CN101385732A - Low dose entecavir formulation and use - Google Patents
Low dose entecavir formulation and use Download PDFInfo
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- CN101385732A CN101385732A CNA2008101492879A CN200810149287A CN101385732A CN 101385732 A CN101385732 A CN 101385732A CN A2008101492879 A CNA2008101492879 A CN A2008101492879A CN 200810149287 A CN200810149287 A CN 200810149287A CN 101385732 A CN101385732 A CN 101385732A
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Abstract
Compositions containing a low dose of entecavir are administered on a daily basis to treat hepatitis B virus infection and/or co-infections. Formulations for the oral administration of a low dose of entecavir are provided. Other pharmaceutically active substances can be included in the entecavir composition or can be separately administered for the treatment of hepatitis B virus infection or for the treatment of co-infected patients.
Description
The application is that the application number submitted on August 29th, 2000 is dividing an application of 00126403.6 the patent application that is entitled as " low dose entecavir preparation and application thereof ".
Technical field
The present invention relates to the purposes that entecavir is used to prepare medicine, be suitable for oral tablet and capsule in particular for preparation.
Entecavir (Entecavir), [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,
Be the antiviral agent that is used for the treatment of hepatitis B virus infection, carrying out clinical evaluation at present.
Background technology
People such as Zahl er disclose the application of entecavir and treatment hepatitis B thereof in United States Patent (USP) 5206244.Effective antiviral dosage of the oral or parenteral introduction of this patent disclosure is about 1.0-50mg/kg body weight, and this required dosage can reasonable time interval administration every day several.
People such as Bisacchi disclose the method for improved synthetic entecavir in WO 98/09964.
Summary of the invention
The present invention relates to contain the pharmaceutical composition of low dose entecavir and the application that this class low dose group compound is used for safe and effective treatment hepatitis B virus infection.
The invention still further relates to the entecavir of low dosage and the method for the active compound combined treatment hepatitis B virus infection of other drug.Other materials that are fit to this purpose comprise other antiviral agent and/or immunomodulator.Entecavir and one or more other drug active substances can be combined in in a kind of dosage form or can be separately independently dosage form plan administration simultaneously or sequentially according to prescription.
The invention still further relates to the pharmaceutical composition for oral administration that contains the low-dose drugs active substance.Said composition is to obtain by the surface that the granule that makes pharmaceutically active substance adheres to carrier matrix.Making the method for pharmaceutically active substance calmness on carrier matrix is in order to make active substance/carrier matrix agglomeration of particles be reduced to minimum.
The present invention relates to contain the pharmaceutical composition of the about 25mg low dosage of 0.001mg-antiviral agent entecavir of having an appointment, said composition is administered once and is used for the treatment of the hepatitis B virus infection of adult patient every day.Preferred pharmaceutical composition contains the entecavir of the about 10mg of 0.01mg-that has an appointment, and most preferred pharmaceutical composition contains the about 5mg entecavir of the 0.01-that has an appointment.And this class preferably is administered once with most preferred pharmaceutical composition and is used for the treatment of the hepatitis B virus infection of adult patient every day.
The term adult patient be defined as the age be about more than 16 years old or 16 years old and body weight be equal to or higher than 50 kilograms patient.The pharmaceutical composition that contains the low entecavir of limiting the quantity of of above-mentioned scope is suitable for child patient or body weight are lower than patient's administration of 50 kilograms.
The above-mentioned low dose entecavir pharmaceutical composition that is used for administration every day also can be not too regularly to some patient's administration.For example, to treating the controlled patient of hepatitis B virus infection who makes them and can implement and keep therapeutic scheme so that it avoids further infection by taking the low dose entecavir pharmaceutical composition every day.This therapeutic scheme of keeping comprises that every day, deficiency was once taken the low dose entecavir compositions.For example, be administered once or be administered once weekly in per three or four days with regard to it is enough.
