CN1698623A - Crystalline-free anti-hepatitis B virus drug dispersion composition and pharmaceutical preparations thereof - Google Patents
Crystalline-free anti-hepatitis B virus drug dispersion composition and pharmaceutical preparations thereof Download PDFInfo
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- CN1698623A CN1698623A CN 200510033793 CN200510033793A CN1698623A CN 1698623 A CN1698623 A CN 1698623A CN 200510033793 CN200510033793 CN 200510033793 CN 200510033793 A CN200510033793 A CN 200510033793A CN 1698623 A CN1698623 A CN 1698623A
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Abstract
The invention relates to a stable non-crystal type anti-hepatitis B virus medicine and a non-crystal type polyvinylpyrrolidone-vinyl acetate (PVP-VA 64) dispersion composition and a real preparation method, which comprises a spray drying method and a reduced pressure distillation method. The invention also relates to a pharmaceutical preparation containing the dispersion composition and the use thereof. The anti-hepatitis B virus medicine in the dispersion composition is adefovir dipivoxil, entecavir or a compound of the adefovir dipivoxil and the entecavir. After the amorphous anti-hepatitis B virus medicine is formed into a dispersion composition, the chemical stability and the crystal form stability of the amorphous anti-hepatitis B virus medicine are obviously improved, and the amorphous state can be still maintained after three months under the relative humidity state of 40 ℃/75 percent.
Description
Technical field the present invention relates to the dispersive composition and preparation method thereof of the adjuvant of the anti-hepatic-B virus medicine of stable non-crystalline form and non-crystalline form, comprises spray drying method and distillation under vacuum.Described anti-hepatic-B virus medicine comprises the compound recipe of Entecavir, adefovir ester or these two kinds of medicines.The invention still further relates to pharmaceutical preparation that contains this dispersive composition and uses thereof.
Background technology Entecavir (entecavir or BMS-200475), chemistry is by name: [1S-(1 α, 3 α, 4 β)]-2-amino-1,9-dihydro-9-[4-hydroxyl-3-methylol]-2-methylene cyclopenta]-the 6H-purine-6-one, chemical constitution is as follows:
Entecavir is a kind of IUDR analog that can effectively suppress hepatitis B replication, is used for the treatment of the hepatitis B disease.This medicine hepatitis B virus load and effect of suppressing aspect the virus replication in reducing the patient body is stronger 100 to 1000 times than lamivudine (lamuvidine).United States Patent (USP) (US 5,206,244) discloses the preparation method of Entecavir and the purposes of anti-hepatitis B virus thereof.Synthetic Entecavir method after the improvement is disclosed among file WO98/09964 and the WO04/052310.
File CN1310999 discloses the method that a kind of preparation contains the pharmaceutical preparation of low dosage Entecavir, be by earlier Entecavir and adhesive material being formed aqueous solution, in the mode of spraying or liquid stream this solution calmness is arrived the particle surface of carrier matrix then, heat drying is removed the solvent on the carrier surface, again with other adjuvant such as disintegrating agent and/or mix lubricant, with the powder tablet forming that obtains or be filled in the capsule, used adhesive material is polyvidone and cellulose derivative then.This method complex process, active substance/carrier matrix granule are assembled easily and are not easy to make the good preparation that the activity substance content uniformity distributes.The applicant has applied for Entecavir of non-crystalline form and preparation method thereof (Chinese patent application number: 200410077396.6).
Adefovir ester (adevofir dipivoxil), chemistry is by name: two (oxy acid methyl neopentyl) 9-[(R)-and 2-(phosphonium mesitoyl methoxy) ethyl] adenine.Chemical constitution is as follows:
United States Patent (USP) (US4,724,233 and US4,808,716) discloses the preparation method of lamivudine (PMEA or adevofir) and the purposes of anti-hepatitis B virus thereof.United States Patent (USP) (US 5,663,159 and US 5,792,756) discloses the preparation method of adefovir ester (adevofir dipivoxil) and the purposes of anti-hepatitis B virus thereof.
The medicine of non-crystalline form has better rate of dissolution or higher bioavailability than its crystalline kenel usually, but the medicine of non-crystalline form might be unstable, easily is converted into crystalline kenel.For example the adefovir ester of non-crystalline form not only can be converted into crystalline kenel, and itself is buttery, only makes the preparation that solid-state dispersive composition just can be used for solid pharmaceutical preparation.And the Entecavir of non-crystalline form has stronger water absorption, also easily is converted into crystalline kenel.Be adefovir ester or the Entecavir that makes full use of non-crystalline form, just must slow down or stop the conversion of this crystal formation, one of effective ways are to make the adefovir ester of non-crystalline form or the dispersive composition of Entecavir and adjuvant.
File (CN1502334) has been described the pharmaceutical composition of adefovir ester and Polyethylene Glycol (PEG) or polyvinylpyrrolidone (PVP) briefly.The used strong hydrophilicity carrier of this document is because water content is too high, easily brings out the adefovir ester recrystallization and degrades by the mode of hydrolysis, thereby influence the crystal formation and the chemical stability of adefovir ester.File (CN1557327) discloses heating and has dissolved the method for adefovir ester and Polyethylene Glycol (PEG) and prepare its fused matter, the gained fused matter contains the Polyethylene Glycol of crystalline form, might bring out the adefovir ester recrystallization, and heating when melting altogether the too high meeting of temperature cause the adefovir ester degraded and influence its chemical stability.
The applicant's (Chinese patent application number: 200510032709.0) applied for the adefovir ester of non-crystalline form and solid-state dispersive compositions such as cellulose derivative of non-crystalline form and preparation method thereof.
The present invention relates to use all not description or used polyvinylpyrrolidone-ethylene acetate (PVP-VA64) dispersive composition and the pharmaceutical preparation thereof that prepare hepatitis B virus resisting medicines such as the Entecavir that contains non-crystalline form or adefovir ester of more than one files of quoting and other disclosed file.
Description of drawings
Fig. 1: the X-ray powder diffraction of the dispersive composition of the polyvinylpyrrolidone of the adefovir ester of non-crystalline form and non-crystalline form-ethylene acetic acid (PVP-VA64) ester, (1) is original state, (2) are after three months
Fig. 2: the X-ray powder diffraction of the dispersive composition of the polyvinylpyrrolidone of the Entecavir of non-crystalline form and non-crystalline form-ethylene acetate (PVP-VA64), (1) is original state, (2) are after three months
Fig. 3: the X-ray powder diffraction of the Entecavir of non-crystalline form, (1) are original state, and (2) are after three months
We are surprised to find that now the solid-state dispersive composition of the hepatitis B virus resisting medicine of stable non-crystalline form and the polyvinylpyrrolidone of non-crystalline form-ethylene acetate (PVP-VA64) can be with spray drying method and distillation under vacuum and make summary of the invention.This law technology is simple and practical relatively, and can make stable, highly homodisperse, as to be applicable to useful in preparing drug formulations solid-state dispersive composition.
