CN102370629B - Entecavir liquid capsule and preparation method thereof - Google Patents
Entecavir liquid capsule and preparation method thereof Download PDFInfo
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- CN102370629B CN102370629B CN201010253995.4A CN201010253995A CN102370629B CN 102370629 B CN102370629 B CN 102370629B CN 201010253995 A CN201010253995 A CN 201010253995A CN 102370629 B CN102370629 B CN 102370629B
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- 229960000980 entecavir Drugs 0.000 title claims abstract description 50
- YXPVEXCTPGULBZ-WQYNNSOESA-N entecavir hydrate Chemical compound O.C1=NC=2C(=O)NC(N)=NC=2N1[C@H]1C[C@H](O)[C@@H](CO)C1=C YXPVEXCTPGULBZ-WQYNNSOESA-N 0.000 title claims abstract description 50
- 239000002775 capsule Substances 0.000 title claims abstract description 32
- 239000007788 liquid Substances 0.000 title claims abstract description 25
- 238000002360 preparation method Methods 0.000 title claims abstract description 25
- 239000007902 hard capsule Substances 0.000 claims abstract description 7
- 239000012467 final product Substances 0.000 claims abstract description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 10
- 238000003756 stirring Methods 0.000 claims description 9
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims description 8
- 229920000053 polysorbate 80 Polymers 0.000 claims description 8
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 claims description 7
- JLFNLZLINWHATN-UHFFFAOYSA-N pentaethylene glycol Chemical compound OCCOCCOCCOCCOCCO JLFNLZLINWHATN-UHFFFAOYSA-N 0.000 claims description 7
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 6
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
- 229920000159 gelatin Polymers 0.000 claims description 3
- 235000019322 gelatine Nutrition 0.000 claims description 3
- 238000010438 heat treatment Methods 0.000 claims description 3
- 108010010803 Gelatin Proteins 0.000 claims description 2
- 229920003081 Povidone K 30 Polymers 0.000 claims description 2
- 239000008273 gelatin Substances 0.000 claims description 2
- 235000011852 gelatine desserts Nutrition 0.000 claims description 2
- 239000000463 material Substances 0.000 claims description 2
- 238000007789 sealing Methods 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims 1
- 150000003839 salts Chemical class 0.000 claims 1
- 239000007901 soft capsule Substances 0.000 abstract description 17
- 238000005516 engineering process Methods 0.000 abstract description 9
- 238000000034 method Methods 0.000 abstract description 9
- 239000003814 drug Substances 0.000 abstract description 8
- 230000032683 aging Effects 0.000 abstract description 4
- 238000004090 dissolution Methods 0.000 abstract description 4
- 229940079593 drug Drugs 0.000 abstract description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 abstract description 3
- 230000018044 dehydration Effects 0.000 abstract description 3
- 238000006297 dehydration reaction Methods 0.000 abstract description 3
- 208000002672 hepatitis B Diseases 0.000 abstract description 3
- 239000001301 oxygen Substances 0.000 abstract description 3
- 229910052760 oxygen Inorganic materials 0.000 abstract description 3
- 238000003860 storage Methods 0.000 abstract description 3
- 239000002994 raw material Substances 0.000 abstract description 2
- 238000010057 rubber processing Methods 0.000 abstract 1
- 239000003826 tablet Substances 0.000 description 8
- 239000000203 mixture Substances 0.000 description 7
- 239000000758 substrate Substances 0.000 description 5
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical group OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 239000002671 adjuvant Substances 0.000 description 3
- 239000011230 binding agent Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 229960003511 macrogol Drugs 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- NYHBQMYGNKIUIF-UUOKFMHZSA-N Guanosine Chemical compound C1=NC=2C(=O)NC(N)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O NYHBQMYGNKIUIF-UUOKFMHZSA-N 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 239000007919 dispersible tablet Substances 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 229940016286 microcrystalline cellulose Drugs 0.000 description 2
