Background technology
Chronic viral hepatitis B (Chronic Viral Hepatitis B, CH-B) is a kind of common disease of serious harm human health, and the control of chronic viral hepatitis B is a global public health problem, has caused the concern of countries in the world.The whole world about has several hundred million people to infect hepatitis B virus, and wherein chronic hepatitis B carriers about has 400,000,000 people.In infected patient, about have 15% ~ 40% will develop into liver cirrhosis, liver declines or liver cancer.In hepatitis B virus carriers, the people of 50% ~ 75% has the chronic viral hepatitis B of reactivity virus replication, estimates that the incidence being liver cirrhosis from chronic viral hepatitis B progress in 5 years is 2% ~ 20%; Be 20% ~ 23% from Compensated cirrhosis to Liver failure; Be 6% ~ 15% from compensatory liver cirrhosis to liver cancer.The whole world has every year dies from primary hepatocarcinoma more than 500,000 people, and wherein nearly the primary hepatocarcinoma of 80% caused by chronic viral hepatitis B, hepatitis B has become the global the tenth-largest cause of death.The whole world several hundred million Chronic Hepatitis B has 75% to live in the Asian-Pacific area, and China is the district occurred frequently of viral hepatitis, and the incidence rate in an average annual is 120 ~ 1,400,000, is wherein outstanding with hepatitis B (HB) especially.China hepatitis B virus (HBV) infection rate is up to 57.63%, and namely the whole nation has at least 600,000,000 people to infect HBV.HBsAg positive rate 9.75%, about has 1.2 hundred million people, accounts for 1/3 of the whole world; Wherein about 1/4 will develop into chronic hepatopathy, some patients can develop into liver cirrhosis, even develops into liver cancer.There is existing disease Chronic Hepatitis B more than 2,000 ten thousand people at present.There are 23.7 ten thousand people to die from the relevant disease of hepatitis B every year, wherein have 15.6 ten thousand people to die from liver cancer.So what the whole world was extremely urgent is find a kind of medicine that can reduce HBV infection rate and treatment chronic hepatitis as early as possible.
Entecavir tablet is studied by Bristol-Myers Squibb Co. of the U.S. (Bristol-Myers Squibb), exploitation, and U.S. food Drug Administration (FDA) is in official approval on March 29 in 2005 Entecavir (English trade(brand)name: Baraclude).Entecavir is white or off-white powder, easily molten in DMF, and slightly separate in 0.1mol/L hydrochloric acid and 0.1mol/L sodium hydroxide, slightly soluble in methyl alcohol, soluble,very slightly in water and ethanol, almost insoluble in acetonitrile, tool does not draw moist.Entecavir is cyclopentyl guanosine-analogue, and its structural formula is:
It is a kind of oral nucleoside medicine of selectivity Anti-HBV activity.This medicine oral absorption is rapid, and tissue distribution is extensive, and in kidney, concentration is higher, plasma protein binding ratio and internal metabolism rate all lower, about 60% ~ 80% with original shape from renal excretion, other meta-bolitess have glucuronide conjugate and two kinds of sulfates.This medicine was originally studied and was used for the treatment of herpes simplex infections, but it only has the suppression of moderate to simplexvirus.Found that this medicine had the effect of extremely strong suppression HBVDNA afterwards, and toxicity is very low, therefore becomes the emphasis in the Anti-HBV activity nucleoside medicine studied at present.The medicine Anti-HBV activity of the HepG2 cell of HBV DNA transfection finds in testing in vitro, and it acts on the strongest one in existing Anti-HBV activity nucleoside analog.It to hepatitis B virus (HBV) polymerase mechanism of action is: by competing with the natural substrate triphosphoric acid deoxyguanosine of HBV polymerase, Entecavir triphosphate can suppress all three kinds of activity of virus polymerase (reversed transcriptive enzyme): the startup of (1) HBV polymerase; (2) formation of pregenomic mRNA reverse transcription minus strand; (3) synthesis of HBV DNA normal chain.So it has the effect of fine effectively anti HBV infecting.