The outstanding advantage of a technology of the present invention is, uses a kind of high plasticity and adjuvant low water absorbable, i.e. polyvinylpyrrolidone-ethylene acetate (PVP-VA64) prepares the dispersive composition of the hepatitis B virus resisting medicine that contains non-crystalline form.Polyvinylpyrrolidone-ethylene acetate not only slows down hepatitis B virus resisting medicine from there not being the speed that crystalline kenel transforms to crystalline kenel as carrier, hepatitis B virus resisting medicine has also slowed down, the water decomposition speed of lamivudine particularly, thus the chemical stability and the stable crystal form of the hepatitis B virus resisting medicine of non-crystalline form strengthened.
The outstanding advantage of another technology of the present invention is, dispersive composition with hepatitis B virus resisting medicine and polyvinylpyrrolidone-ethylene acetate (PVP-VA64) composition, add other pharmacy acceptable auxiliary, can make the solid-state drug preparation of the activity substance content high homogeneity, stable, as to contain non-crystalline form hepatitis B virus resisting medicine.The content of active component is lower in the preparation of the compound recipe that hepatitis B virus resisting medicine such as adefovir ester, Entecavir or this two kinds of medicines are formed, be generally 0.1-15 milligram/sheet or agent, be difficult to make the solid-state drug preparation of content high homogeneity distribution with the method for simple mixed active component commonly used and carrier.
Hepatitis B virus resisting medicine described in the present invention is adefovir ester, Entecavir or this two kinds of compound recipes that medicine is formed.
Polyvinylpyrrolidone of the present invention-ethylene acetate (PVP-VA64) is also referred to as vinylpyrrolidone-ethylene acetate copolymer.The CTFA name is called N-VinylPyrrolidone/Vinyl AcetateCopolymers or Poly, and (N-VinylPyrrolidone/Vinyl Acetate, CAS is encoded to 25086-89-9.Its K=25-36, mean molecule quantity is about 24,000-50,000.English PVP-VA64 by name, PVP-VA, PVA or Copovidone, its molecular structure is as follows:
Pharmaceutically Chang Yong polyvinylpyrrolidone-ethylene acetate (PVP-VA64) is a kind of synthetic N-vinyl-2-Pyrrolidone-vinylacetic acid ester copolymer, and wherein the polyvinylpyrrolidone part is about 60: 40 with the quantity ratio of ethylene acetate part.This adjuvant has been applied to the preparation of multiple solid dispersion compositions and pharmaceutical preparation.
On the one hand, the invention provides spray drying and two kinds of methods of distilling under reduced pressure of the polyvinylpyrrolidone-ethylene acetate dispersive composition of the hepatitis B virus resisting medicine of the stable non-crystalline form of preparation and non-crystalline form.The dispersive composition of the hepatitis B virus resisting medicine that contains non-crystalline form that is made by these two kinds of methods can keep causing less trimestral stable crystal form in 40 ℃/75% relative humidity environment.
On the other hand, the present invention also provides preparation to contain the pharmaceutical preparation of the dispersive composition of the hepatitis B virus resisting medicine of stable non-crystalline form and the polyvinylpyrrolidone of non-crystalline form-ethylene acetate.
The dispersive composition of the polyvinylpyrrolidone of the hepatitis B virus resisting medicine of the non-crystalline form described in the present invention and non-crystalline form-ethylene acetate is meant the hepatitis B virus resisting medicine that contains the crystalline form below 10% in the solid composite, the hepatitis B virus resisting medicine that preferably contains the crystalline form below 5% most preferably contains below 0.5% or is substantially devoid of the hepatitis B virus resisting medicine of crystalline form.Simultaneously, polyvinylpyrrolidone-ethylene the acetate that contains the crystalline form below 10% in the solid composite, polyvinylpyrrolidone-ethylene the acetate that preferably contains the crystalline form below 5% most preferably contains below 0.5% or is substantially devoid of the polyvinylpyrrolidone-ethylene acetate of crystalline form.
Hepatitis B virus resisting medicine described in the present invention is selected from the compound recipe of adefovir ester, Entecavir or these two kinds of medicines.
The feature of the dispersive composition described in the present invention is, the hepatitis B virus resisting medicine of non-crystalline form is evenly dispersed in the polyvinylpyrrolidone-ethylene acetate of non-crystalline form, the compositions of this high degree of dispersion is not owing to contain the material of crystalline form, and the hepatitis B virus resisting medicine that can not bring out non-crystalline form is converted into crystalline kenel again.For adefovir ester, because the adefovir ester high degree of dispersion of non-crystalline form is in solid-state polyvinylpyrrolidone-ethylene acetate, it can not resemble the adefovir ester of simple non-crystalline form to grease again or be converted into crystalline kenel.This dispersive composition also has free mobility required in the pharmaceutical preparation, crystal formation and chemical stability, characteristics such as high density and the distribution of content of active substance uniformity.So the dispersive composition described in the present invention is suitable to be used to prepare and to contain adefovir ester or the Entecavir various solid-state drug preparations as active substance.
The content of the adefovir ester of crystalline form in the dispersive composition of the adefovir ester of non-crystalline form and the polyvinylpyrrolidone of non-crystalline form-ethylene acetate is measured with X-ray powder diffraction method usually.In like manner, the content also available X-ray powder diffraction method of the Entecavir of crystalline form in the dispersive composition of the Entecavir of non-crystalline form and the polyvinylpyrrolidone of non-crystalline form-ethylene acetate or other adjuvant measured.Because its structure is in amorphous state, the dispersive composition of the polyvinylpyrrolidone of the adefovir ester of non-crystalline form or Entecavir and non-crystalline form-ethylene acetate does not represent any peak shape in its X-line powder diffraction spectrum, only show as smooth curve (seeing accompanying drawing 1-2).Can prove conclusively the dispersive composition that the prepared product of preparation method of the present invention is the adefovir ester of non-crystalline form or the polyvinylpyrrolidone of Entecavir and non-crystalline form-ethylene acetate with X-ray powder diffraction method.
Dispersive composition described in the present invention be meant hepatitis B virus resisting medicine and polyvinylpyrrolidone-ethylene acetate or other adjuvant by a certain percentage homodisperse mix and the compositions formed, in this compositions, the weight ratio of hepatitis B virus resisting medicine and adjuvant is 1: 100-300: 100, preferred 10: 100-150: 100, most preferably 50: 100-100: 100.
Selected adjuvant must be the material of non-crystalline form or the material that is transformed into non-crystalline form with crystalline form among the present invention, proper supplementary material also must be easily to be dissolved in water, methanol, the mixed solvent of ethanol or above optional two kinds of solvents, proper supplementary material also must be pharmaceutically acceptable material.
The adjuvant that is applicable to the Entecavir dispersive composition of preparation non-crystalline form among the present invention comprises polyvinylpyrrolidone-ethylene acetate (PVP-VA64, as Plasdone S-630), polyvinylpyrrolidone (PVPK15, K25, K30, K60 or K90), solid Polyethylene Glycol (PEG4000, PEG 5000, PEG6000 or PEG8000), methylcellulose, carboxymethyl cellulose, ethyl cellulose, hydroxyethyl-cellulose, hydroxypropyl cellulose, hydroxypropyl emthylcellulose (HPMC), glucosan, adjacent benzene two formic acid esters of hydroxypropyl emthylcellulose or maltodextrin.Proper supplementary material also comprises cyclodextrin such as alpha-cyclodextrin and derivant thereof, beta-schardinger dextrin-and derivant thereof such as HP-among the present invention.Preferably polyethylene ketopyrrolidine-ethylene acetate and solid-state poly-second two alcohol.