Low dose entecavir pharmaceutical composition of the present invention can be mixed with the form through any suitable administration.For example the preferred oral administration compositions can be tablet, capsule, granule or powder type, perhaps can be elixir, solution or form of suspension.According to method well known in the art, the low dose entecavir pharmaceutical composition also can be mixed with the form of non-gastrointestinal, rectum or via intranasal application administration.This class preparation can comprise pharmaceutically acceptable excipient, and described excipient comprises extender commonly used in this based composition, lubricant, disintegrating agent, binding agent etc.The present invention also comprises slow releasing preparation.
Unexpectedly find now, take once low dose entecavir pharmaceutical composition of the present invention every day and can treat hepatitis B virus infection effectively, and can not be created in the harmful side effect that the high dose scheme administration described in the United States Patent (USP) 5206244 brings.
The invention still further relates to the method for uniting one or more other drug active substance treatment hepatitis B virus infections with above-mentioned low dose entecavir compositions.The other drug active substance that is suitable for this purpose comprises one or more antiviral agent, didanosine for example, lamivudine, abacavir, adefovir, adefovir dipivoxil, famciclovir, (2R, 4R)-4-(2,6-diaminourea-9H-purine-9-yl)-2-methylol-1,3-dioxolanes (DPAD), hepatitis B immune is regulated albumen (EHT 899 of Enzo Biochem), emtricitabine, 1-(2-deoxidation-2-fluoro-beta-D-arabinofuranosyl base) thymus pyrimidine (FMAU), GLQ-223 (compd A. α-trichosanthin), epvudine (L-dT), epcitabine (L-dC), ribavirin, tenofovir (PMPA), 2 ', 3 '-dideoxy-2 ', 3 '-two dehydrogenations-β-L (-)-5-fluorine cytidine [L (-) Fd4C], and other fluoro L-and D-nucleoside.The pharmaceutically active substance that is suitable for this purpose also comprises one or more immunomodulators, for example alpha-interferon, beta-interferon, pegylated interferon, alpha-Thymosin and Hepatitis B virus vaccine, for example HBV/MF59, Hepagene and Theradigm-HBV.
When the other drug active substance was suitable for oral administration, they can combine tablet or the capsule that forms single dose with low dose entecavir.If one or more other drug active substances can not with the entecavir compatibility be combined in in a kind of dosage form, for example, if if administering mode is different or the administration frequency difference, then one or more other pharmaceutically active substance can be individually dosed.The dosage of one or more other active substances be its separately treatment usual amounts or decide the minimizing consumption by the doctor of treatment.Independently dosage form can be planned administration simultaneously or sequentially according to prescription.
The present invention also comprises the method with above-mentioned low dose entecavir combination treatment accompanying infection patient.The accompanying infection patient is except that infecting hepatitis B virus, also suffers from other the infecteds viral or the non-viral disease.Especially, this class Therapeutic Method can be used for the hepatitis B patient of accompanying infection hepatitis C or HIV.This accompanying infection patient preferably uses above-mentioned low dose entecavir compositions and the active compound combined treatment of one or more above-mentioned other drugs.The patient of for example concurrent hepatitis B and hepatitis C also should use the low dose entecavir compositions to treat except that using ribavirin and interferon treat.
On the other hand, the present invention is the pharmaceutical composition that content is less than or equal to about 10mg entecavir, especially tablet and capsular preparation method.This based composition is not by making evenly good preparation of content with active substance and mixed with excipients simply.Traditional method of granulating also is unsuitable for the biologically active prod of low dosage like this.
The tablet and the capsule preparations that contain the about 10mg entecavir of the 0.001mg-that has an appointment can be prepared according to following method, with efficient and the good homogeneous of guaranteeing product.At first the entecavir calmness is prepared compositions to the surface of carrier matrix.This step is finished by following operation: form the solution of entecavir and adhesive material, use this solution in the mode of spraying or liquid stream then when the carrier matrix granule keeps motion.Controlled condition is so that agglomeration of particles drops to minimum.Subsequently, except that desolvating, be left to adhere to the entecavir on carrier matrix surface from carrier surface.This has prevented that entecavir from separating with substrate and make the loss of entecavir drop to minimum in operation subsequently.