Entecavir water-soluble poor, prior art has open entecavir tablets or entecavir capsule preparation.Chinese patent application CN201310383392.X discloses a kind of entecavir capsule, Contents Fill is in capsule shell, described content is obtained pastille fine powder and mix lubricant, described pastille fine powder is that after Entecavir, meglumine and water-soluble filler being dissolved in the water, spraying dry forms, the weight ratio of Entecavir and meglumine is 1:15 ~ 50, by using a large amount of meglumines to improve the water-soluble of Entecavir, thus improve the uniformity coefficient of Entecavir.Chinese patent application CN201210004946.6 discloses a kind of entecavir capsule, its component comprises Entecavir, pregelatinized Starch and Microcrystalline Cellulose, containing Entecavir 0.5g, pregelatinized Starch 30 ~ 100g, Microcrystalline Cellulose 30 ~ 100g in 1000 capsules, lubricant 0 ~ 2g, adopt equivalent method of progressively increasing to mix by Entecavir and Microcrystalline Cellulose, then mix with pregelatinized Starch, incapsulate in shell, its dissolution rate is comparatively slow, thus onset is slow.A kind of Enticawer release-controllable capsule disclosed in Chinese patent application CN200710026680.4, the composition in capsule is Entecavir 0.01 ~ 5%, weighting agent 50 ~ 90%, tackiness agent 0.5 ~ 15%, glidant 0.1 ~ 5%; Film controlled release coat composition is film clothing material 1 ~ 15%, antisticking agent 0.1 ~ 5%, pore-creating agent 0.1 ~ 5%, softening agent 0.1 ~ 5%, its dissolution rate of this capsule is slower, and within 4 hours, discharge 26.38% activeconstituents, after 24 hours, the active ingredient of more than 94% all discharges.
Usually, for pharmaceutical preparation, the entecavir capsule preparation of concrete the application, wish that active ingredient is stablized, auxiliary material is more few better, and auxiliary material is the smaller the better to the side effect of human body, for the preparation that activeconstituents dosage is few, the difference of the active component content in each capsule needs to reduce as much as possible, in other words, ensure that active ingredient can evenly stripping be most important rapidly in auxiliary material, discharge medicine as far as possible at short notice, reach therapeutic plasma concentrations, simultaneously, obtain long-time therapeutic plasma concentrations stably, make the onset in a short time in vivo of this active ingredient, and keep drug effect for a long time, improve the conformability of patient.Special proposition the present invention for this reason.
Summary of the invention
An object of the present invention is to provide a kind of Entecavir crystalline compounds, the water-soluble of this Entecavir crystalline compounds is significantly improved.
Another object of the present invention is to provide entecavir capsule, entecavir capsule of the present invention excipient substance used has side effect hardly to human body, through experiment in vitro checking, can discharge at short notice and reach therapeutic plasma concentrations, and keep therapeutic plasma concentrations for a long time.
The preparation method being to provide a kind of entecavir capsule an object of the present invention.
For realizing object of the present invention, adopt following technical scheme:
A kind of Entecavir crystalline compounds, this crystalline compounds uses Cu-K α
1the X-ray powder diffraction of radionetric survey as shown in Figure 1.
Concrete, Entecavir crystal carries out Cu-K α
1in the X-ray powder diffraction (as shown in Figure 1) of radionetric survey, at 11.1 ° ± 0.1 °, 13.9 ° ± 0.1 °, 14.4 ° ± 0.1 °, 21.1 ° ± 0.1 °, 21.8 ° ± 0.1 °, 22.1 ° ± 0.1 °, 23.5 ° ± 0.1 °, 25.2 ° ± 0.1 °, 25.4 ° ± 0.1 ° diffraction angle (2 θ) indicating characteristic peak.
The preparation method of above-mentioned Entecavir crystalline compounds, comprises the steps:
(1) added by Entikawei solid in the mixed solvent of N,N-DIMETHYLACETAMIDE and methyl alcohol, temperature is under the condition of 35 ~ 40 DEG C, and Entikawei solid all dissolves;
(2) control temperature is under the condition of 35 ~ 40 DEG C, adds the aqueous solution of Virahol in the solution that step (1) obtains, and wherein, the mass percent containing Virahol in the aqueous solution of Virahol is 30% ~ 40%;
(3) after adding the aqueous solution of Virahol, be that 2.5 ~ 3.5 DEG C/10min is cooled to 0 ~-10 DEG C with speed, leave standstill 12 ~ 20 hours, crystallize out at 0 ~-10 DEG C, filter, filter cake washed with diethylether, after vacuum-drying, obtains Entecavir crystal.
