CN105001223B - A kind of Entecavir crystalline compounds and capsule preparations thereof - Google Patents

A kind of Entecavir crystalline compounds and capsule preparations thereof Download PDF

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CN105001223B
CN105001223B CN201510372885.2A CN201510372885A CN105001223B CN 105001223 B CN105001223 B CN 105001223B CN 201510372885 A CN201510372885 A CN 201510372885A CN 105001223 B CN105001223 B CN 105001223B
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entecavir
capsule
crystal
starch
mixing
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CN105001223A (en
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张舰
李马理
徐燕
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HUNAN SANQING PHARMACEUTICAL CO Ltd
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CHANGSHA BOYA MEDICINE TECHNOLOGY DEVELOPMENT Co Ltd
HUNAN SANQING PHARMACEUTICAL CO Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/18—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 one oxygen and one nitrogen atom, e.g. guanine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

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Abstract

A kind of Entecavir crystalline compounds, this crystalline compounds uses Cu K α1As shown in Figure 1, and containing the capsule of this kind of Entecavir crystalline compounds, its component includes the X ray powder diffraction of radionetric survey: Entecavir crystalline compounds, solubilizing agent, filler, disintegrating agent, lubricant, binding agent.Excipient substance used by the entecavir capsule of the present invention has side effect hardly to human body, through vivo and vitro experimental verification, can discharge at short notice and reach therapeutic plasma concentrations, and keep therapeutic plasma concentrations for a long time.

Description

A kind of Entecavir crystalline compounds and capsule preparations thereof
Technical field
The present invention relates to oral nucleoside medicine Entecavir crystalline compounds and the capsule preparations thereof of a kind of Anti-HBV activity.
Background technology
Chronic viral hepatitis B (Chronic Viral Hepatitis B, CH-B) is a kind of serious harm mankind Healthy commonly encountered diseases, the preventing and treating of chronic viral hepatitis B is a global public health problem, has caused the concern of countries in the world.The whole world There are about several hundred million people and infected hepatitis B virus, wherein chronic hepatitis B carriers there are about 400,000,000 people.Infected patient In, there are about 15%～40% and will develop into liver cirrhosis, liver declines or hepatocarcinoma.In hepatitis B virus carriers, the people of 50%～75% Have the chronic viral hepatitis B of activeness virus replication, in estimating 5 years from chronic viral hepatitis B progress to the incidence rate of liver cirrhosis be 2%～ 20%；It is 20%～23% from Compensated cirrhosis to Liver failure；It is 6%～15% from compensatory liver cirrhosis to hepatocarcinoma.Entirely Ball has more than 500,000 people every year and dies from primary hepatocarcinoma, and the primary hepatocarcinoma of the most up to 80% is to be 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, the most especially with hepatitis B (HB) be prominent. China's hepatitis B virus (HBV) infection rate is up to 57.63%, i.e. the whole nation at least 600,000,000 people infected HBV.HBsAg positive rate 9.75%, there are about 1.2 hundred million people, account for the 1/3 of the whole world；The most about 1/4 would develop into chronic hepatopathy, and it is hard that some patients can develop into liver Change, even develop into hepatocarcinoma.There is existing disease Chronic Hepatitis B more than 2,000 ten thousand people at present.23.7 ten thousand people are had to die from hepatitis B every year Relevant disease, wherein has 15.6 ten thousand people to die from hepatocarcinoma.So, what the whole world was extremely urgent is to find one to reduce as early as possible HBV infection rate and the medicine for the treatment of chronic hepatitis.
