CN1931138A - Entecavir granule and its prepn process - Google Patents
Entecavir granule and its prepn process Download PDFInfo
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- CN1931138A CN1931138A CN 200610152510 CN200610152510A CN1931138A CN 1931138 A CN1931138 A CN 1931138A CN 200610152510 CN200610152510 CN 200610152510 CN 200610152510 A CN200610152510 A CN 200610152510A CN 1931138 A CN1931138 A CN 1931138A
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Abstract
The present invention relates to entecavir granule as one hepatitis B treating medicine and its preparation process, and aims at providing one kind of entecavir granule preparation with the features of accurate dosage, stable quality, easy production and convenient carrying like other common solid preparation, and the features of easy swallow, high bioavailability, less stimulation on gastrointestinal tract, etc like orally taken liquid preparation. The entecavir granule is prepared with entecavir as main material and proper amount of medicine supplementary material and through a conventional technological process.
Description
Technical field
The present invention relates to a kind of is the granule of active component with the Entecavir, and the preparation method of this granule.
Background technology
Entecavir is a kind of 2 '-penta ring deoxidation urine purine nucleoside analog, has extremely strong hepatitis virus resisting ability.Its chemical name is [1s-(1 α, 3 α, 4 β)]-2-amino-1,9-dihydro-9-[4-hydroxy-3-(hydroxymethyl)-2-methylenecyclopentyl]-6H-purin-6-one monohyxdrate.Be mainly used in the treatment adult and continue to increase with serum transaminase, or liver histological is the chronic viral hepatitis B infection of activeness pathological changes with virus replication is active.
Hepatitis B, particularly chronic viral hepatitis B have become global public health problem.Show that according to related data the whole world has 2,000,000,000 people to infect hepatitis B virus approximately, wherein chronic viral hepatitis B virus carrier has 400,000,000 approximately, in infected patient, has 15%～40% will develop into liver cirrhosis, liver failure or hepatocarcinoma HCC approximately.Have every year 500000 people dead approximately, so hepatitis B has become the global the tenth-largest cause of death because of hepatitis B virus infection.And among the 400000000 chronic viral hepatitis B the infecteds of the whole world, have 75% to live in the Asian-Pacific area, wherein China is again global hepatitis B and the heaviest country of hepatocarcinoma burden.The HBV prevalence rate of China's Mainland is the highest, and the HBV virus carrier here accounts for more than 1/3 of whole world sum.According to estimates, there are 1.2-1.3 hundred million hepatitis B virus carrierss the China's Mainland.
The medicine that is in the active development stage for treatment or prevention hepatitis B virus has 58 kinds at present, comprising: the lamivudine of antiviral class and adefovirdipivoxil (Adefovir), adefovir ester (Adefovir Dipivoxil) and many unmodified Polyethylene Glycol interferon (Pegylated Interferon) or the like.But the Entecavir of having introduced to the market at present may become the choice drug for the treatment of hepatitis B in the near future.
Shang Shi Entecavir formulation is conventional tablet and oral liquid abroad.Wherein oral liquid is the big packing of 210ml, takes 10-20ml at every turn.Neither be convenient for carrying, also since dosage on restive, cause patient's overdose or taking dose deficiency easily.The present invention relates to the granule dosage form of Entecavir, be easy to carry for the patient provides a kind of, dosage is accurate, simultaneously the pharmaceutical dosage form that can take with drink form.
Summary of the invention
Entecavir is a kind of potent antiviral agent, and it has shown the good efficacy to hepatitis B virus.Because Entecavir is very effective, low-down dosage just is enough to reach the desired therapeutic effect.Yet, this medicine poorly water-soluble, the bioavailability of common peroral dosage form is lower, and disintegration of tablet is slow; And the liquid dosage form that goes on the market at present exists again and carries inconvenience, the problem that taking dose is restive.
The dosage that granule had both had a solid preparation accurately, steady quality, be convenient to the characteristics of producing, being convenient for carrying, can before taking, be made into liquid again, have liquid preparation be easy to swallow, the bioavailability height, to characteristics such as the intestines and stomach zest are little, just satisfy the requirement of Entecavir aspect preparation.