It is preferred, and in step (1), the volume between N,N-DIMETHYLACETAMIDE and methyl alcohol is 2.0:(1.5-2.0); Preferred, the volume between described N,N-DIMETHYLACETAMIDE and methyl alcohol is 2.0:2.0.
Described Entecavir and the mass volume ratio of mixed solvent are (10-15) g:100ml.
A kind of Entecavir capsule, the weighting material in capsule comprises: Entecavir crystalline compounds, solubilizing agent, weighting agent, disintegrating agent, lubricant and tackiness agent.
Described Entecavir crystal uses Cu-K α
1as shown in Figure 1, the content of Entecavir is every 0.5mg to the X-ray powder diffraction of radionetric survey.
Weight ratio in capsule between each component is:
Described solubilizing agent comprises one or more mixing of sucrose monostearate, sucrose tristearate, polyethylene glycol 6000, poloxamer, Natvosol, hydroxypropylcellulose.
Described weighting agent comprises lactose, starch, Microcrystalline Cellulose, one or more mixing of dextrin, Icing Sugar, calcium sulfate, sucrose, N.F,USP MANNITOL, Microcrystalline Cellulose, glucose, pregelatinized Starch, magnesium oxide, calcium sulfate.
Described disintegrating agent comprises one or more mixing of sodium starch glycolate, low-substituted hydroxypropyl methylcellulose, starch, Microcrystalline Cellulose, croscarmellose sodium, polyvinylpolypyrrolidone, Lalgine, Citric Acid, Polysorbate 80, glycyl Starch Sodium.
Described lubricant comprises one or more mixing of silicon-dioxide, Magnesium Stearate, talcum powder, hydrogenated vegetable oil, aluminum hydroxide gel, magnesium oxide, paraffin, white oil, glycerine, glycine, glyceryl monostearate.
Described tackiness agent comprises one or more mixing of hydroxypropylcellulose, starch slurry, Xylo-Mucine, dextrin, polyvidone, ethyl cellulose, ethanol.
The preparation method of above-mentioned Entecavir capsule, comprises the steps:
(1) configure binder solution, place for subsequent use;
(2) 100 mesh sieves are for subsequent use excessively respectively to get the Entecavir crystalline compounds of recipe quantity, weighting agent, disintegrating agent, lubricant;
(3) weighting agent is mixed with the disintegrating agent of recipe quantity, make mixed accessories;
(4) by Entecavir crystalline compounds and solubilizing agent mixing, the mixed accessories then pressing equal increments method and step (3) mixes;
(5) with binder solution softwood, granulation, drying; Drying temperature controls at 50 ~ 60 DEG C;
(6) dried particle is carried out whole grain, then mix with lubricant, then filled capsules, obtain entecavir capsule.
Compared with prior art, Entecavir crystalline compounds provided by the invention increases than the water-soluble of Entecavir, and more stable.The entecavir capsule that Entecavir crystal is made has that release rate is fast, effective blood drug concentration holds time long feature.
Embodiment
Below that entecavir compound prepared and entecavir capsule of the present invention and preparation method are described in further detail:
Embodiment 1
Added by 10g Entikawei solid in the mixed solvent 100ml of N,N-DIMETHYLACETAMIDE and methyl alcohol, the volume between N,N-DIMETHYLACETAMIDE and methyl alcohol is 2.0:1.5, and temperature is under the condition of 40 DEG C, and Entikawei solid all dissolves; Control temperature, under the condition of 35 ~ 40 DEG C, adds the aqueous solution of Virahol in the solution obtained, and wherein, the mass percent containing Virahol in the aqueous solution of Virahol is 35%; After adding the aqueous solution of Virahol, be that 3.5 DEG C/10min is cooled to-5 DEG C with speed, leave standstill 13 hours, crystallize out at-5 DEG C, filter, filter cake washed with diethylether, after vacuum-drying, obtains Entecavir crystal.Cu-K α is carried out to products obtained therefrom Entecavir crystal
1in the X-ray powder diffraction (as shown in Figure 1) of radionetric survey, at 11.1 °, 13.9 °, 14.4 °, 21.1 °, 21.8 °, 22.1.9 °, 23.5 °, 25.2 °, 25.4 °, ° diffraction angle (2 θ ± 0.1) display diffraction peak.