Entecavir tablet is studied by Bristol-Myers Squibb Co. of the U.S. (Bristol-Myers Squibb), is developed, the U.S. Food and medicine Surveillance Authority (FDA) in official approval on March 29 in 2005 Entecavir (English trade name: Baraclude).Entecavir is white or off-white powder, readily soluble in DMF, at 0.1mol/L hydrochloric acid and 0.1mol/L hydrogen Sodium oxide slightly solves, slightly soluble in methanol, soluble,very slightly in water and ethanol, the most insoluble in acetonitrile, do not have draw moist.Grace Being cyclopenta guanosine analog for card Wei, its structural formula is:
It is the oral nucleoside medicine of a kind of selectivity Anti-HBV activity.This medicine oral absorption is rapid, and tissue distribution is extensive, kidney Dirty interior concentration is higher, and plasma protein binding rate and internal metabolism rate are the most relatively low, about 60%～80% with original shape from renal excretion, its His metabolite has glucuronide conjugate and two kinds of sulfates.It is sick for treating herpes simplex that this medicine was studied originally Poison infects, but it only has the suppression of moderate to herpesvirus.Found that this medicine had the effect of extremely strong suppression HBV DNA later, And toxicity is the lowest, therefore become the emphasis in the Anti-HBV activity nucleoside medicine currently studied.HBV DNA transfects in vitro The medicine Anti-HBV activity of HepG2 cell is it was found that, it is to act on the strongest one in existing Anti-HBV activity nucleoside analog.It is to second Hepatovirus (HBV) polymerase mechanism of action is: competing by the natural substrate triphosphoric acid NSC 22837 with HBV polymerase Strive, Entecavir triphosphate can suppress virus polymerase (reverse transcriptase) all three activity: opening of (1) HBV polymerase Dynamic；(2) formation of pregenomic mRNA reverse transcription minus strand；(3) synthesis of HBV DNA normal chain.So it has the most effective The effect of anti HBV infecting.
The water solublity of Entecavir is poor, and prior art has open entecavir tablets or entecavir capsule preparation. Chinese patent application CN201310383392.X discloses a kind of entecavir capsule, and Contents Fill is in capsule shells, described Content be that pastille fine powder and mix lubricant are obtained, described pastille fine powder is by Entecavir, meglumine and water-soluble Property filler be dissolved in the water after be spray-dried and form, Entecavir and the weight ratio of meglumine are 1:15～50, by using Substantial amounts of meglumine improves the water solublity of Entecavir, thus improves the uniformity of Entecavir.Chinese patent application The open a kind of entecavir capsule of CN201210004946.6, its component includes Entecavir, pregelatinized Starch and microcrystalline cellulose Element, 1000 seed lac capsules are contained within Entecavir 0.5g, pregelatinized Starch 30～100g, microcrystalline Cellulose 30～100g, lubricant 0 ～2g, use equivalent method of progressively increasing to mix by Entecavir and microcrystalline Cellulose, then mix with pregelatinized Starch, loading capsule In shell, its dissolution rate is relatively slow, thus onset is slow.A kind of grace disclosed in Chinese patent application CN200710026680.4 For card Wei controlled release capsule, the composition in capsule is Entecavir 0.01～5%, filler 50～90%, binding agent 0.5～ 15%, fluidizer 0.1～5%；Film controlled release coat composition is film clothing material 1～15%, antiplastering aid 0.1～5%, porogen 0.1 ～5%, plasticizer 0.1～5%, its dissolution rate of this capsule is slower, discharges 26.38% active component within 4 hours, and 24 After hour, the active component of more than 94% all discharges.
Typically for pharmaceutical preparation, the entecavir capsule preparation of concrete the application, it is desirable to active component is stable, adjuvant The fewest more good, and the side effect to human body of adjuvant is the smaller the better, for the preparation that active component dosage is few, in each capsule The difference of active component content needs to reduce as far as possible, in other words, it is ensured that active component can be uniformly and quickly in adjuvant Dissolution is most important, discharges medicine the most at short notice, reaches therapeutic plasma concentrations, simultaneously, it is thus achieved that be the most stable Therapeutic plasma concentrations so that this active component onset the most in a short time and keep drug effect for a long time, improves complying with of patient Property.For this special proposition present invention.
Summary of the invention
It is an object of the present invention to provide a kind of Entecavir crystalline compounds, the water of this Entecavir crystalline compounds Dissolubility is significantly improved.
It is a further object to provide entecavir capsule, the medicine used by the entecavir capsule of the present invention is auxiliary Material has side effect hardly to human body, verifies through experiment in vitro, 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 a purpose of the present invention.