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 2
- 239000008108 microcrystalline cellulose Substances 0.000 description 2
- 230000035699 permeability Effects 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- UNXRWKVEANCORM-UHFFFAOYSA-N triphosphoric acid Chemical class OP(O)(=O)OP(O)(=O)OP(O)(O)=O UNXRWKVEANCORM-UHFFFAOYSA-N 0.000 description 2
- 239000000080 wetting agent Substances 0.000 description 2
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- ZEMPKEQAKRGZGQ-AAKVHIHISA-N 2,3-bis[[(z)-12-hydroxyoctadec-9-enoyl]oxy]propyl (z)-12-hydroxyoctadec-9-enoate Chemical compound CCCCCCC(O)C\C=C/CCCCCCCC(=O)OCC(OC(=O)CCCCCCC\C=C/CC(O)CCCCCC)COC(=O)CCCCCCC\C=C/CC(O)CCCCCC ZEMPKEQAKRGZGQ-AAKVHIHISA-N 0.000 description 1
- 208000000419 Chronic Hepatitis B Diseases 0.000 description 1
- MIKUYHXYGGJMLM-GIMIYPNGSA-N Crotonoside Natural products C1=NC2=C(N)NC(=O)N=C2N1[C@H]1O[C@@H](CO)[C@H](O)[C@@H]1O MIKUYHXYGGJMLM-GIMIYPNGSA-N 0.000 description 1
- NYHBQMYGNKIUIF-UHFFFAOYSA-N D-guanosine Natural products C1=2NC(N)=NC(=O)C=2N=CN1C1OC(CO)C(O)C1O NYHBQMYGNKIUIF-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 239000001828 Gelatine Substances 0.000 description 1
- 241000701076 Macacine alphaherpesvirus 1 Species 0.000 description 1
- 206010068052 Mosaicism Diseases 0.000 description 1
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 239000004141 Sodium laurylsulphate Substances 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 102000003929 Transaminases Human genes 0.000 description 1
- 108090000340 Transaminases Proteins 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000003026 cod liver oil Substances 0.000 description 1
- 235000012716 cod liver oil Nutrition 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000007922 dissolution test Methods 0.000 description 1
- 239000008157 edible vegetable oil Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 239000004519 grease Substances 0.000 description 1
- 229940029575 guanosine Drugs 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 229960003943 hypromellose Drugs 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 231100000915 pathological change Toxicity 0.000 description 1
- 230000036285 pathological change Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 210000003765 sex chromosome Anatomy 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000001226 triphosphate Substances 0.000 description 1
- 235000011178 triphosphate Nutrition 0.000 description 1
- 230000029812 viral genome replication Effects 0.000 description 1
Abstract
The invention relates to a medicinal preparation for treating hepatitis B, and especially relates to an entecavir liquid capsule and a preparation method thereof. Content of the entecavir liquid capsule comprises an entecavir raw material and accessories; the content is packaged in a hard capsule casing, and includes 0.02-2.0wt% of entecavir and 98-99.98wt% of accessories. The entecavir liquid capsule of the invention solves a homogeneity problem of main drug content in an entecavir low dosage preparation, and a problem of demanded simultaneous operations of copying, rubber processing and content wrapping of an existing soft capsule preparation technology, and problems of high moisture and high oxygen transmissivity, disadvantage for medicine storage and susceptibility to dehydration and ageing of the soft capsule, and difficulty in disintegrating and dissolving of a final product. Provided is an entecavir liquid capsule with good homogeneity, simple preparing process, high dissolution and high bioavailability.
Description
Technical field
The present invention relates to the pharmaceutical preparation for the treatment of hepatitis B, particularly relate to a kind of entecavir liquid capsule and preparation method thereof.
Background technology
Entecavir is a kind of guanosine acid-like substance with anti-HBV effect, inhibited to B virus polymerase lymerase.It can become the activated triphosphate of tool by phosphorylation, and this triphosphate is 15 hours in the intracellular half-life, and it is more lasting to act on.Be mainly used in treatment adult clinically to continue to increase with serum transaminase with virus replication is active, or be organized as the chronic hepatitis B of activeness pathological changes.