After the drying, with any other composition that comprises in the carrier matrix granule of entecavir coating and the compositions, for example disintegrating agent and/or mix lubricant.Then with the powder tablet forming that obtains or be filled in the capsule.
During spray step, make the carrier matrix granule keep motion by mechanical agitation or air-flow stirring.In the mechanical agitation method, carrier matrix is put into machinery (high shear) blender stir.The solution that will contain entecavir and adhesion substance is sprayed on the carrier matrix granule under atomizing pressure (0-2 crust) with the speed of controlling.For making entecavir maximum ground calm to carrier, spray round carrier guaranteeing in the position of adjusting sprayer unit.Speed that control is calm and spray pattern are so that agglomeration of particles drops to minimum.In case contain the solution of entecavir on the calmness, in exsiccator, pan dryer or fluidized bed dryer all are suitable for wet entecavir/carrier matrix transfer of granules.Remove at elevated temperatures and desolvate.When solvent was water or the water of regulating pH, suitable temperature was about 50 ℃-Yue 80 ℃.
In the air-flow stirring means, carrier matrix is put into the tube that the bottom has fine ga(u)ge screen.The air-flow that adjusting enters is so that the motion of matrix granule keeps constant and mobile.The balance carrier mass makes it reach about 25 ℃-Yue 80 ℃.The solution that will contain entecavir and adhesive material is being sprayed on the carrier matrix granule under the above-mentioned atomizing pressure with control speed.Having, sprays round carrier guaranteeing in the position of adjusting sprayer unit again, and the calm speed of control is so that agglomeration of particles drops to minimum.In case the calm entecavir solution of going up desolvates the temperature rising to remove.When solvent was water or the water of regulating pH, suitable temperature was about 50 ℃-Yue 80 ℃.In the air-flow stirring means, the entecavir calmness on the carrier matrix and remove the two steps operation desolvate and can carry out, but in the mechanical agitation method, is then needed two kinds of devices in same device.
Said method also has and reduces contacting of operator and entecavir in the facility environment.
Though what top method was described is the preparation of drug combination that contains the about 10mg entecavir of about 0.005mg-, they also can be used for preparing the pharmaceutical composition that contains any soluble agents active substance of low dosage.
Preferred solvent in the said method is water or the water of regulating pH.Can be by adding acid, for example the pH of hydrochloric acid reduction water improves the dissolubility of entecavir in water.
Adhesive material preferably has the polymer of high-consistency.The material that is fit to comprises polyvidone, methylcellulose, hydroxy methocel, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl-cellulose, gelatin, guar gum and xanthan gum, and polyvidone is preferred.The content of adhesive material is preferably about 10% (weight) of about 1%-of compositions gross weight in the whole compositions.
Carrier matrix is to be easy to by spray coating and to be difficult for accumulative pharmaceutically useful material.The material that is fit to comprises microcrystalline Cellulose, calcium phosphate, dextrin, glucose, dextrates, mannitol, sorbitol and sucrose, and microcrystalline Cellulose is preferred.The content of carrier mass is preferably about 95% (weight) of about 80%-of compositions gross weight in the whole compositions.
The disintegrant content that comprises in the whole compositions is preferably about 1%-about 7% of compositions gross weight.The disintegrating agent that is fit to comprises polyvinylpolypyrrolidone, cross-linked carboxymethyl cellulose, Explotab, pre-gelatinized starch and corn starch, and polyvinylpolypyrrolidone is preferred.
The lubricant content that comprises in the whole compositions is preferably about 0.1%-about 5% of compositions gross weight.The disintegrating agent that is fit to comprises magnesium stearate, stearic acid, stearyl fumarate and sodium lauryl sulfate, and magnesium stearate is preferred.