For realizing the purpose of the present invention, adopt the following technical scheme that
A kind of Entecavir crystalline compounds, this crystalline compounds uses Cu-K α1The X-ray powder diffraction of radionetric survey As shown in Figure 1.
Concrete, Entecavir crystal carries out Cu-K α1In the X-ray powder diffraction (as shown in Figure 1) of radionetric survey, 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 ° angle of diffraction (2 θ) display characteristic peak.
The preparation method of above-mentioned Entecavir crystalline compounds, comprises the steps:
(1) being added by Entikawei solid in the mixed solvent of dimethyl acetylamide and methanol, temperature is at 35～40 DEG C Under the conditions of, Entikawei solid all dissolves；
(2) control temperature is under conditions of 35～40 DEG C, adds the water-soluble of isopropanol in the solution that step (1) obtains Liquid, wherein, in the aqueous solution of isopropanol, the mass percent containing isopropanol is 30%～40%；
(3), after adding the aqueous solution of isopropanol, it is that 2.5～3.5 DEG C/10min is cooled to 0～-10 DEG C, 0 with speed ～-10 DEG C stand 12～20 hours, separating out crystal, filter, filter cake ether washs, and after vacuum drying, obtains Entecavir brilliant Body.
It is preferred, and in step (1), the volume between dimethyl acetylamide and methanol is 2.0:(1.5-2.0)；More preferably , the volume between described dimethyl acetylamide and methanol is 2.0:2.0.
Described Entecavir is (10-15) g:100ml with the mass volume ratio of mixed solvent.
A kind of Entecavir capsule, the implant in capsule includes: Entecavir crystalline compounds, solubilizing agent, filling Agent, disintegrating agent, lubricant and binding agent.
Described Entecavir crystal uses Cu-K α1The X-ray powder diffraction of radionetric survey as shown in Figure 1, replace by grace The content of card Wei is every 0.5mg.
In capsule, the weight ratio between each component is:
Described solubilizing agent include sucrose monostearate, sucrose tristearate, polyethylene glycol 6000, poloxamer, Hydroxyethyl cellulose, one or more mixing of hydroxypropyl cellulose.
Described filler includes lactose, starch, microcrystalline Cellulose, dextrin, Icing Sugar, calcium sulfate, sucrose, mannitol, micro- Crystalline cellulose, glucose, pregelatinized Starch, magnesium oxide, one or more mixing of calcium sulfate.
Described disintegrating agent includes carboxymethyl starch sodium, low-substituted hydroxypropyl methylcellulose, starch, microcrystalline Cellulose, crosslinking Sodium carboxymethyl cellulose, polyvinylpolypyrrolidone, alginic acid, citric acid, polyoxyethylene sorbitan monoleate, glycyl Starch Sodium one or both Above mixing.
Described lubricant includes silicon dioxide, magnesium stearate, Pulvis Talci, hydrogenated vegetable oil, gel aluminum hydroxide, oxidation Magnesium, paraffin, white oil, glycerol, glycine, one or more mixing of glyceryl monostearate.
Described binding agent includes that hydroxypropyl cellulose, starch slurry, sodium carboxymethyl cellulose, dextrin, polyvidone, ethyl are fine Dimension element, one or more mixing of ethanol.
The preparation method of above-mentioned Entecavir capsule, comprises the steps:
(1) configuration binder solution, places standby；
(2) the Entecavir crystalline compounds of recipe quantity, filler, disintegrating agent, lubricant 100 mesh sieves excessively respectively are taken standby With；
(3) filler is mixed homogeneously with the disintegrating agent of recipe quantity, make mixed accessories；
(4) Entecavir crystalline compounds and solubilizing agent are mixed, then press equal increments method auxiliary with the mixing of step (3) Material mixing；
(5) with binder solution soft material, pelletize, be dried；Baking temperature controls at 50～60 DEG C；
(6) dried granule is carried out granulate, then mix with lubricant, be subsequently filled capsule, obtain entecavir Wei capsule.