Purpose of the present invention just is to provide a kind of entecavir granule that has the advantage of solid preparation and oral liquid concurrently, make its advantage that had both had Entecavir oral liquid instant effect, have again common Entecavir tablet be convenient to deposit, transport, carry, need not add the preparation of the advantage of antiseptic.
Another object of the present invention provides a kind of method for preparing above-mentioned entecavir granule.
Entecavir granule provided by the invention contains Entecavir active component and the excipient substance that is fit to make granule, and wherein the percentage by weight of Entecavir is 0.001-20%, and the percentage by weight of adjuvant is 80-99.999%.Described Entecavir preferably contains Entecavir 0.01-5mg in granule.
The present invention is through selection, and the adjuvant that is fit to entecavir granule comprises: one or more in filler, binding agent, correctives, sweeting agent, the food coloring.
Filler can be: one or more in mannitol, sugar alcohol, Sorbitol (higher alcohol), lactose, sucrose, maltose (hydrocolloid), dextrin, starch, the edible cellulose.The content of filler in every entecavir granule is the 5-70% of weight per package, is preferably the 10-50% of weight per package.
Binding agent can be: the alcoholic solution of dehydrated alcohol, Different concentrations of alcohol solution, crospolyvinylpyrrolidone, polyvinylpyrrolidone, sodium carboxymethyl cellulose, sugar and polyhydric alcohol, in the glycine one or more.The content of binding agent in every bag entecavir granule is the 0.01-15% of weight per package, is preferably 0.1-15%.
Sweeting agent can be: one or more in protein sugar, aspartame, cyclamate, saccharin sodium, Calcium o-benzolsulfimide, cyclohexane sulfamic acid, cyclohexane sulfamic acid sodium, cyclohexane sulfamic acid potassium, agedoite, glycyrrhizin, the pure sugar.The content of sweeting agent in every entecavir granule is the 0.01-5% of weight per package.And protein sugar, aspartame, sweet close element, saccharin sodium, Calcium o-benzolsulfimide, cyclohexane sulfamic acid, cyclohexane sulfamic acid sodium, the content of cyclohexane sulfamic acid potassium in every bag entecavir granule are the 0.01-1% of weight per package.Agedoite, glycyrrhizin, the content of alcohol sugar in every bag entecavir granule are the 0.5-5% of weight per package.
Correctives can be: one or more in citric acid, Oleum menthae, various edible essence, Cortex Cinnamomi, the various fruity material.The content of correctives in every bag of entecavir granule is the 0.1-3% of weight per package, is preferably 0.5-2%.
The preparation method of entecavir granule can have two kinds of wet granulation and dry granulations.
A kind of method for making of entecavir granule of the present invention, form by the following step:
(1) raw material, adjuvant are all placed under 60 ℃ of conditions dry 4 hours, it is standby to cross 80 mesh sieves;
(2) get Entecavir and mix, must mix powder with other adjuvants except that binding agent;
(3) preparation of wet granular: after mixed powder adds binding agent, add 20% ethanol and mediate the system soft material, the wet grain of the 20 mesh sieve systems of crossing;
(4) drying: the grain that will wet place 50 ℃～60 ℃ oven drying 3-4 hour, cross 18 mesh sieve granulate after, must do granule.
(5), maybe, promptly get entecavir granule of the present invention with packing behind dried granule and the food coloring mixing with dried granule packaging.
Among the present invention, the another kind of preparation method of entecavir granule is:
(1) raw material, adjuvant are all placed under 60 ℃ of conditions dry 4 hours, it is standby to cross 80 mesh sieves;
(2) get Entecavir and mix, must mix powder with other adjuvants;
(3) the mixed powder of step 2 is added or not with the food coloring dry granulation, packing promptly gets entecavir granule of the present invention.
Embodiment
Below with specific embodiment entecavir granule of the present invention and preparation method thereof is described further.