Embodiment 2
Added by 15g Entikawei solid in the mixed solvent 100ml of N,N-DIMETHYLACETAMIDE and methyl alcohol, the volume between N,N-DIMETHYLACETAMIDE and methyl alcohol is 2.0:2.0, and temperature is under the condition of 35 DEG C, and Entikawei solid all dissolves; Control temperature, under the condition of 35 ~ 40 DEG C, adds the aqueous solution of Virahol in the solution obtained, and wherein, the mass percent containing Virahol ethanol in the aqueous solution of Virahol is 30%; After adding the aqueous solution of Virahol, be that 2.5 DEG C/10min is cooled to-10 DEG C with speed, leave standstill 18 hours, crystallize out at-10 DEG C, filter, filter cake washed with diethylether, after vacuum-drying, obtains Entecavir crystal.Show through the analysis of powder X-ray RD detector, conform to the result shown in accompanying drawing 1.
Embodiment 3
Added by 12 Entikawei solids in the mixed solvent 100ml of N,N-DIMETHYLACETAMIDE and methyl alcohol, the volume between N,N-DIMETHYLACETAMIDE and methyl alcohol is 2.0:2.0, and temperature is under the condition of 40 DEG C, and Entikawei solid all dissolves; Control temperature, under the condition of 35-40 DEG C, adds the aqueous solution of Virahol in the solution obtained, and wherein, the mass percent containing Virahol ethanol in the aqueous solution of Virahol is 40%; After adding the aqueous solution of Virahol, be that 3.0 DEG C/10min is cooled to 0 DEG C with speed, leave standstill 20 hours, crystallize out at 0 DEG C, filter, filter cake washed with diethylether, after vacuum-drying, obtains Entecavir crystal.Show through the analysis of powder X-ray RD detector, conform to the result shown in accompanying drawing 1.
Embodiment 4
Entecavir capsule prescription
The preparation method of Entecavir capsule, comprises the steps:
(1) take a certain amount of hypromellose, make the hypromellose cellulose solution of 2% with water, place for subsequent use;
(2) the Entecavir crystal raw material of recipe quantity and each auxiliary material are crossed 100 mesh sieves respectively for subsequent use;
(3) take lactose, starch, carboxymethylstach sodium by recipe quantity, lactose, starch, carboxymethylstach sodium are mixed, makes mixed accessories;
(4) the Entecavir crystalline compounds of recipe quantity and sucrose tristearate are mixed, the mixed accessories then pressing equal increments method and step (3) mixes;
(5) with 2% hypromellose aqueous solution softwood, 20 mesh sieves granulate, 50 ~ 60 DEG C of dryings;
(6) dried particle is carried out whole grain, more fully mix with the silicon-dioxide of recipe quantity, then filled capsules, obtains entecavir capsule.
Embodiment 5
Entecavir capsule prescription
The preparation method of Entecavir capsule, comprises the steps:
(1) take a certain amount of polyvidone, make the polyvidone ethanolic soln of 2% with ethanol, place for subsequent use;
(2) Entecavir crystal raw material and each auxiliary material are crossed 100 mesh sieves respectively for subsequent use;
(3) take N.F,USP MANNITOL, starch, low-substituted hydroxypropyl cellulose by recipe quantity, N.F,USP MANNITOL, starch, low-substituted hydroxypropyl cellulose are mixed, makes mixed accessories;
(4) the Entecavir crystalline compounds of recipe quantity and sucrose monostearate are mixed, then press equal increments method and the mixed accessories described in step (3) mixes;
(5) with 2% polyvidone ethanolic soln softwood, 20 mesh sieves granulate, 50 ~ 60 DEG C of dryings;
(6) dried particle is carried out whole grain, more fully mix with the Magnesium Stearate of recipe quantity, then filled capsules, obtains entecavir capsule.
Embodiment 6
Entecavir capsule prescription
The preparation method of Entecavir capsule, comprises the steps:
(1) take a certain amount of hypromellose, make the hypromellose cellulose solution of 2% with water, place for subsequent use;
(2) Entecavir crystal raw material and each auxiliary material are crossed 100 mesh sieves respectively for subsequent use;
(3) take N.F,USP MANNITOL, Microcrystalline Cellulose, carboxymethylstach sodium by recipe quantity, N.F,USP MANNITOL, Microcrystalline Cellulose, carboxymethylstach sodium are mixed, makes mixed accessories;
(4) the Entecavir crystalline compounds of recipe quantity and polyethylene glycol 6000 are mixed, then press equal increments method and step (3) described mixed accessories mixes;
(5) with 2% hypromellose aqueous solution softwood, 20 mesh sieves granulate, 50 ~ 60 DEG C of dryings;
(6) dried particle is carried out whole grain, more fully mix with the silicon-dioxide of recipe quantity, then filled capsules, obtains entecavir capsule.