Compared with prior art, the Entecavir crystalline compounds that the present invention provides has carried than the water solublity of Entecavir Height, and more stable.When the entecavir capsule that Entecavir crystal is made has that rate of release is fast, effective blood drug concentration maintains Between long feature.
Accompanying drawing explanation
The X-ray powder diffractogram of the Entecavir crystalline compounds of Fig. 1 present invention
The entecavir capsule of Fig. 2 embodiment of the present invention 4 compares figure with listing sample stripping curve
Detailed description of the invention
The following is and the entecavir compound prepared of the present invention and entecavir capsule and preparation method are chatted the most in detail State:
Embodiment 1
10g Entikawei solid is added in the dimethyl acetylamide mixed solvent 100ml with methanol, dimethyl acetylamide With the volume between methanol is 2.0:1.5, temperature is under conditions of 40 DEG C, and Entikawei solid all dissolves；Control temperature to exist Under conditions of 35～40 DEG C, the solution obtained adds the aqueous solution of isopropanol, wherein, containing different in the aqueous solution of isopropanol The mass percent of propanol is 35%；After adding the aqueous solution of isopropanol, it is that 3.5 DEG C/10min is cooled to-5 DEG C with speed, Standing 13 hours at-5 DEG C, separate out crystal, filter, filter cake ether washs, and after vacuum drying, obtains Entecavir crystal.Right Products obtained therefrom Entecavir crystal carries out Cu-K α1In 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 °, ° angle of diffraction (2 θ ± 0.1) display diffraction maximum.
Embodiment 2
15g Entikawei solid is added in the dimethyl acetylamide mixed solvent 100ml with methanol, dimethyl acetylamide With the volume between methanol is 2.0:2.0, temperature is under conditions of 35 DEG C, and Entikawei solid all dissolves；Control temperature to exist Under conditions of 35～40 DEG C, the solution obtained adds the aqueous solution of isopropanol, wherein, containing different in the aqueous solution of isopropanol The mass percent of propanol ethanol is 30%；Add isopropanol aqueous solution after, with speed be 2.5 DEG C/10min be cooled to- 10 DEG C, standing 18 hours at-10 DEG C, separate out crystal, filter, filter cake ether washs, and after vacuum drying, obtains Entecavir brilliant Body.Show through the detector analysis of powder X-ray RD, be consistent with the result shown in accompanying drawing 1.
Embodiment 3
12 Entikawei solids are added in the dimethyl acetylamide mixed solvent 100ml with methanol, dimethyl acetylamide With the volume between methanol is 2.0:2.0, temperature is under conditions of 40 DEG C, and Entikawei solid all dissolves；Control temperature to exist Under conditions of 35-40 DEG C, the solution obtained adds the aqueous solution of isopropanol, wherein, containing different in the aqueous solution of isopropanol The mass percent of propanol ethanol is 40%；After adding the aqueous solution of isopropanol, it is that 3.0 DEG C/10min is cooled to 0 with speed DEG C, standing 20 hours at 0 DEG C, separate out crystal, filter, filter cake ether washs, and after vacuum drying, obtains Entecavir crystal. Show through the detector analysis of powder X-ray RD, be consistent with the result shown in accompanying drawing 1.
Embodiment 4
Entecavir capsule prescription
The preparation method of Entecavir capsule, comprises the steps:
(1) weigh a certain amount of hypromellose, make the hypromellose cellulose solution of 2% with water, place standby；
(2) the Entecavir crystal raw material of recipe quantity is crossed respectively 100 mesh sieves standby with each adjuvant；
(3) lactose, starch, carboxymethylstach sodium are weighed by recipe quantity, by lactose, starch, carboxymethylstach sodium mix homogeneously, system Become mixed accessories；
(4) the Entecavir crystalline compounds of recipe quantity is mixed with sucrose tristearate, then press equal increments method Mix with the mixed accessories of step (3)；
(5) pelletize with hypromellose aqueous solution soft material, 20 mesh sieves of 2%, be dried at 50～60 DEG C；
(6) dried granule is carried out granulate, then be sufficiently mixed uniformly with the silicon dioxide of recipe quantity, be subsequently filled glue Capsule, obtains entecavir capsule.