In the preferred version of the present invention, the adjuvant that is used to prepare the Entecavir dispersive composition of non-crystalline form is polyvinylpyrrolidone-ethylene acetate (PVP-VA64), and its specification is K=25-36, and its mean molecule quantity is 24,000-50,000.
The adjuvant that is used to prepare the adefovir ester dispersive composition that contains non-crystalline form among the present invention is polyvinylpyrrolidone-ethylene acetate (PVP-VA64), and its specification is K=25-36, and mean molecule quantity is 24,000-50,000.
The selected adjuvant for preparing dispersive composition is commercial maybe can make by known method for usefulness among the present invention.
On the one hand, the invention provides the distillation under vacuum of the dispersive composition of the polyvinylpyrrolidone-ethylene acetate of the hepatitis B virus resisting medicine of the stable non-crystalline form of preparation and non-crystalline form or other adjuvant, it is characterized in that may further comprise the steps:
A) polyvinylpyrrolidone of hepatitis B virus resisting medicine initial feed and non-crystalline form-ethylene acetate or other adjuvant all are dissolved in the solvent that is under the heated condition,
B) stir gained solution,
C) under reduced pressure rotary distillation evaporative removal solvent obtains solid matter,
D) vacuum and heating drying solid matter, behind screening or the grinding gained solid matter, further vacuum and heating drying solid matter, and obtain the dispersive composition of the hepatitis B virus resisting medicine of non-crystalline form and the polyvinylpyrrolidone of non-crystalline form-ethylene acetate or other adjuvant.
Normally the adjuvant of hepatitis B virus resisting medicine initial feed crystalline form or that do not have the junction type crystalline state and non-crystalline form is dissolved in and adds in the water of pining for or alcohols solvent, for example in methanol or the ethanol.For adefovir ester, solvent for use is methanol or ethanol, and for Entecavir, solvent for use is water, methanol or ethanol.The concentration of hepatitis B virus resisting medicine be from 1% (bulking value, w/v) compare 20% (weight/volume, w/v, down with) between, preferentially select concentration between 2% to 15%.The concentration of polyvinylpyrrolidone-ethylene acetate or other adjuvant is from 1% (bulking value, w/v) compare 50% (weight/volume, w/v, down together), the preferential concentration of selecting is between 1% to 30%, and the weight ratio of hepatitis B virus resisting medicine and polyvinylpyrrolidone-ethylene acetate or other adjuvant is 1: 100-300: 100, preferred 10: 100-150: 100, most preferably 50: 100-100: 100.Heated solution evaporates all solvents and obtains exsiccant solid with the rotary distillation method under decompression state to fluidized state.Decompression state is meant pressure less than 400mm Hg, and preferential selection pressure is less than 100mm Hg, and most preferably pressure is the 30-80 millimetres of mercury.Last resulting solid matter removes last solvent with dry, use the vacuum pan exsiccator, and thermopnore exsiccator or obtain not having crystalline material with rotary vacuum drier temperature prioritisedly when dry is chosen in 20 and spends to 70 degree (Celsius, down together).Preferred temperature is 20 to 60 degree when coming these materials of drying with vacuum pan, and the preferred time, preferred version was that temperature is spent between 40 degree individual hour of dry about 12-15 35 from 6 hours to 20 hours.Solid behind screening or the mill-drying, further spend between 40 degree again in temperature 35, the about 8-12 of vacuum drying hour, promptly obtain the dispersive composition of the hepatitis B virus resisting medicine of non-crystalline form and the polyvinylpyrrolidone of non-crystalline form-ethylene acetate or other adjuvant.
According to preparation method of the present invention, also can water, the mixed solvent of two kinds of optional solvents is realized in methanol and the alcohol solvent.
According to a preferred realization preparation method of the present invention, can operate according to following steps: initiation material is dissolved in adds the water of pining for, in methanol or alcohol solvent or the wherein any two kinds of mixed solvents, preferably be heated to the boiling point of solvent, under decompression state, evaporate all solvents then with the rotary distillation method, dry gained solid matter under heating (35-45 degree) state grinds the gained solid in the vacuum, at last dry gained solid matter under heating (35-45 degree) state in the vacuum.
According to preparation method of the present invention, earlier hepatitis B virus resisting medicine and polyvinylpyrrolidone-ethylene acetate or other adjuvant are dissolved in the solution of making in the solvent separately respectively, then hepatitis B virus resisting medicine solution is joined in polyvinylpyrrolidone-ethylene acetate or other adjuvant solution, or polyvinylpyrrolidone-ethylene acetate or other adjuvant solution joined in the hepatitis B virus resisting medicine solution, make the mixture solution of hepatitis B virus resisting medicine and polyvinylpyrrolidone-ethylene acetate or other adjuvant.
On the other hand, the present invention further provides the spray drying method of the dispersive composition of the polyvinylpyrrolidone-ethylene acetate (PVP-VA64) of the hepatitis B virus resisting medicine of the stable non-crystalline form of preparation and non-crystalline form or other adjuvant, it is characterized in that may further comprise the steps:
A) the hepatitis B virus resisting medicine parent material all is dissolved in the solvent solvent under the heated condition,
B) stir gained solution,
C) behind the cooling solution, remove solvent with spray drying method and obtain solid matter,
D) vacuum and heating drying solid matter obtains the dispersive composition of the hepatitis B virus resisting medicine of non-crystalline form and the polyvinylpyrrolidone of non-crystalline form-ethylene acetate or other adjuvant.
Usually the polyvinylpyrrolidone of hepatitis B virus resisting medicine initial feed and non-crystalline form-ethylene acetate or other adjuvant are dissolved in the mixed solvent of water in the heating (40-50 ℃) or alcohols solvent such as methanol, ethanol or these two kinds of solvents.For adefovir ester, solvent for use is methanol or ethanol.For Entecavir, solvent for use is water, methanol or ethanol.The concentration of hepatitis B virus resisting medicine be from 1% (bulking value, w/v) compare 35% (weight/volume, w/v, down with) between, preferentially select concentration between 2% to 15%.The concentration of polyvinylpyrrolidone-ethylene acetate or other adjuvant is from 1% (bulking value, w/v) compare 40% (weight/volume, w/v, down together), the preferential concentration of selecting is between 1% to 20%, and the weight ratio of hepatitis B virus resisting medicine and polyvinylpyrrolidone-ethylene acetate or other adjuvant is 1: 100-300: 100, preferred 10: 100-150: 100, most preferably 50: 100-100: 100.After being cooled to 30 ℃, solution carries out spray drying.Used spray dryer can be small-sized or produce in medium-and-large-sized number commonly used.Its operating principle is parallel nozzle spray, flows on same direction as spray product and dry gas.Spray drying gas can be air, inert nitrogen gas, argon or two carbonoxides.Preferred nitrogen is a dry gas.The spray drying inlet temperature is the 125-180 degree, and outlet temperature is the 60-85 degree.Logistics speed is 2 milliliters/second-30 milliliters/second.The further drying of the resulting solid matter of spray drying removes last solvent, use the vacuum pan exsiccator, thermopnore exsiccator or obtain the material of non-crystalline form with rotary vacuum drier temperature prioritisedly when dry is chosen in 20 and spends to 75 degree (Celsius).Preferred temperature is 20 to 60 degree when coming these materials of drying with vacuum pan, and the preferred time, preferred version was that temperature is spent between 40 degree about 12-15 of vacuum drying hour 35 from 6 hours to 20 hours.Dried solid is the dispersive composition of the hepatitis B virus resisting medicine of non-crystalline form and the polyvinylpyrrolidone of non-crystalline form-ethylene acetate or other adjuvant.