The preparation that Entecavir uses clinically, domestic have conventional tablet, dispersible tablet and conventional capsule, has conventional tablet and oral liquid abroad.Because the specification of all kinds of preparation of Entecavir is very little, the specification of single dose is only 0.5 or 1mg.Therefore in various dosage form, active constituent content is difficult to keep constant (the States Pharmacopoeia specifications detection level uniformity) in single dose, for the preparation of existing low specification ordinary preparation (granule before tabletting or fill capsule).Many employings equal increments method mixes, and this method complex operation in actual production, effect is also not fully up to expectations.Entecavir dispersible tablet disclosed in Chinese patent CN1732944A, have employed conventional equal increments method, and the homogeneity problem of its content is not resolved.
Entecavir crude drug belongs to the material being slightly soluble in water, poorly water-soluble, and in common tablet or capsule, stripping is comparatively slow, and bioavailability is low.
Domestic patent 200510097962.4 discloses the preparation method of entecavir soft capsule.Soft capsule is a kind of novel form, can be encapsulated in glued membrane by pressure injections such as grease, drug solution or drug suspension pastel, form the seal capsule that size shape is different.The bioavailability of soft capsule is high, but the key issue of soft capsule is preparation process copies, and rubber process and content wrap up and must carry out simultaneously; In addition the moisture of soft capsule and oxygen permeability higher, be unfavorable for the storage of medicine, the easy dehydration of rubber is aging, final products not easy disintegrating stripping.
Summary of the invention
The object of the present invention is to provide that a kind of content is even, bioavailability is high, stripping is qualified, the simple entecavir liquid capsule of preparation technology.
Another object of the present invention is to the preparation method that a kind of entecavir liquid capsule is provided.
In order to solve Problems existing in background technology, realize foregoing invention object, the present invention adopts following technical scheme:
Entecavir liquid capsule, content comprises Entecavir stock and adjunct, and content is packaged in hard capsule case, and the percentage by weight that Entecavir accounts for content is 0.02% ~ 2.0%, and it is 98% ~ 99.98% that adjuvant accounts for content kind percentage ratio.
Described hard capsule case is gelatine capsule, hypromellose cellulose capsule, alginates capsule.
Described adjuvant comprises substrate, wetting agent, solubilizing agent, PH regulator.
Described substrate is water-soluble base or oil-soluble substrate.
Described water-soluble base is Macrogol 200, Liquid Macrogol, PEG400, Macrogol 600.
Described oil-soluble substrate is edible oil, Oleum Ricini, cod-liver oil.
Described PH regulator is one or more mixing in hydrochloric acid, phosphoric acid, citric acid, tartaric acid, and the use amount of PH regulator is adjusted to 4 ~ 6 for making capsule 's content PH.
Described solubilizing agent is one or more mixing in polyvidone, Tween 80, sodium lauryl sulphate, lecithin.
Prepare 1000, adopt following formula: Entecavir 1.0g, PEG400 256.0g, glycerol 40.0g, polyvidone k32 2.0g, Tween 80 1.0g, hydrochloric acid regulates pH value to be 5 in right amount.
The invention also discloses a kind of preparation method of entecavir liquid capsule, first solubilizing agent is added by after substrate heating in water bath, after stirring, add Entecavir raw material, stirring and dissolving, add wetting agent, pH value to 4 ~ 6 are regulated with PH regulator after stirring, be cooled to room temperature, then fill is in hard capsule case, seals and get final product.
Entecavir liquid capsule of the present invention solves the uniform content sex chromosome mosaicism of principal agent composition in Entecavir low dose formulation in background technology, and the preparation process that existing soft capsule exists copies, and rubber process and content wrap up and must carry out simultaneously; In addition the moisture of soft capsule and oxygen permeability higher, be unfavorable for the storage of medicine, the easy dehydration of rubber is aging, and final products are the problem such as easy disintegrating stripping not.Provide the entecavir liquid capsule that a kind of medicine homogeneity is good, preparation process is simple, dissolution is high, bioavailability is high.
Detailed description of the invention
Below by specific embodiment, the present invention is described further.