Embodiment 5
Entecavir capsule prescription
The preparation method of Entecavir capsule, comprises the steps:
(1) weigh a certain amount of polyvidone, make the polyvidone ethanol solution of 2% with ethanol, place standby；
(2) Entecavir crystal raw material is crossed respectively 100 mesh sieves standby with each adjuvant；
(3) mannitol, starch, low-substituted hydroxypropyl cellulose are weighed by recipe quantity, by mannitol, starch, low-substituted hydroxypropyl Cellulose mix homogeneously, makes mixed accessories；
(4) the Entecavir crystalline compounds of recipe quantity is mixed with sucrose monostearate, then press equal increments method Mix with the mixed accessories described in step (3)；
(5) pelletize with polyvidone ethanol solution soft material, 20 mesh sieves of 2%, be dried at 50～60 DEG C；
(6) dried granule is carried out granulate, then be sufficiently mixed uniformly with the magnesium stearate of recipe quantity, be subsequently filled glue Capsule, obtains entecavir capsule.
Embodiment 6
Entecavir capsule prescription
The preparation method of Entecavir capsule, comprises the steps:
(1) weigh a certain amount of hypromellose, make the hypromellose cellulose solution of 2% with water, place standby；
(2) Entecavir crystal raw material is crossed respectively 100 mesh sieves standby with each adjuvant；
(3) mannitol, microcrystalline Cellulose, carboxymethylstach sodium are weighed by recipe quantity, by mannitol, microcrystalline Cellulose, carboxylic first Starch Sodium mix homogeneously, 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) pelletize with hypromellose aqueous solution soft material, 20 mesh sieves of 2%, be dried at 50～60 DEG C；
(6) dried granule is carried out granulate, then be sufficiently mixed uniformly with the silicon dioxide of recipe quantity, be subsequently filled glue Capsule, obtains entecavir capsule.
Embodiment 7
Entecavir capsule prescription
The preparation method of Entecavir capsule, comprises the steps:
(1) weigh a certain amount of starch, make the starch slurry of 8% with water, place standby；
(2) Entecavir crystal raw material is crossed respectively 100 mesh sieves standby with each adjuvant；
(3) lactose, mannitol, polyvinylpolypyrrolidone are weighed by recipe quantity, by lactose, mannitol, polyvinylpolypyrrolidone mixing all Even, make mixed accessories；
(4) the Entecavir crystalline compounds of recipe quantity is mixed with sucrose tristearate, then press equal increments method Mix with the mixed accessories described in step (3)；
(5) pelletize with starch slurry soft material, 20 mesh sieves of 8%, be dried at 50～60 DEG C；
(6) dried granule is carried out granulate, then be sufficiently mixed uniformly with the Pulvis Talci of recipe quantity, be subsequently filled glue Capsule, obtains entecavir capsule.
Embodiment 8
Entecavir capsule prescription；
The preparation method of Entecavir capsule, comprises the steps:
(1) weigh a certain amount of sodium carboxymethyl cellulose, make the sodium carboxymethyl cellulose solution of 1% with water, place Standby；
(2) Entecavir crystal raw material is crossed respectively 100 mesh sieves standby with each adjuvant；
(3) mannitol, dextrin, low-substituted hydroxypropyl cellulose are weighed by recipe quantity, by mannitol, dextrin, low-substituted hydroxypropyl Cellulose mix homogeneously, makes mixed accessories；
(4) the Entecavir crystalline compounds of recipe quantity is mixed with sucrose tristearate, then press equal increments method Mix with the mixed accessories described in step (3)；
(5) pelletize with sodium carboxymethyl cellulose solution soft material, 20 mesh sieves of 1%, be dried at 50～60 DEG C；
(6) dried granule is carried out granulate, then be sufficiently mixed uniformly with the silicon dioxide of recipe quantity, be subsequently filled glue Capsule, obtains entecavir capsule.