We find, by this simple and practical and recursive method, can make the dispersive composition of the hepatitis B virus resisting medicine of uniform solid-state non-crystalline form and the polyvinylpyrrolidone of non-crystalline form-ethylene acetate or other adjuvant.Hepatitis B virus resisting medicine of the present invention comprises the compound recipe of adefovir ester or Entecavir or these two kinds of medicines.
According to preparation method of the present invention, the dispersive composition of the polyvinylpyrrolidone of the hepatitis B virus resisting medicine of non-crystalline form and non-crystalline form-ethylene acetate or other adjuvant can be analyzed with X-ray powder diffraction (X-RPD) method, as described in the accompanying drawing 1-2, the X-ray powder diffraction pattern does not show any peak shape.A kind of feature that this has shown the dispersive composition of the hepatitis B virus resisting medicine of non-crystalline form and the polyvinylpyrrolidone of non-crystalline form-ethylene acetate or other adjuvant has shown simultaneously that also products therefrom is the character that belongs to non-crystalline form.
In the preparation method of the present invention, can use the adefovir ester that makes with any method to initial feed.Can be the adefovir ester of thick or purification, the purity of preferred adefovir ester be greater than 95%, and most preferably the purity of adefovir ester is greater than 98%.Initial feed can be the adefovir ester of any physics kenel, the adefovir ester that comprises non-crystalline form (oily), the adefovir ester of crystalline form, adefovir ester hydrate or solvate, lamivudine ester admixture crystalline form and non-crystalline form, wherein the adefovir ester of crystalline form comprises pure crystal formation 1, crystal formation 2, crystal formation 3, the mixture that crystal formation 4 or crystal formation E or they are formed with any ratio.Above-mentioned various kenel adefovir ester initial feed can be by file US5,663,159, US5,792,756, J.Med.Chem., 1994,19:1857-1864 or US6,451,340 and the file quoted in the method described prepare.
In the preparation method of the present invention, can use thick or pure Entecavir material to initial feed, the purity of preferred Entecavir is greater than 95%, and most preferably the purity of Entecavir is greater than 98%.Can use by file US5,206,244 and file WO98/09964 in the prepared Entecavir material of method described.Initial feed can be the Entecavir of any physics kenel, comprises the Entecavir of non-crystalline form, the Entecavir of crystalline form, Entecavir hydrate or solvate, Entecavir mixture crystalline form and non-crystalline form.Prepare thick or pure hydration Entecavir, but reference paper US 5,206,244 and file WO98/09964.The Entecavir hydrate of preparation crystalline form has description in file WO04/052310.
On the other hand, the present invention also provides preparation to contain the pharmaceutical preparation of the dispersive composition of the hepatitis B virus resisting medicine of stable non-crystalline form and the polyvinylpyrrolidone of non-crystalline form-ethylene acetate (PVP-VA).By prepared dispersive composition among the present invention, the pharmaceutical carrier of adding other can further be processed into various pharmaceutical preparatioies, so the present invention further provides a kind of pharmaceutical preparation of hepatitis B virus resisting medicine of the non-crystalline form that contains effective dose, its form is single as a slice or a pharmaceutical preparation, as powder, tablet and capsule.This single pharmaceutical preparation has multiple, can be the pharmaceutical preparation of oral or injection form.
The dispersive composition of the hepatitis B virus resisting medicine that contains non-crystalline form among the present invention and the polyvinylpyrrolidone of non-crystalline form-ethylene acetate or other adjuvant also can be by the form administration of suction form or external preparation for skin.Dispersive composition among the present invention can be by multiple injection form administration such as intravenous or intramuscular.In addition, the experienced technical staff in the art be it is evident that the pharmaceutical preparation described in the present invention should comprise hepatitis B virus resisting medicine and pharmaceutically acceptable other salt thereof of non-crystalline form.Hepatitis B virus resisting medicine of the present invention is the compound recipe of adefovir ester, Entecavir or these two kinds of medicines.
Contain the pharmaceutical preparation of the dispersive composition of the hepatitis B virus resisting medicine of no crystallization shape kenel and the polyvinylpyrrolidone of non-crystalline form-ethylene acetate or other adjuvant for preparation, selected pharmaceutically acceptable carrier is solid or liquid.
The pharmaceutical preparation of solid kenel comprises powder, tablet, pill, capsule, suppository and dispersible tablet.Solid-state carrier can be one or more materials.These materials can be diluent, flavoring agent, lytic agent, lubricant, suspending agent, binding agent, antiseptic, be used to make the disintegrating agent of tablet or a kind of capsule material of filled type.
For powder, its carrier is a kind of scattered very subtly granular solids, and mixes mutually with dispersed active component subtly.For tablet, the dispersive composition that contains active component mixes mutually with the carrier with sticking and character, is pressed into respective shapes and suitably big or small tablet later on according to certain mixed.
In pharmaceutical preparation, the content of hepatitis B virus resisting medicine is 0.1% to 50% weight ratio.Other suitable carriers comprises magnesium carbonate, magnesium stearate, Talcum, sugar or lactose, pectin, dextrin, starch, gelatin, tragacanthin, methylcellulose, Sodium Tvlose, the wax of LMP or cocoa Adeps Bovis seu Bubali.Tablet, powder, capsule, dispersible tablet, pill and dragee also can be as the solid pharmaceutical preparations of taking with oral form.
For the preparation of tablet, can be by making by compression and molded method with one or more carriers.The production method of compressed tablets is dispersive composition and the binding agent that compresses the active component that exists with powder or particle form with suitable tablet machine.For example, gel, hydroxypropyl emthylcellulose sodium), lubricant, inert excipients, antiseptic and disintegrating agent (pyrrole as Explotab, cross link omits alkane ketone, Sodium Tvlose) or dispersant.The production method of molded tablet is to come the dispersive composition of the molded active component that exists with powder or particle form and the mixture that other inert carrier is formed with suitable moulding machine.Tablet can also be made coated tablet, also can be formulated as slow release or controlled release form.The preparation method of tablet can be further referring to example 4 of the present invention.
Preparation for capsule, after can mixing equably by the dispersive composition of the active component that exists with one or more carriers and powder or particle form, in the capsule shells of the suitable specification of packing into, the preparation method of capsule can be further referring to example 4 of the present invention.
