug-eluting pond and flow ipe peripheral hardware thereof have constent temperature heater, and also being provided with outside the drug-eluting pond can be so that the device that the drug-eluting pond is shaken.
7. device according to claim 6 is characterized in that, described drug-eluting pool volume is 0.5～10mL.
8. device according to claim 6 is characterized in that, comprises in UV-detector, fluorescence detector, electrochemical detector or the evaporative light-scattering detector one or more at thread detector.
9. according to claim 6 or 8 each described devices, it is characterized in that, also be connected with the on-line monitoring device at thread detector, the on-line monitoring device comprises registering instrument, digital treating meter and controller.
10. each described device is characterized in that according to claim 6 ~ 8, and drug-eluting pond flow ipe caliber is less than flowing out pipeline, and stretches in the drug-eluting pond.
11. each described device is characterized in that according to claim 6 ~ 8, described outflow pipeline is provided with that a three-way pipe is connected with respectively the forcing pump II and at thread detector.
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