The tablet of gained or capsule can be the film coatings, so that take.The suitable material that is used for the film coating is polymeric coating materials, pigment, plasticizer, solubilizing agent etc.The coating materials that is fit to comprises hydroxypropyl methylcellulose, hydroxyethyl-cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose phthalate etc.Also can comprise Polyethylene Glycol in the film coated composition as plasticizer.Also can use other plasticizer in the film coated composition, for example citric acid diethylester and triethyl citrate.Suitable solubilizing agent comprises polyoxyethylene sorbitan carboxylic ester, especially polysorbate80.Suitable pigment comprises titanium dioxide and various ferrum oxide.
Composition in the coated composition is dispersed in The suitable solvent, in the preferred water.Coated composition can adopt conventional pan coating or spray coating technology to be used for tablet or capsule.
The specific embodiment
The following example illustrates low dose entecavir compositions of the present invention.
Embodiment 1
Adopt method for preparing 10 microgram entecavir tablets.
| Composition | Amount % (w/w) | Amount/sheet |
| Entecavir | 0.01 | 0.01mg |
| Microcrystalline Cellulose, NF | 93.24 | 93.24mg |
| Polyvinylpolypyrrolidone, NF | 4.00 | 4.00mg |
| Polyvidone, USP | 2.50 | 2.50mg |
| Magnesium stearate, NF | 0.25 | 0.25mg |
| Pure water, USP * | In right amount | --- |
| Amount to | 100.00 | 100.00mg |
* remove by drying.
Embodiment 2
Adopt 10 milligrams of entecavir capsules of method for preparing.
| Composition | Amount % (w/w) | Amount/piece |
| Entecavir | 10.00 | 10.00mg |
| Microcrystalline Cellulose, NF | 82.03 | 82.03mg |
| Polyvinylpolypyrrolidone, NF | 4.00 | 4.00mg |
| Polyvidone, USP | 2.50 | 2.50mg |
| Magnesium stearate, NF | 0.25 | 0.25mg |
| Hydrochloric acid | 1.22 | 1.22mg |
| Pure water, USP * | In right amount | --- |
| Amount to | 100.00 | 100.00mg |
Capsule shells----
* remove by drying.
Embodiment 3
Adopt method for preparing 50 microgram entecavir capsules.
| Composition | Amount % (w/w) | Amount/piece |
| Entecavir | 0.05 | 0.05mg |
| Dicalcium phosphate, NF | 93.20 | 93.20mg |
| Polyvinylpolypyrrolidone, NF | 4.00 | 4.00mg |
| Hydroxypropyl cellulose, NF | 2.50 | 2.50mg |
| Magnesium stearate, NF | 0.25 | 0.25mg |
| Pure water, USP * | In right amount | --- |
| Amount to | 100.00 | 100.00mg |
Capsule shells----
* remove by drying.
Embodiment 4
Adopt 1 milligram of entecavir tablet of method for preparing.
| Composition | Amount % (w/w) | Amount/sheet |
| Entecavir | 1.00 | 1.00mg |
| Mannitol, NF | 90.00 | 90.00mg |
| Cross-linking sodium carboxymethyl cellulose, NF | 4.00 | 4.00mg |
| Methylcellulose, NF | 2.50 | 2.50mg |
| Stearic acid, NF | 2.50 | 0.25mg |
| Pure water, USP * | In right amount | --- |
| Amount to | 100.00 | 100.00mg |
* remove by drying.
Embodiment 5
Adopt conventional pan coating or spray coating technology to carry out the film coating to the 100mg tablet that contains the 0.01mg entecavir of embodiment 1 and the 100mg tablet that contains the 1.0mg entecavir of embodiment 4 with the compositions of listing below.
* remove by drying.
1Suppose with sheet heavily to be that 100mg calculates.
2Suitable plasticizer is citric acid diethylester and triethyl citrate.
Embodiment 6
Human patients to chronic hbv-infection gives 28 days entecavir, with at random, the safety and the antiviral activity of double blinding, placebo, dose titration test method research entecavir.Under all test doses, entecavir all demonstrates effective antiviral activity.Take dose every day respectively and be 0.05,0.1,0.5 and 1.0mg entecavir medicament, the average logarithm of the hepatitis B virus DNA level in the time of the 28th day in the blood reduces and is respectively 2.21,2.25,2.81 and 2.42.Entecavir is easy to the tolerance into the patient.