Embodiment 9
Entecavir capsule prescription；
The preparation method of Entecavir capsule, comprises the steps:
(1) weigh a certain amount of hypromellose, make 2% hypromellose cellulose solution with water, place standby；
(2) Entecavir crystal raw material is crossed respectively 100 mesh sieves standby with each adjuvant；
(3) weigh lactose, microcrystalline Cellulose, pregelatinized Starch by recipe quantity, lactose, microcrystalline Cellulose, pregelatinated are formed sediment Powder mix homogeneously, makes mixed accessories；
(4) the Entecavir crystalline compounds of recipe quantity is mixed with sucrose tristearate, then press equal increments method Mix with the mixed accessories described in step (3)；
(5) pelletize with hypromellose aqueous solution soft material, 20 mesh sieves of 2%, be dried at 50～60 DEG C；
(6) dried granule is carried out granulate, then be sufficiently mixed uniformly with the silicon dioxide of recipe quantity, be subsequently filled glue Capsule, obtains entecavir capsule.
Embodiment 10
Entecavir capsule prescription；
The preparation method of Entecavir capsule, comprises the steps:
(1) ethanol of measured amounts, makes the ethanol solution of 70% with water, places standby；
(2) Entecavir crystal raw material is crossed respectively 100 mesh sieves standby with each adjuvant；
(3) weigh mannitol, dextrin, alginic acid by recipe quantity, by mannitol, dextrin, alginic acid mix homogeneously, make mixed Close adjuvant；
(4) the Entecavir crystalline compounds of recipe quantity is mixed with sucrose tristearate, then press equal increments method Mix with the mixed accessories described in step (3)；
(5) with 70% ethanol solution soft material, granulation, 50～60 DEG C be dried；
(6) dried granule is carried out granulate, then be sufficiently mixed uniformly with the magnesium stearate of recipe quantity, be subsequently filled glue Capsule, obtains entecavir capsule.
Experimental example 1
This experimental example is accelerated stability test to the entecavir capsule of embodiment 4, the results are shown in Table 1:
Packaging: polrvinyl chloride solid medicinal stiff sheet, drug packaging aluminium foil, investigation condition: 40 ± 2 DEG C of RH75% of temperature ± 5%
Table 1 accelerated stability test
Conclusion: to the sample of three batches after simulation commercially available back through accelerated test 6 months, every inspection target and 0 Moon detection results contrast, is showed no significant change.
Experimental example 2
This experimental example is that the entecavir capsule to embodiment 4 carries out in vivo test.Concrete grammar is, study subject is 28 Name healthy male volunteer, the age (25 ± 1.5) year, body weight is in (65 ± 3.0) kilogram, and height is at (1.72 ± 0.25) rice. Tested front all volunteers all check UP, and the most every all normal, not used medicine prejudicial to internal organs within half a year, In experimenter before administration 1 month and other any medicines are not taken in whole off-test.24h and experimental period before taking medicine Between prohibit drink tea, quit smoking, wine, and containing caffeine and the beverage of ethanol.According to random dual crossing EXPERIMENTAL DESIGN by 28 health Volunteer is divided into two groups, fasting 12 hours, mined out white blood 5ml before taking medicine morning.
28 experimenters are randomly divided into A, B bis-groups, often organize 14 people, intersect respectively two cycles and take present invention enforcement The entecavir capsule of example 4 and commercially available entecavir capsule, the entecavir capsule of the most oral embodiment of the present invention 4 and city Sell entecavir capsule each 0.5mg, take medicine latter 2 hours and can drink water in right amount, unified feed low fat light diet after 4 hours.Clothes 10min after medicine, 20min, 30min, 45min, 1h, 1.5h, 2h, 3h, 5,8h, 12,24,48,72h adopt at experimenter's upper arm respectively Collection venous blood 5ml, takes blood plasma after being centrifuged, to be measured-80 DEG C of preservations.HPLC-MS/MS is used to measure Entecavir in blood plasma dense Degree.In the period 1, A group experimenter is administered orally the entecavir capsule of the embodiment of the present invention 4, and B group takes commercially available Entecavir Capsule；Being second round after one week, two groups exchange another kind of Entecavir formulation respectively, and same method gathers blood sample.Pass through Detect the comparison of two kinds of preparation blood drug level kinetic parameters, evaluate the bioequivalence of two kinds of preparations.