Oral liquid described in the present invention can be by making uniform solution and suspension, for example water or water and third liang of alcoholic solution.Also can make water and poly-third liang of alcoholic solution to injection.This oral liquid can be by conventional method with pharmaceutically acceptable carrier such as suspension reagent: as Pyrusussuriensis (sugar) alcohol slurry, edible fat after cellulose derivative or the hydrogenation, emulsifying agent (as lecithin), nonaqueous carrier and antiseptic (methyl or propyl group ethylbenzene acid esters) prepare.Oral liquid formulations also can contain pigment, sweeting agent and buffer salt.
The oral liquid made from aqueous suspension can prepare with following method: the dispersive composition of active component is soluble in water, add higher material of viscosity such as natural or synthetic glue again, resin, methylcellulose, the suspending agent that hydroxypropyl emthylcellulose sodium etc. are commonly used.
Oral liquid described in the present invention also comprises makes after the uniform dry powder doses reuse water dissolution before use.The preferred single pharmaceutical preparation of pharmaceutical preparation described in the present invention, the preparation of this form can also further divide the single preparation of the active component that is converted into appropriate amount.Single pharmaceutical preparation can be the form that places phial or peace bottle of packing, and it contains a certain amount of pharmaceutical preparation such as tablet, capsule or powder etc.In addition, single pharmaceutical preparation can be tablet, capsule or powder or any dosage form that places packing.
The content of active component is at 0.5 milligram to 100 milligrams among the single pharmaceutical preparation of adefovir ester such as every or every dose, preferred 1 milligram to 20 milligrams, most preferably 5 milligrams to 10 milligrams, and decide according to the intensity of active component and concrete purposes, it is contained in this scope is variable or adjustable.In addition, contain in the pharmaceutical preparation of the adefovir ester of non-crystalline form and the polyvinylpyrrolidone of non-crystalline form-ethylene acetate dispersive composition and also can contain another medical substance that is complementary such as Entecavir or contain other two kinds of medical substances that are complementary such as Entecavir and lamivudine.
The content of active component is variable or adjustable at 0.1 milligram to 10 nanogram ranges among the single pharmaceutical preparation of Entecavir such as every or every dose, preferred 0.2 milligram to 2 milligrams, most preferably 0.5 milligram to 1 milligram, and decide according to the intensity of active component and concrete purposes.In addition, contain in the pharmaceutical preparation of dispersive composition of the Entecavir of non-crystalline form and the polyvinylpyrrolidone of non-crystalline form-ethylene acetate or other adjuvant and also can contain other a kind of medical substance that is complementary such as adefovir ester or contain other two kinds of medical substances that are complementary such as adefovir ester and emtricitabine.
The content of active component is variable or adjustable at 0.1 milligram to 100 nanogram ranges among the single pharmaceutical preparation of Entecavir and adefovir ester compound recipe such as every or every dose, preferred 0.5 milligram to 20 milligrams, most preferably 5 milligrams to 10 milligrams, and decide according to the intensity of active component and concrete purposes.In compound recipe, the weight ratio of Entecavir and adefovir ester is 0.1: 10, preferred 0.5: 10.In addition, contain a kind of medical substance that is complementary such as the lamivudine or the emtricitabine that also can contain other in the pharmaceutical preparation of dispersive composition of the Entecavir of non-crystalline form and the polyvinylpyrrolidone of adefovir ester compound recipe and non-crystalline form-ethylene acetate or other adjuvant.
As previously mentioned, adefovir ester and Entecavir are the highly effective medicines of ucleosides anti-hepatitis virus of new generation (HBV).This medicine has the activity of extremely strong inhibition hbv replication in vivo and in vitro.The activity test of vitro inhibition hbv replication shows that adefovir ester and Entecavir are also effective to the hepatitis B virus (HBV) that the YMDD that suppresses to be produced by lamivudine resistance makes a variation.Therefore, the adefovir ester of non-crystalline form of the present invention or Entecavir dispersive composition and pharmaceutical preparation thereof can be used for anti-hepatitis B virus.
Though described the concrete scheme of the present invention, also should be included within this scope to conspicuous some modification of experienced technical staff in the art or the situation that is equal to.
Following examples are used for illustrating concrete scheme of the present invention, and embodiment does not limit the scope of the invention.
The specific embodiment
The adefovir ester of embodiment 1 preparation non-crystalline form and the Entecavir and the stability thereof of non-crystalline form
Method A: the adefovir ester of 5.0g crystalline form is dissolved in 250 milliliters, is heated in the alcohol solvent of 40-50 degree (Celsius, together following).Behind the gained settled solution cool to room temperature (25-30 degree), come all solution of spray drying with disk (Buchi Model-190 type) and nitrogen, and control inlet temperature be that 119-130 degree outlet temperature is the 50-65 degree, the white grease that makes therefrom is the adefovir ester (4.3g) of non-crystalline form.The adefovir ester of the non-crystalline form that makes pack into (HDFE) in 75 milliliters of plastic bottles, and seal, place 40 degree/75% relative humidity state to keep three months down, the crystalline material that with the naked eye can be observed 55-10% is distributed in the buttery adefovir ester.Show that with high performance liquid chromatogram (HPLC) analysis result 2.5% adefovir ester catabolite is arranged.High performance liquid chromatogram (HPLC) experimental technique is: Alltech C8,150 millimeters * 3.9 millimeters, 5 microns HPLC pillar, earlier with the phosphate buffer eluting of 10% second eyeball/80%pH=6.0 10 minutes, used gradient elution from the 10th minute to 25 minutes, eluent is being increased to the phosphate buffer of 50% second eyeball/50%pH=6.0 during this period of time from the phosphate buffer linearity of 10% second eyeball/80%pH=6.0, keep 20 minutes eluting then again with the phosphate buffer of 50% second eyeball/50%pH=6.0, the bulk analysis time is 45 minutes, and the liquid phase flow is 1.0 a milliliters/per minute.Catabolite and adefovir ester are all with calculated by peak area.Detect with 266nm UV.
Method B: the Entecavir of 5.0g crystalline form is dissolved in 200 milliliters, is heated in the alcohol solvent of 40-50 degree.Behind the gained settled solution cool to room temperature (25-30 degree), come all solution of spray drying with disk (Buchi Model-190 type) and nitrogen, and the control inlet temperature is that the 120-135 degree is (Celsius, down together) outlet temperature is the 50-65 degree, the white solid state material that makes therefrom is the Entecavir (4.5g) of non-crystalline form, shown in Fig. 3-(1), the X-ray powder diffraction has proved that the material that obtains is the Entecavir of non-crystalline form.The Entecavir of the non-crystalline form that makes is packed into (HDFE) in 75 milliliters of plastic bottles, and seal, place 40 degree/75% relative humidity to keep three months, shown in Fig. 3-(2), the Entecavir that the X-ray powder diffraction is observed crystalline form forms.There is 1.8% Entecavir catabolite to form with high performance liquid chromatogram (HPLC) analysis result surface.High performance liquid chromatogram HPLC experimental technique is: Alltech C18,150 millimeters * 4.6 millimeters, 5 microns HPLC pillar, earlier with the phosphate buffer eluting of 5% second eyeball/95%pH=6.0 5 minutes, used gradient elution from the 5th minute to 30 minutes, eluent is being increased to the phosphate buffer of 50% second eyeball/50%pH=6.0 during this period of time from the phosphate buffer linearity of 5% second eyeball/95%pH=6.0, keep 15 minutes eluting then again with the phosphate buffer of 50% second eyeball/50%pH=6.0, the bulk analysis time is 45 minutes, and the liquid phase flow is 1.0 a milliliters/per minute.Catabolite and Entecavir are all with calculated by peak area.Detect with 225nm UV.