Embodiment 1: prepare 1000 entecavir liquid capsules
Prescription: Entecavir 1.0g PEG400 256.0g
Glycerol 40.0g polyvidone k32 2.0g
Tween 80 1.0g hydrochloric acid is appropriate
Preparation technology: by PEG400 heating in water bath to 50 DEG C, add 30 POVIDONE K 30 BP/USP 32, after stirring, add Entecavir and Tween 80 stirring and dissolving, add glycerol, after stirring, regulate pH value to be 5 with hydrochloric acid, be cooled to room temperature, fill, in hard capsule case, with 20% aqueous gelatin solution sealing, to obtain final product.
The entecavir liquid capsule that the present embodiment obtains, Entecavir content is even, stable, solve the problem of the content uniformity of Entecavir low dose formulation in background technology, and adopt hard capsule case parcel, overcome in entecavir soft capsule, the rubber of capsule shells is easily aging, the problems such as content poor stability.
Embodiment 2: prepare 1000 entecavir tablets.
Prescription: Entecavir 1.0g lactose 70g
Microcrystalline Cellulose 10 150g starch 60g
Polyvidone k29 0.5g Tween 80 0.2g
Magnesium stearate 1.0g
Preparation technology: mix with microcrystalline Cellulose, starch again after Entecavir is mixed with lactose equal increments method, obtain mixture; Tween 80, as binding agent, is dissolved in binding agent by the PVP aqueous solution of configuration 3%; Binding agent is joined wet granular processed in said mixture, add additional adjuvant tabletting after oven dry and obtain entecavir tablets.
Embodiment 3: prepare 1000 entecavir soft capsules
Prescription: Entecavir 1.0g PEG400 190g
Propylene glycol 0.5g
According to the preparation technology of soft capsule, prepare entecavir soft capsule.
Embodiment 4: the product uniformity compares
By Content uniformity test in the annex of Chinese Pharmacopoeia, check the uniformity of dosage units of the entecavir liquid capsule of preparation in embodiment 1,2,3, Entecavir tablet and entecavir soft capsule, result is as follows:
| Dosage form | A+1.80S(≤15.0) |
| Embodiment 1 liquid capsule | 2.6 |
| Embodiment 2 tablet | 18.8 |
| Embodiment 3 soft capsule | 5.4 |
Be prepared into liquid capsule or soft capsule as seen from the above table, formulation content is even.
Embodiment 5: by dissolution test method first method in the annex of Chinese Pharmacopoeia, adopt simulated gastric fluid as medium, rotating speed selects 75rpm, and dielectric capacity is 900ml, and check the stripping of the liquid capsule of preparation in embodiment 1,2,3, tablet and soft capsule, result is as follows:
| Embodiment | 10 minutes | 20 minutes | 30 minutes | 45 minutes | 60 minutes |
| Embodiment 1 | 52％ | 76％ | 89％ | 96％ | 99％ |
| Embodiment 2 | 22％ | 35％ | 59％ | 85％ | 91％ |
| Embodiment 3 | 48％ | 69％ | 88％ | 95％ | 97％ |
The dissolution of entecavir liquid capsule prepared by result display embodiment 1 is best.
Transfer accelerated test in 40 DEG C of conditions, the dissolution of embodiment 1,2,3 is compared as follows:
| Embodiment | 0 month | January | February | March | June |
| Embodiment 1 | 96％ | 95％ | 93％ | 95％ | 95％ |
| Embodiment 2 | 85％ | 86％ | 83％ | 83％ | 81％ |
| Embodiment 3 | 95％ | 93％ | 89％ | 94％ | 75％ |
Result shows, entecavir liquid capsule steady quality prepared by embodiment 1.