Use non-chamber dependent form parameter evaluation method, with DAS2.0 pharmacokinetics routine processes plasma drug concentration data and calculate Pharmacokinetic parameters, Cmax, Tmax are practical measurement numerical value.The main pharmacokinetic parameters of two kinds of preparations is shown in Table 2:
Table 2 is administered orally the main pharmacokinetic parameters after entecavir capsule
As can be seen from Table 2, the entecavir capsule of the present invention is absorbing soon in vivo, and keeps treatment for a long time Blood drug level.
Experimental example 3
This experimental example is that the entecavir capsule to embodiment 4 carries out dissolved corrosion contrast with Entecavir tablet listing sample Test.
Take this product each 6 and listing control sample Entecavir tablet 6, respectively according to dissolution method (Chinese Pharmacopoeia Two annex Ⅹ C the second methods of version in 2005), with 0.05mol/L potassium dihydrogen phosphate (PH6.8) 1000ml as dissolution medium, Rotating speed is 50 turns per minute, operates in accordance with the law, and when the 15th, 30,45,60 minutes, draw solution (added equivalent in right amount simultaneously respectively Mutually synthermal dissolution medium), filter, take subsequent filtrate as need testing solution；Separately take Entecavir reference substance appropriate, accurate title Fixed, add 0.05mol/L potassium dihydrogen phosphate and dissolve and dilute the solution made in every 1ml containing about 0.5 μ g, molten as reference substance Liquid.Take above-mentioned need testing solution and each 100 μ l of reference substance solution, inject chromatograph of liquid, record chromatogram, by external standard method with peak Areal calculation goes out stripping quantity, draws stripping curve and sees Fig. 2.Result of the test is shown in Table 3, table 4.
Table 3 entecavir capsule stripping curve result of the test
Table 4 lists sample Entecavir tablet stripping curve result of the test
Test result indicate that: the entecavir capsule of embodiment 4 is fast compared with the dissolution rate of Entecavir tablet listing sample.

Claims (8)

1. an Entecavir crystal, this crystal uses Cu-K α1The X-ray powder diffraction of radionetric survey as shown in Figure 1, 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 ° angle of diffraction 2 θ shows characteristic peak.
2. a preparation method for Entecavir crystal, comprises the steps:
(1) being added by Entikawei solid in the mixed solvent of dimethyl acetylamide and methanol, temperature is the condition of 35～40 DEG C Under, Entikawei solid all dissolves；
(2) control temperature is under conditions of 35-40 DEG C, adds the aqueous solution of isopropanol in the solution that step (1) obtains, its In, in the aqueous solution of isopropanol, the mass percent containing isopropanol is 30%～40%；
(3), after adding the aqueous solution of isopropanol, it is that 2.5～3.5 DEG C/10min is cooled to-10～0 DEG C with speed ,-10～0 DEG C stand 12～20 hours, separate out crystal, filter, filter cake with ether wash, after vacuum drying, obtain Entecavir crystal,
Wherein, in step (1), the volume ratio between dimethyl acetylamide and methanol is 2.0: (1.5～2.0).
The preparation method of Entecavir crystal the most according to claim 2, it is characterised in that in step (1), dimethyl second Volume ratio between amide and methanol is 1.0: 1.0.
4. an Entecavir capsule, it is characterised in that principal agent is the Entecavir crystal described in claim 1, entecavir The content of Wei Jingti is every 0.5mg.
Entecavir capsule the most according to claim 4, it is characterised in that the implant in capsule includes Entecavir Crystal, solubilizing agent, filler, disintegrating agent, lubricant, binding agent.