The adefovir ester of embodiment 2 preparation non-crystalline forms and the polyvinylpyrrolidone-second of non-crystalline form
The dispersive composition of alkene acetate
Method C: with the adefovir ester of 5.0g crystalline form and the polyvinylpyrrolidone of 10.0g non-crystalline form-ethylene acetate (PVP-VA64, PlasdoneS-630, copovidone, down together) all be dissolved in 250 milliliters, be heated in the alcohol solvent of 50 degree, and continuous agitating solution.The hot solution that makes therefrom further is heated to fluidized state, and (30-80 millimetres of mercury) evaporates all solvents and obtain solid with the rotary distillation method under decompression state.The solid that makes places vacuum to keep 40 degree dry 15 hours.Solid behind the mill-drying is further spent between 40 degree in temperature 35 again, removes solvent, and makes the adefovir ester of non-crystalline form and the dispersive composition (13.2g) of polyvinylpyrrolidone-ethylene acetate in dry about 12 hours.X-ray powder diffraction pattern (accompanying drawing 1-(1)) has proved that products therefrom belongs to the adefovir ester of non-crystalline form and the polyvinylpyrrolidone of non-crystalline form-ethylene acetate dispersive composition.
Method D: the adefovir ester of 5.0g crystalline form and the polyvinylpyrrolidone of 10.0g non-crystalline form-ethylene acetate all are dissolved in 250 milliliters, are heated in the methanol solvate of 50 degree, and continuous agitating solution.Make adefovir ester and the polyvinylpyrrolidone-ethylene acetate or the dispersive composition (13.3g) of non-crystalline form by the described step of method C.
Method E: the adefovir ester of 5.0g oily type and the polyvinylpyrrolidone of 10.0g non-crystalline form-ethylene acetate all are dissolved in 250 milliliters, are heated in the alcohol solvent of 40-50 degree.Behind the gained settled solution cool to room temperature (25-30 degree), come all solution of spray drying with disk (Buchi Model-190 type) and nitrogen, and the control inlet temperature is that the 139-175 degree is (Celsius, down together) outlet temperature is the 65-85 degree, and the white powdery solid that makes therefrom is the adefovir ester and the polyvinylpyrrolidone-ethylene acetate dispersive composition (13.3g) of non-crystalline form.The gained solid places vacuum to keep 40 degree dry 15 hours.X-ray powder diffraction pattern (seeing accompanying drawing 1-(1)) has proved that products therefrom belongs to the adefovir ester of non-crystalline form and the polyvinylpyrrolidone of non-crystalline form-ethylene acetate dispersive composition.The dispersive composition of the non-crystalline form that makes pack into (HDFE) in 75 milliliters of plastic bottles, and seal, place the state of 40 ℃/75% relative humidity to preserve three months down, shown in Fig. 1-(2), adefovir ester has still been kept no crystalline kenel in dispersive composition.Show to have only 0.8% adefovir ester catabolite with high performance liquid chromatogram (HPLC) analysis result.High performance liquid chromatogram (HPLC) experiment condition is referring to the method A of the example among the present invention 1.
The Entecavir of embodiment 3 preparation non-crystalline forms and the polyvinylpyrrolidone-ethylene of non-crystalline form
The dispersive composition of acetate
Method F: the Entecavir of 5.0g crystalline form and the polyvinylpyrrolidone of 10.0g non-crystalline form-ethylene acetate all are dissolved in 200 milliliters, are heated in the alcohol solvent of 50 degree, and continuous agitating solution.The hot solution that makes therefrom further is heated to fluidized state, and (30-80 millimetres of mercury) evaporates all solvents and obtain solid with the rotary distillation method under decompression state.The solid that makes places vacuum to keep 40 degree dry 15 hours.Solid behind the mill-drying is further spent between 40 degree in temperature 35 again, removes solvent, and makes the Entecavir of non-crystalline form and the dispersive composition (13.0g) of polyvinylpyrrolidone-ethylene acetate in dry about 12 hours.X-ray powder diffraction pattern (seeing accompanying drawing 2-(1)) has proved that products therefrom belongs to the Entecavir of non-crystalline form and the polyvinylpyrrolidone of non-crystalline form-ethylene acetate dispersive composition.
Method G: the Entecavir of 5.0g crystalline form and the polyvinylpyrrolidone of 10.0g non-crystalline form-ethylene acetate all are dissolved in 150 milliliters, are heated in the methanol solvate of 50 degree, and continuous agitating solution.Make Entecavir and the polyvinylpyrrolidone-ethylene acetate or the dispersive composition (13.5g) of non-crystalline form by the described step of method F.
Method H: the Entecavir of 5.0g crystalline form and 10.0g all are dissolved in 200 milliliters of polyvinylpyrrolidones-ethylene acetate, are heated in the alcohol solvent of 40-50 degree.Behind the gained settled solution cool to room temperature (25-30 degree), come all solution of spray drying with disk (Buchi Model-190 type) and nitrogen, and the control inlet temperature is that the 142-175 degree is (Celsius, down together) outlet temperature is the 65-80 degree, and the white powdery solid that makes therefrom is the Entecavir and the polyvinylpyrrolidone-ethylene acetate dispersive composition (13.3g) of non-crystalline form.The gained solid places vacuum to keep 40 degree dry 15 hours.X-ray powder diffraction pattern (seeing accompanying drawing 2-(1)) has proved that products therefrom belongs to the Entecavir of non-crystalline form and the polyvinylpyrrolidone of non-crystalline form-ethylene acetate dispersive composition.The dispersive composition of the non-crystalline form that makes is packed into (HDFE) in 75 milliliters of plastic bottles, and seal, places following three months of the state of 40 ℃/75% relative humidity, and as described in Fig. 2-(2), Entecavir has still kept no crystalline kenel in dispersive composition.Show to have only 0.7% Entecavir catabolite with high performance liquid chromatogram (HPLC) analysis result.High performance liquid chromatogram (HPLC) experiment condition is referring to the method B of the example among the present invention 1.
Embodiment 4 preparations contain the pharmaceutical preparation of the Entecavir or the adefovir ester dispersive composition of non-crystalline form
Contain the Entecavir or the adefovir ester dispersive composition of non-crystalline form in order to preparation, add that the prescription of the medicinal tablet of other carrier sees Table one.Contain the Entecavir or the adefovir ester dispersive composition of non-crystalline form in order to preparation, add that the prescription of the medicine capsule of other carrier sees Table two.