Claims (1)
1. entecavir liquid capsule, is characterized in that preparation 1000 entecavir liquid capsules adopt following material: Entecavir 1.0g PEG400 256.0g
Glycerol 40.0g polyvidone k32 2.0g
Tween 80 1.0g hydrochloric acid is appropriate
And adopt following preparation method to prepare:
By PEG400 heating in water bath to 50 DEG C, add 30 POVIDONE K 30 BP/USP 32, after stirring, add Entecavir and Tween 80 stirring and dissolving, add glycerol, be 5 with salt acid for adjusting pH value after stirring, be cooled to room temperature, fill, in hard capsule case, with 20% aqueous gelatin solution sealing, to obtain final product.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
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| CN201010253995.4A CN102370629B (en) | 2010-08-13 | 2010-08-13 | Entecavir liquid capsule and preparation method thereof |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201010253995.4A CN102370629B (en) | 2010-08-13 | 2010-08-13 | Entecavir liquid capsule and preparation method thereof |
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| CN102370629A CN102370629A (en) | 2012-03-14 |
| CN102370629B true CN102370629B (en) | 2015-01-07 |
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Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104083374A (en) * | 2014-07-18 | 2014-10-08 | 石家庄创建医药科技有限公司 | Entecavir oral liquid composition |
| WO2023076878A1 (en) * | 2021-10-26 | 2023-05-04 | Emphascience Inc. | Ready-to-dilute formulation |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1732943A (en) * | 2005-09-02 | 2006-02-15 | 北京阜康仁生物制药科技有限公司 | Entecavir soft capsule and its preparation method |
| CN101703489A (en) * | 2009-11-10 | 2010-05-12 | 金三九 | Entecavir soft capsule |
-
2010
- 2010-08-13 CN CN201010253995.4A patent/CN102370629B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1732943A (en) * | 2005-09-02 | 2006-02-15 | 北京阜康仁生物制药科技有限公司 | Entecavir soft capsule and its preparation method |
| CN101703489A (en) * | 2009-11-10 | 2010-05-12 | 金三九 | Entecavir soft capsule |
Non-Patent Citations (1)
| Title |
|---|
| 液体灌装硬胶囊技术的研究概况;沈航孝 等;《中国医药工业杂志》;20051231;第36卷(第6期);377-381 * |
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Address after: Hangzhou City, Zhejiang province Binjiang District 310052 shore road 1180 China Science and Technology Park 2 Building 4 floor West Applicant after: HANGZHOU SHARPLY PHARM R&D INSTIT. Co.,Ltd. Applicant after: Hainan Poly Pharm Co.,Ltd. Applicant after: ZHEJIANG POLY PHARMACEUTICAL Co.,Ltd. Address before: Hangzhou City, Zhejiang province Binjiang District 310052 shore road 1180 China Science and Technology Park 2 Building 4 floor West Applicant before: HANGZHOU SHARPLY PHARM R&D INSTIT. Co.,Ltd. Applicant before: Hainan Poly Pharm Co.,Ltd. Applicant before: Zhejiang Ruida Pharm Co.,Ltd. |
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Address after: Hangzhou City, Zhejiang province Binjiang District 310052 shore road 1180 China Science and Technology Park 2 Building 4 floor West Patentee after: HANGZHOU SHARPLY PHARM R&D INSTIT. Co.,Ltd. Patentee after: HAINAN POLY PHARM. Co.,Ltd. Patentee after: ZHEJIANG POLY PHARMACEUTICAL Co.,Ltd. Address before: Hangzhou City, Zhejiang province Binjiang District 310052 shore road 1180 China Science and Technology Park 2 Building 4 floor West Patentee before: HANGZHOU SHARPLY PHARM R&D INSTIT. Co.,Ltd. Patentee before: Hainan Poly Pharm Co.,Ltd. Patentee before: ZHEJIANG POLY PHARMACEUTICAL Co.,Ltd. |
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Effective date of registration: 20230119 Address after: 571127 Guilin Ocean Economic Development Zone, Meilan District, Haikou City, Hainan Province Patentee after: HAINAN POLY PHARM. Co.,Ltd. Patentee after: ZHEJIANG POLY PHARMACEUTICAL Co.,Ltd. Address before: West side of 4/F, Building 2, Huaye Science Park, No. 1180 Bin'an Road, Binjiang District, Hangzhou, Zhejiang 310052 Patentee before: HANGZHOU SHARPLY PHARM R&D INSTIT. Co.,Ltd. Patentee before: HAINAN POLY PHARM. Co.,Ltd. Patentee before: ZHEJIANG POLY PHARMACEUTICAL Co.,Ltd. |
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Addressee: Zhu Xulei Document name: Notification of Conformity |