Entecavir capsule the most according to claim 5, it is characterised in that weight ratio between each component in capsule For:
7. according to the Entecavir capsule described in claim 5 or 6, it is characterised in that solubilizing agent includes sucrose monostearate Ester, sucrose tristearate, polyethylene glycol 6000, poloxamer, hydroxyethyl cellulose, hydroxypropyl cellulose one or both Above mixing；
Described filler include lactose, starch, dextrin, Icing Sugar, calcium sulfate, sucrose, mannitol, microcrystalline Cellulose, glucose, Pregelatinized Starch, one or more mixing of magnesium oxide；
Described disintegrating agent includes carboxymethyl starch sodium, low-substituted hydroxypropyl methylcellulose, starch, microcrystalline Cellulose, crosslinking carboxylic first Base sodium cellulosate, polyvinylpolypyrrolidone, alginic acid, citric acid, polyoxyethylene sorbitan monoleate, glycyl Starch Sodium one or more Mixing；
Described lubricant include silicon dioxide, magnesium stearate, Pulvis Talci, hydrogenated vegetable oil, gel aluminum hydroxide, magnesium oxide, Paraffin, white oil, glycerol, glycine, one or more mixing of glyceryl monostearate；
Described binding agent includes hydroxypropyl cellulose, starch slurry, sodium carboxymethyl cellulose, dextrin, polyvidone, ethyl cellulose Element, one or more mixing of ethanol.
8. a preparation method for the Entecavir capsule described in any one of claim 5～7, comprises the steps:
(1) weigh binder solution, place standby；
(2) the Entecavir crystal of recipe quantity, filler, disintegrating agent, lubricant 100 mesh sieves excessively respectively are taken standby；
(3) filler is mixed homogeneously with the disintegrating agent of recipe quantity, make mixed accessories；
(4) Entecavir crystal and solubilizing agent are mixed, then press the mixed accessories mixing of equal increments method and step (3)；
(5) with binder solution soft material, pelletize, be dried；Baking temperature controls at 50～60 DEG C；
(6) dried granule is carried out granulate, then mix with lubricant, be subsequently filled capsule, obtain Entecavir glue Capsule.
CN201510372885.2A 2015-06-30 2015-06-30 A kind of Entecavir crystalline compounds and capsule preparations thereof Expired - Fee Related CN105001223B (en)

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CN112028890B (en) * 2019-06-03 2023-03-31 鲁南制药集团股份有限公司 Deoxyguanosine analogue crystal form
CN112028889B (en) * 2019-06-03 2023-03-17 鲁南制药集团股份有限公司 Crystal form of deoxyguanosine analogue
CN116650497A (en) * 2022-09-30 2023-08-29 广州帝奇医药技术有限公司 Antiviral pharmaceutical composition and preparation process and application thereof

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CN101693713A (en) * 2009-10-28 2010-04-14 福建广生堂药业有限公司 New crystal system of entecavir, preparation process and medicament application thereof
WO2011046303A2 (en) * 2009-10-12 2011-04-21 Hanmi Holdings Co., Ltd. Novel method for preparing entecavir and intermediate used therein
CN102417506A (en) * 2010-09-27 2012-04-18 杭州赛利药物研究所有限公司 Preparation method of antiviral drug Entecavir
CN103304566A (en) * 2013-07-09 2013-09-18 北京凯因科技股份有限公司 Novel crystalline entecavir
CN103435614A (en) * 2013-08-23 2013-12-11 四川海思科制药有限公司 Entecavir compound

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WO2011046303A2 (en) * 2009-10-12 2011-04-21 Hanmi Holdings Co., Ltd. Novel method for preparing entecavir and intermediate used therein
CN101693713A (en) * 2009-10-28 2010-04-14 福建广生堂药业有限公司 New crystal system of entecavir, preparation process and medicament application thereof
CN102417506A (en) * 2010-09-27 2012-04-18 杭州赛利药物研究所有限公司 Preparation method of antiviral drug Entecavir
CN103304566A (en) * 2013-07-09 2013-09-18 北京凯因科技股份有限公司 Novel crystalline entecavir
CN103435614A (en) * 2013-08-23 2013-12-11 四川海思科制药有限公司 Entecavir compound

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