Claims (34)
1, a kind of administration frequency is once a day or is less than the pharmaceutical composition that once is used for the treatment of hepatitis B virus infection and/or accompanying infection, contains pharmaceutically suitable carrier and the about 25mg entecavir of about 0.001mg-.
2, the compositions of claim 1, the content of wherein said entecavir is the about 10mg of about 0.01mg-.
3, the compositions of claim 1, the content of wherein said entecavir is the about 5mg of about 0.01mg-.
4, the compositions of claim 3, the content of wherein said entecavir is about 0.01mg.
5, the compositions of claim 3, the content of wherein said entecavir is about 0.05mg.
6, the compositions of claim 3, the content of wherein said entecavir is about 0.1mg.
7, the compositions of claim 3, the content of wherein said entecavir is about 0.5mg.
8, the compositions of claim 3, the content of wherein said entecavir is about 1.0mg.
9, the compositions of claim 1 is tablet or capsule form.
10, the compositions of claim 1 contains one or more other drug active substances.
11, a kind of oral drug preparation of low dose entecavir contains the about 10mg entecavir of the about 0.001mg-that is adhered to carrier matrix.
12, the compositions of claim 11, wherein said carrier matrix is selected from microcrystalline Cellulose, calcium phosphate, dextrin, glucose, dextrates, mannitol, sorbitol and sucrose, and described entecavir adheres on the described substrate by having viscous enough polymeric adhesive material.
13, the compositions of claim 12, wherein said stickum is selected from polyvidone, methylcellulose, hydroxy methocel, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl-cellulose, gelatin, guar gum and xanthan gum.
14, the compositions of claim 11 comprises lubricant and disintegrating agent.
15, the compositions of claim 14, wherein said lubricant is magnesium stearate, stearic acid, stearyl fumarate, sodium lauryl sulfate, and described disintegrating agent is selected from polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose, Explotab, pre-gelatinized starch and corn starch.
16, a kind of combination of oral medication of low dose entecavir, contain by entecavir, lubricant and the disintegrating agent of stickum coating to the carrier matrix, wherein:
The content of described entecavir is that about 0.001-of described composition weight is about 10%,
The content of described stickum is that about 1-of described composition weight is about 10%,
The content of described carrier is that about 80-of described composition weight is about 95%,
The content of described disintegrating agent is about 1-about 5% of described composition weight.
The content of described lubricant is about 0.1-about 5% of described composition weight.
17, the compositions of claim 16, wherein said stickum is selected from polyvidone, methylcellulose, hydroxy methocel, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl-cellulose, gelatin, guar gum and xanthan gum,
Described carrier matrix is selected from microcrystalline Cellulose, calcium phosphate, dextrin, glucose, dextrates, mannitol, sorbitol and sucrose,
Described disintegrating agent is selected from polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose, Explotab, pre-gelatinized starch and corn starch, and
Described lubricant is selected from magnesium stearate, stearic acid, stearyl fumarate and sodium lauryl sulfate.
18, the compositions of claim 17, wherein said stickum is a polyvidone.
19, the compositions of claim 17, wherein said carrier matrix is a microcrystalline Cellulose.
20, the compositions of claim 17, wherein said disintegrating agent is a polyvinylpolypyrrolidone.
21, the compositions of claim 17, wherein said lubricant is a magnesium stearate.
22, low dose entecavir tablet composition, contain:
About 0.01% entecavir,
About 93.24% microcrystalline Cellulose,
About 4.0% polyvinylpolypyrrolidone,
About 2.50% polyvidone and
About 0.25% magnesium stearate, described percent are based on w/w.
23, low dose entecavir tablet composition, contain:
About 1.0% entecavir,
About 90.0% mannitol,
About 4.0% cross-linking sodium carboxymethyl cellulose,
About 2.50% methylcellulose and
About 2.50% stearic acid, described percent are based on w/w.