Embodiment 7
Entecavir capsule prescription
The preparation method of Entecavir capsule, comprises the steps:
(1) take a certain amount of starch, make the starch slurry of 8% with water, place for subsequent use;
(2) Entecavir crystal raw material and each auxiliary material are crossed 100 mesh sieves respectively for subsequent use;
(3) take lactose, N.F,USP MANNITOL, polyvinylpolypyrrolidone by recipe quantity, lactose, N.F,USP MANNITOL, polyvinylpolypyrrolidone are mixed, makes mixed accessories;
(4) the Entecavir crystalline compounds of recipe quantity and sucrose tristearate are mixed, then press equal increments method and the mixed accessories described in step (3) mixes;
(5) with 8% starch slurry softwood, 20 mesh sieves granulate, 50 ~ 60 DEG C of dryings;
(6) dried particle is carried out whole grain, more fully mix with the talcum powder of recipe quantity, then filled capsules, obtains entecavir capsule.
Embodiment 8
Entecavir capsule prescription;
The preparation method of Entecavir capsule, comprises the steps:
(1) take a certain amount of Xylo-Mucine, make the sodium carboxymethyl cellulose solution of 1% with water, place for subsequent use;
(2) Entecavir crystal raw material and each auxiliary material are crossed 100 mesh sieves respectively for subsequent use;
(3) take N.F,USP MANNITOL, dextrin, low-substituted hydroxypropyl cellulose by recipe quantity, N.F,USP MANNITOL, dextrin, low-substituted hydroxypropyl cellulose are mixed, makes mixed accessories;
(4) the Entecavir crystalline compounds of recipe quantity and sucrose tristearate are mixed, then press equal increments method and the mixed accessories described in step (3) mixes;
(5) with 1% sodium carboxymethyl cellulose solution softwood, 20 mesh sieves granulate, 50 ~ 60 DEG C of dryings;
(6) dried particle is carried out whole grain, more fully mix with the silicon-dioxide of recipe quantity, then filled capsules, obtains entecavir capsule.
Embodiment 9
Entecavir capsule prescription;
The preparation method of Entecavir capsule, comprises the steps:
(1) take a certain amount of hypromellose, make 2% hypromellose cellulose solution with water, place for subsequent use;
(2) Entecavir crystal raw material and each auxiliary material are crossed 100 mesh sieves respectively for subsequent use;
(3) take lactose, Microcrystalline Cellulose, pregelatinized Starch by recipe quantity, lactose, Microcrystalline Cellulose, pregelatinized Starch are mixed, makes mixed accessories;
(4) the Entecavir crystalline compounds of recipe quantity and sucrose tristearate are mixed, then press equal increments method and the mixed accessories described in step (3) mixes;
(5) with 2% hypromellose aqueous solution softwood, 20 mesh sieves granulate, 50 ~ 60 DEG C of dryings;
(6) dried particle is carried out whole grain, more fully mix with the silicon-dioxide of recipe quantity, then filled capsules, obtains entecavir capsule.
Embodiment 10
Entecavir capsule prescription;
The preparation method of Entecavir capsule, comprises the steps:
(1) ethanol of measured amounts, makes the ethanolic soln of 70% with water, place for subsequent use;
(2) Entecavir crystal raw material and each auxiliary material are crossed 100 mesh sieves respectively for subsequent use;
(3) take N.F,USP MANNITOL, dextrin, Lalgine by recipe quantity, N.F,USP MANNITOL, dextrin, Lalgine are mixed, makes mixed accessories;
(4) the Entecavir crystalline compounds of recipe quantity and sucrose tristearate are mixed, then press equal increments method and the mixed accessories described in step (3) mixes;
(5) with 70% ethanolic soln softwood, granulation, 50 ~ 60 DEG C of dryings;
(6) dried particle is carried out whole grain, more fully mix with the Magnesium Stearate of recipe quantity, then filled capsules, obtains entecavir capsule.