Preparation for tablet, it is that the adefovir ester of 10 milligrams and 20 milligrams is three kinds of prescriptions of active component that table one has been enumerated Entecavir that content is 1 milligram of non-crystalline form or content, the A that wherein fills a prescription is that content is the fast-release tablet of 10 milligrams of adefovir esters, prescription B is for content is the fast-release tablet of 1 milligram of Entecavir, and prescription C is the slow releasing tablet of 20 milligrams of adefovir esters for content.The preparation of tablet mainly contained for two steps: the Entecavir of (1) preparation non-crystalline form or the sheet heart layer that adefovir ester is active component; (2) surface covering is modified sheet heart layer and is made coated tablet.Concrete steps are: dispersive composition 60 mesh sieves, other carrier 80 mesh sieves.The material of mesh sieve changes mixer with drum to be mixed 15 minutes with 100rpm speed, made even mixed materials.Make sheet heart layer with the tablet machine tabletting.Sheet heart layer changes tablet surface blanketing machine over to, and lathe is with hot air to 60 degree centigrade, and before the spraying beginning, rotary speed transfers to 5-9rpm, and aerofluxus keeps 40-50 degree centigrade.Dry 5-10 minute of coated tablet behind the surface covering.Tablet is sub-packed in the medicine bottle that contains desiccant, seals up storage.
Table one: contain the Entecavir of non-crystalline form or the tablet formulation of adefovir ester dispersive composition
| Component | Milligram/sheet | ||
| Prescription A | Prescription B | Prescription C | |
| The adefovir ester of non-crystalline form and polyethylene are given a tongue-lashing slightly alkane ketone-ethylene acetate (PVP-VA64, Plasdone S-630, copovidone) dispersive composition | 30 | - | ?60 |
| The Entecavir of non-crystalline form and polyethylene are given a tongue-lashing slightly alkane ketone-ethylene acetate (PVP-VA64, Plasdone S-630, copovidone) dispersive composition | - | 3 | ?- |
| Cellulose (Avicel PH-101/102) | 58 | 70 | ?58 |
| Dried lactose | 15 | - | ?20 |
| Dried | 30 | 40 | ?45 |
| Mannitol | - | 20 | ?- |
| | 2 | 2 | ?2 |
| Surface covering agent (slow releasing tablet), hydroxypropyl emthylcellulose (HPMC) | - | - | ?15 |
| Finishing (fast-release tablet), Virgin's milk is done (opadry white), water * | 5 | 5 | ?- |
| Total amount | 140 | 140 | ?200 |
* evaporate in the preparation process
Preparation for capsule, table two has been enumerated the Entecavir of non-crystalline form or the adefovir ester prescription as three kinds of capsules of active component, the A that wherein fills a prescription is the capsule of releasing for 10 milligrams of adefovir ester speed of content, prescription B is for content is the quick-release capsules agent of 1 milligram of Entecavir, and prescription C is that content is the slow releasing capsule of 20 milligrams of adefovir esters.The preparation of capsule mainly contains following steps: dispersive composition 60 mesh sieves, other carrier 80 mesh sieves.The material of mesh sieve changes mixer with drum to be mixed 15 minutes with 100rpm speed, obtained even mixed materials.To the quick-release capsules agent, mix table two: contain the Entecavir of non-crystalline form or the capsule prescription of adefovir ester dispersive composition
| Component | Milligram/grain | ||
| Prescription A | Prescription B | Prescription C | |
| The adefovir ester of non-crystalline form and polyethylene are given a tongue-lashing slightly alkane ketone-ethylene acetate (PVP-VA64, Plasdone S-630, copovidone) dispersive composition | 30 | - | ?60 |
| The Entecavir of non-crystalline form and polyethylene are given a tongue-lashing slightly alkane ketone-ethylene acetate (PVP-VA64, Plasdone S-630, copovidone) dispersive composition | - | 3 | ?- |
| Cellulose (Avicel PH-101/102) | 70 | 97 | ?100 |
| Dried lactose | 20 | - | ?20 |
| Dried starch | 51 | 51 | ?51 |
| Mannitol | - | 20 | ?- |
| Pulvis Talci | 4 | 4 | ?4 |
| Ball sheet surface covering (slow releasing tablet), and hydroxypropyl emthylcellulose (HPMC, E50/K50) | - | - | ?15 |
| Total amount | 175 | 175 | ?250 |
The compound material is directly packed in the examples of suitable shell.To slow releasing capsule, mixed material is further made the ball sheet, the ball sheet with ball tablet surface blanketing machine with carrying out surface covering (coating).Ball sheet behind the surface covering is packed into after dry 5-10 minute in the examples of suitable shell.Capsule subpackage is sealed up storage in the medicine bottle that contains desiccant.
The Entecavir of embodiment 5 preparation non-crystalline forms and the dispersive composition of cellulose or cyclodextrin
Method I: the Entecavir of 3.0g crystalline form and the hydroxypropyl emthylcellulose (HPMC) of 10.0g non-crystalline form all are dissolved in 200 milliliters, are heated in second alcohol and water (1: 1, the volume ratio) solvent of 40-50 degree.Behind the gained settled solution cool to room temperature (25-30 degree), come all solution of spray drying with disk (Buchi Model-190 type) and nitrogen, and the control inlet temperature is the 145-165 degree, outlet temperature is the 75-89 degree, obtains Entecavir and hydroxypropyl cellulose dispersive composition (12.2g) that white powdery solid is non-crystalline form therefrom.The gained solid places vacuum to keep 40 degree dry 15 hours.Products therefrom is the Entecavir of non-crystalline form and the hydroxypropyl cellulose dispersive composition of non-crystalline form.
Method J: the Entecavir of 3.0g crystalline form and the HP-of 10.0g non-crystalline form all are dissolved in 200 milliliters, be heated to the second alcohol and water (3: 1 of 40-50 degree, volume ratio) in the solvent, makes the Entecavir of non-crystalline form and the HP-dispersive composition (11.5g) of non-crystalline form by the described step of method I.Products therefrom is the adefovir ester of non-crystalline form and the HP-dispersive composition of non-crystalline form.
The Entecavir of embodiment 6 preparation non-crystalline forms and the dispersive composition of poly-second two alcohol
Method K: the Entecavir of 3.0g crystalline form and the Polyethylene Glycol of 10.0g non-crystalline form (PEG 6000) all are dissolved in 200 milliliters, are heated in second alcohol and water (1: 1, the volume ratio) solvent of 40-50 degree.Behind the gained settled solution cool to room temperature (25-30 degree), come all solution of spray drying with disk (Buchi Model-190 type) and nitrogen, and the control inlet temperature is the 155-175 degree, outlet temperature is the 75-89 degree, obtains Entecavir and hydroxypropyl cellulose dispersive composition (12.0g) that white powdery solid is non-crystalline form therefrom.The gained solid places vacuum to keep 40 degree dry 15 hours.Products therefrom is the Entecavir of non-crystalline form and the Polyethylene Glycol of non-crystalline form (PEG6000) dispersive composition.
Claims (17)
1. the dispersive composition of an adefovir ester and polyvinylpyrrolidone-ethylene acetate, it is characterized in that adefovir ester and polyvinylpyrrolidone-ethylene acetate are non-crystalline forms in the dispersive composition, wherein the weight ratio of adefovir ester and polyvinylpyrrolidone-ethylene acetate is 1: 100-300: 100.