24, the low dose entecavir tablet composition of claim 22 has the outer coatings film.
25, the low dose entecavir tablet composition of claim 23 has the outer coatings film.
26, low dose entecavir capsule composition, contain:
About 10.0% entecavir,
About 82.03% microcrystalline Cellulose,
About 4.00% polyvinylpolypyrrolidone,
About 2.50% polyvidone,
About 0.25% magnesium stearate and
About 1.22% hydrochloric acid, described percent are based on w/w.
27, low dose entecavir capsule composition, contain:
About 0.05% entecavir,
About 93.20% dicalcium phosphate,
About 4.00% polyvinylpolypyrrolidone,
About 2.50% hydroxypropyl cellulose and
About 0.25% magnesium stearate, described percent are based on w/w.
28, contain the preparation method of the combination of oral medication of low dosage soluble agents active substance, comprising:
(a) described pharmaceutically active substance and stickum are dissolved in the solvent,
(b) with the solution spray of step (a) to moving carrier matrix simultaneously,
(c) the described coating carrier substrate of drying steps (b) and
(d) the described exsiccant coating carrier substrate of step (c) and other required compositions are mixed and made into described pharmaceutical composition.
29, the method for claim 28, the content of wherein said pharmaceutically active substance account for about 10% (w/w) of about 0.001-of described composition weight.
30, the method for claim 29, wherein said pharmaceutically active substance is an entecavir, and described solvent is water or the water with acid pH.
31, the method for claim 28, wherein during spray step (b), described carrier matrix keeps motion by mechanical agitation, and in step (c), described coating carrier substrate is carried out drying in pan dryer or fluidized bed dryer.
32, the method for claim 28, wherein during spray step (b), described carrier matrix stirs by air-flow and keeps motion, and in step (c), described coating carrier substrate also stirs by air-flow carries out drying.
33, a kind of administration frequency is once a day or is less than the pharmaceutical composition that once is used for the treatment of hepatitis B virus infection and/or accompanying infection, contains second kind of pharmaceutically active substance of pharmaceutically suitable carrier, the about 25mg entecavir of about 0.001mg-and effective dose.
34, the compositions that contains pharmaceutically suitable carrier and the about 25mg entecavir of about 0.001mg-at the preparation administration frequency for once a day or be less than application in once the medicine that is used for the treatment of hepatitis B virus infection and/or accompanying infection.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US18567200P | 2000-02-29 | 2000-02-29 | |
| US60/185672 | 2000-02-29 |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 00126403 Division CN1310999A (en) | 2000-02-29 | 2000-08-29 | Low dose Etikavi Prepn. and the use thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101385732A true CN101385732A (en) | 2009-03-18 |
Family
ID=22681972
Family Applications (5)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2008101492879A Pending CN101385732A (en) | 2000-02-29 | 2000-08-29 | Low dose entecavir formulation and use |
| CN 200510128719 Ceased CN1813753B (en) | 2000-02-29 | 2000-08-29 | Low dose entecavir formulation and use |
| CN2012101468842A Pending CN102772413A (en) | 2000-02-29 | 2000-08-29 | Low dose entecavir formulation and use |
| CN 00126403 Pending CN1310999A (en) | 2000-02-29 | 2000-08-29 | Low dose Etikavi Prepn. and the use thereof |