Experimental example 1
This experimental example carries out accelerated stability test to the entecavir capsule of embodiment 4, the results are shown in Table 1:
Packaging: polyvinyl chloride solid medicinal stiff sheet, drug packaging aluminium foil, investigates condition: temperature 40 ± 2 DEG C of RH75% ± 5%
Table 1 accelerated stability test
Conclusion: to the samples of three batches after simulation commercially available back through accelerated test 6 months, every inspection target and detect results contrast in 0 month, is showed no considerable change.
Experimental example 2
This experimental example carries out in vivo test to the entecavir capsule of embodiment 4.Concrete grammar is, study subject is 28 healthy male volunteers, and the age, body weight was in (65 ± 3.0) kilogram, and height is at (1.72 ± 0.25) rice in (25 ± 1.5) year.Tested front all volunteers all check UP, and all every all normal, not used to the prejudicial medicine of internal organs within half a year, in experimenter before administration 1 month and whole off-test do not take other any medicines.Before taking medicine 24h and duration of test prohibit drink tea, quit smoking, wine, and the beverage containing caffeine and ethanol.According to random dual crossing test design, 28 healthy premenopausal volunteers are divided into two groups, fasting 12 hours, before taking medicine morning, adopt blank blood 5ml.
28 experimenters are divided into A, B bis-groups at random, often organize 14 people, the entecavir capsule and commercially available entecavir capsule of taking the embodiment of the present invention 4 is intersected respectively two cycles, the entecavir capsule of the oral embodiment of the present invention 4 of empty stomach and each 0.5mg of commercially available entecavir capsule, take medicine and can drink water in right amount for latter 2 hours, unified feed low fat light diet after 4 hours.10min, 20min, 30min, 45min, 1h, 1.5h, 2h, 3h after taking medicine, 5,8h, 12,24,48,72h gather venous blood 5ml at experimenter's upper arm respectively, get blood plasma after centrifugal, to be measured-80 DEG C of preservations.HPLC-MS/MS is adopted to measure Entecavir concentration in blood plasma.In the period 1, the entecavir capsule of the oral embodiment of the present invention 4 of A group experimenter, B group takes commercially available entecavir capsule; Be second cycle after one week, two groups exchange another kind of Entecavir formulation respectively, same method blood sample collection.By detecting the comparison of two kinds of preparation Plasma Concentration kinetic parameters, evaluate the bioequivalence of two kinds of preparations.
Adopt non-chamber dependent form parameter evaluation method, calculate pharmacokinetic parameters with DAS2.0 pharmacokinetics routine processes plasma drug concentration data, Cmax, Tmax are practical measurement numerical value.The main pharmacokinetic parameters of two kinds of preparations is in table 2:
Main pharmacokinetic parameters after the oral entecavir capsule of table 2
As can be seen from Table 2, entecavir capsule of the present invention is absorbing soon in vivo, and keeps therapeutic plasma concentrations for a long time.
Experimental example 3
This experimental example carries out dissolved corrosion simultaneous test to the entecavir capsule of embodiment 4 and the Entecavir tablet sample that goes on the market.
Get this product each 6 and listing control sample Entecavir tablet 6, respectively according to dissolution method (China's coastal port two annex Ⅹ C second methods), with 0.05mol/L potassium dihydrogen phosphate (PH6.8) 1000ml for dissolution medium, rotating speed is per minute 50 turns, operate in accordance with the law, draw solution appropriate (simultaneously adding the dissolution medium of equivalent uniform temp) the 15th, 30,45,60 minute time, filters, gets subsequent filtrate as need testing solution respectively; Separately get Entecavir reference substance appropriate, accurately weighed, add 0.05mol/L potassium dihydrogen phosphate and dissolve and dilute the solution made about containing 0.5 μ g in every 1ml, product solution in contrast.Get above-mentioned need testing solution and each 100 μ l of reference substance solution, injection liquid chromatography, record color atlas, goes out stripping quantity by external standard method with calculated by peak area, draws stripping curve and sees Fig. 2.Test-results is in table 3, table 4.
Table 3 entecavir capsule stripping curve test-results
Table 4 goes on the market sample Entecavir tablet stripping curve test-results
Experimental result shows: the entecavir capsule of embodiment 4 is fast compared with the dissolution rate of Entecavir tablet listing sample.