2. the preparation method of a dispersive composition according to claim 1 is characterized in that may further comprise the steps:
A) adefovir ester and polyvinylpyrrolidone-ethylene acetate all are dissolved in the methanol or ethanol or this two kinds of mixed solvents that is under the heated condition, agitating solution is to even, b) obtain solid matter with the distillation under vacuum solvent evaporated, c) after the vacuum and heating drying, the abrasive solid material, d) solid matter after further vacuum and heating drying is ground, and make the dispersive composition of the adefovir ester of non-crystalline form and the polyvinylpyrrolidone of non-crystalline form-ethylene acetate.
3. the preparation method of a dispersive composition according to claim 1 is characterized in that may further comprise the steps:
A) adefovir ester and polyvinylpyrrolidone-ethylene acetate all are dissolved in the methanol or ethanol or this two kinds of mixed solvent solvents that is under the heated condition, agitating solution is to even, b) behind the cooling solution, remove solvent with spray drying method and obtain solid matter, c) vacuum and heating drying solid matter, and make the adefovir ester of non-crystalline form and the polyvinylpyrrolidone of non-crystalline form-ethylene acetate dispersive composition.
4. according to the preparation method of claim 2 or 3 described dispersive compositions, used polyvinylpyrrolidone-ethylene acetate is PVP-VA64, and K=25-35, mean molecule quantity are 24,000-50,000.
5. the dispersive composition of Entecavir and adjuvant is characterized in that Entecavir and adjuvant are non-crystalline forms in the dispersive composition, and wherein the weight ratio of Entecavir and adjuvant is 1: 100-300: 100.
6. the preparation method of a dispersive composition according to claim 5 is characterized in that may further comprise the steps:
A) Entecavir and adjuvant all are dissolved in the solvent that is under the heated condition, agitating solution is to even, b) obtain solid matter with the distillation under vacuum solvent evaporated, c) after the vacuum and heating drying, the abrasive solid material, d) solid matter after further vacuum and heating drying is ground, and make the Entecavir of non-crystalline form and the adjuvant dispersive composition of non-crystalline form.
7. the preparation method of a dispersive composition according to claim 5 is characterized in that may further comprise the steps:
A) Entecavir and adjuvant all are dissolved in the solvent that is under the heated condition, agitating solution is to even, b) behind the cooling solution, remove solvent with spray drying and obtain solid matter, c) vacuum and heating drying solid matter and make the Entecavir of non-crystalline form and the adjuvant dispersive composition of non-crystalline form.
8. according to the preparation method of claim 6 or 7 described dispersive compositions, it is characterized in that used solvent is the mixed solvent of two kinds of solvents optional in methanol, second alcohol and water or these solvents.
9. claim 5,6 or 7 described adjuvants are polyvinylpyrrolidone-ethylene acetate, solid-state Polyethylene Glycol, methylcellulose, carboxymethyl cellulose, ethyl cellulose, hydroxyethyl-cellulose, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, hydroxypropyl cellulose phthalate or HP-.
10. the described adjuvant of claim 5,6 or 7 is polyvinylpyrrolidone-ethylene acetate, PVP-VA64, and K=25-35, mean molecule quantity are 24,000-50,000.
11. according to claim 2, the preparation method of 3,6 or 7 described dispersive compositions is characterized in that used vacuum and heating drying temperature is 35-50 ℃.
12. dispersive composition according to claim 1 or 5 is characterized in that Entecavir or adefovir ester can keep trimestral no crystalline kenel in dispersive composition under 40 ℃/75% relative humidity state.
13. one kind contains the pharmaceutical preparation that right requires 1 described dispersive composition, it is characterized in that containing adefovir ester and other pharmaceutically acceptable carrier of 1 milligram to 100 milligrams.
14. one kind contains the pharmaceutical preparation that right requires 5 described dispersive compositions, it is characterized in that containing Entecavir and other pharmaceutically acceptable carrier of 0.1 milligram to 10 milligrams.
15., it is characterized in that powder, tablet, suppository, pill, dragee, capsule, dispersible tablet, injection and oral liquid according to claim 13 or 14 described pharmaceutical preparatioies.
16. claim 1 or 5 described dispersive compositions in the viral hepatitis b disease is cured the disease in preparation as the purposes of medicine.
17. claim 13 or 14 described pharmaceutical preparatioies in the viral hepatitis b disease is cured the disease in preparation as the purposes of medicine.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2010032958A3 (en) * | 2008-09-17 | 2010-06-24 | 씨제이제일제당 (주) | Stabilized solid dispersion of adefovir dipivoxil and preparation method thereof |
| WO2012079035A1 (en) * | 2010-12-10 | 2012-06-14 | Sigmapharm Laboratories, Llc | Highly stable compositions of orally active nucleotide analogues or orally active nucleotide analogue prodrugs |
| CN102552920A (en) * | 2012-02-20 | 2012-07-11 | 北京协和药厂 | Entecavir-containing medicinal composition and preparation method thereof |
| CN102908312A (en) * | 2011-11-10 | 2013-02-06 | 陈小花 | Liquid combination for resisting hepatitis B viruses |
| 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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- 2005-03-30 CN CN 200510033793 patent/CN1698623A/en active Pending
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2010032958A3 (en) * | 2008-09-17 | 2010-06-24 | 씨제이제일제당 (주) | Stabilized solid dispersion of adefovir dipivoxil and preparation method thereof |
| WO2012079035A1 (en) * | 2010-12-10 | 2012-06-14 | Sigmapharm Laboratories, Llc | Highly stable compositions of orally active nucleotide analogues or orally active nucleotide analogue prodrugs |
| CN103338754A (en) * | 2010-12-10 | 2013-10-02 | 西格玛制药实验有限责任公司 | Highly stable compositions of orally active nucleotide analogs or orally active nucleotide analog prodrugs |
| JP2014502597A (en) * | 2010-12-10 | 2014-02-03 | シグマファーム ラボラトリーズ エルエルシー | Highly stable compositions of orally active nucleotide analogs or orally active nucleotide analog prodrugs |
| CN104666315A (en) * | 2010-12-10 | 2015-06-03 | 西格玛制药实验有限责任公司 | Highly stable compositions of orally active nucleotide analogues or orally active nucleotide analogue prodrugs |
| RU2606845C2 (en) * | 2010-12-10 | 2017-01-10 | СИГМАФАРМ ЛЭБОРЭТОРИЗ, ЭлЭлСи | Highly stable compositions of orally active nucleotide analogues or orally active nucleotide analogue prodrugs |
| US9622967B2 (en) | 2010-12-10 | 2017-04-18 | Sigmapharm Laboratories, Llc | Highly stable compositions of orally active nucleotide analogues or orally active nucleotide analogue prodrugs |
| AU2011338162B2 (en) * | 2010-12-10 | 2017-06-15 | Sigmapharm Laboratories, Llc | Highly stable compositions of orally active nucleotide analogues or orally active nucleotide analogue prodrugs |
| CN102908312A (en) * | 2011-11-10 | 2013-02-06 | 陈小花 | Liquid combination for resisting hepatitis B viruses |
| CN102552920A (en) * | 2012-02-20 | 2012-07-11 | 北京协和药厂 | Entecavir-containing medicinal composition and preparation method thereof |
| CN102552920B (en) * | 2012-02-20 | 2014-01-29 | 北京协和药厂 | Entecavir-containing medicinal composition and preparation method thereof |
| 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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