| CN 200810170016 Expired - Lifetime CN101444511B (en) | 2000-02-29 | 2000-08-29 | Low dose entecavir formulation and use |
Family Applications After (4)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 200510128719 Ceased CN1813753B (en) | 2000-02-29 | 2000-08-29 | Low dose entecavir formulation and use |
| CN2012101468842A Pending CN102772413A (en) | 2000-02-29 | 2000-08-29 | Low dose entecavir formulation and use |
| CN 00126403 Pending CN1310999A (en) | 2000-02-29 | 2000-08-29 | Low dose Etikavi Prepn. and the use thereof |
| CN 200810170016 Expired - Lifetime CN101444511B (en) | 2000-02-29 | 2000-08-29 | Low dose entecavir formulation and use |
Country Status (4)
| Country | Link |
|---|---|
| CN (5) | CN101385732A (en) |
| HK (1) | HK1040196A1 (en) |
| UY (1) | UY26595A1 (en) |
| ZA (1) | ZA200205900B (en) |
Families Citing this family (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1732944B (en) * | 2005-09-02 | 2013-05-08 | 海南中和药业有限公司 | Entecavir dispersible tablet and its preparation process |
| CN1820744B (en) * | 2006-04-04 | 2011-01-26 | 中国人民解放军军事医学科学院毒物药物研究所 | Oseltamivir phosphate granula and its preparing method |
| CN101244260B (en) * | 2007-02-14 | 2011-12-28 | 成都地奥九泓制药厂 | Combined medicament for treating chronic hepatitis B |
| CN101371841A (en) * | 2007-08-23 | 2009-02-25 | 浙江医药股份有限公司新昌制药厂 | Crystallization type Entecavir formulation as well as preparation method and use thereof |
| CN102578564A (en) * | 2011-11-01 | 2012-07-18 | 江苏江山制药有限公司 | Preparation method for rapid-disintegrating directly-pressed particle mannitol preparation |
| CN102416003A (en) * | 2011-12-08 | 2012-04-18 | 南京优科生物医药有限公司 | Method for preparing entecavir tablets |
| CN102552210B (en) * | 2012-01-10 | 2013-12-11 | 四川海思科制药有限公司 | Entecavir capsule and preparation method thereof |
| KR101285008B1 (en) * | 2012-04-18 | 2013-07-10 | 제일약품주식회사 | A method for preparing oral formulation of low dose entecavir |
| US10111836B2 (en) * | 2015-02-01 | 2018-10-30 | Orsenix Holdings Bv | High surface-area lyophilized compositions comprising arsenic for oral administration in patients |
| CN112535736B (en) * | 2020-12-14 | 2023-08-29 | 石家庄四药有限公司 | Entecavir composition and preparation method thereof |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4489026A (en) * | 1982-09-07 | 1984-12-18 | The Upjohn Company | Process for preparing solid unit dosage forms of ultra-low dose drugs |
| US5206244A (en) * | 1990-10-18 | 1993-04-27 | E. R. Squibb & Sons, Inc. | Hydroxymethyl (methylenecyclopentyl) purines and pyrimidines |
| PH30929A (en) * | 1992-09-03 | 1997-12-23 | Janssen Pharmaceutica Nv | Beads having a core coated with an antifungal and a polymer. |
-
2000
- 2000-08-29 CN CNA2008101492879A patent/CN101385732A/en active Pending
- 2000-08-29 CN CN 200510128719 patent/CN1813753B/en not_active Ceased
- 2000-08-29 CN CN2012101468842A patent/CN102772413A/en active Pending
- 2000-08-29 CN CN 00126403 patent/CN1310999A/en active Pending
- 2000-08-29 CN CN 200810170016 patent/CN101444511B/en not_active Expired - Lifetime
-
2001
- 2001-02-23 UY UY26595A patent/UY26595A1/en not_active IP Right Cessation
-
2002
- 2002-03-04 HK HK02101639.3A patent/HK1040196A1/en unknown
- 2002-07-23 ZA ZA200205900A patent/ZA200205900B/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| CN101444511B (en) | 2013-01-02 |
| CN102772413A (en) | 2012-11-14 |
| CN1310999A (en) | 2001-09-05 |
| ZA200205900B (en) | 2004-03-29 |
| CN1813753A (en) | 2006-08-09 |
| UY26595A1 (en) | 2001-09-28 |
| CN101444511A (en) | 2009-06-03 |
| CN1813753B (en) | 2010-04-07 |
| HK1040196A1 (en) | 2002-05-31 |
| CN1813753C (en) |
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