Embodiment 1
Composition weight (g)
Entecavir 0.5
Citric acid 800
Sodium carboxymethyl cellulose 800
Saccharin sodium 200
The agent 200 of orange flavor
At first, raw material, adjuvant are all placed under 60 ℃ of conditions dry 4 hours, standby; Get Entecavir 0.5g, saccharin sodium 200g, orange flavor agent 200g, anhydrous citric acid 800g then,, cross 60 mesh sieves by equivalent incremental method mix homogeneously; Add and to add 20% Diluted Alcohol solution again behind the sodium carboxymethyl cellulose 800g and make soft material in right amount, the wet grain of the 20 mesh sieve systems of crossing, 50 ℃-60 ℃ dry 3-4 hour, cross 18 mesh sieve granulate, aluminum-plastic composite membrane is packaged into 1000 bags, whenever comprises Entecavir 0.5mg.
Embodiment 2
Composition weight (g)
Entecavir 1
Citric acid 800
Sodium carboxymethyl cellulose 630
Mannitol 400
Aspartame 35
The agent 135 of orange flavor
At first, raw material, adjuvant are all placed under 60 ℃ of conditions dry 4 hours, standby; Get Entecavir 0.5g, Aspartame 35g, orange flavor agent 135g, anhydrous citric acid 800g and mannitol 400g then,, cross 60 mesh sieves by equivalent incremental method mix homogeneously; Add and to add 20% Diluted Alcohol solution again behind the sodium carboxymethyl cellulose 630g and make soft material in right amount, the wet grain of the 20 mesh sieve systems of crossing, 50 ℃-60 ℃ dry 3-4 hour, cross 18 mesh sieve granulate, aluminum-plastic composite membrane is packaged into 1000 bags, whenever comprises Entecavir 1mg.
Embodiment 3
Composition weight (g)
Entecavir 0.5
Dextrin 1000
Protein sugar 800
Strawberry essence 100
At first, raw material, adjuvant are all placed under 60 ℃ of conditions dry 4 hours, standby; Then, get Entecavir 0.5g, anhydrous citric acid 1000g, protein sugar 800g, strawberry essence 100g,, cross 60 mesh sieves by equivalent incremental method mix homogeneously; Add food coloring, mix homogeneously, dry granulation is crossed 18 mesh sieve granulate, and aluminum-plastic composite membrane is packaged into 1000 bags, whenever comprises Entecavir 0.5mg.
Embodiment 4
Composition weight (g)
Entecavir 0.5
Mannitol 800
Polyvidon (PVP) 150
Cyclamate 50
At first, raw material, adjuvant are all placed under 60 ℃ of conditions dry 4 hours, standby; Get Entecavir 0.5g, cyclamate 50g, mannitol 800g then,, cross 60 mesh sieves by equivalent incremental method mix homogeneously; Add and to add 20% Diluted Alcohol solution again behind the polyvidon 150g and make soft material in right amount, the wet grain of the 20 mesh sieve systems of crossing, 50 ℃-60 ℃ dry 3-4 hour, cross 18 mesh sieve granulate, aluminum-plastic composite membrane is packaged into 1000 bags, whenever comprises Entecavir 0.5mg.
Embodiment 5
Composition weight (g)
Entecavir 0.5
Citric acid 800
Dextrin 200
Glycyrrhizin 60
Herba Marsileae Quadrifoliae fruit flavor agent 40
At first, raw material, adjuvant are all placed under 60 ℃ of conditions dry 4 hours, standby; Then, get Entecavir 0.5g, anhydrous citric acid 800g, dextrin 200g, glycyrrhizin 60g, Herba Marsileae Quadrifoliae fruit flavor agent 40g,, cross 60 mesh sieves by equivalent incremental method mix homogeneously; Add food coloring 5g, mix homogeneously, dry granulation is crossed 18 mesh sieve granulate, and aluminum-plastic composite membrane is packaged into 1000 bags, whenever comprises Entecavir 0.5mg.
Above-mentioned granule should be under doctor's guidance, and to get the 1-2 bag soluble in water at every turn, takes under the empty stomach state.
Claims (9)
1, a kind of entecavir granule is characterized in that this granule contains active component Entecavir and the excipient substance that is fit to make granule.
2, granule as claimed in claim 1 is characterized in that: wherein the percentage by weight of Entecavir is 0.001-20%, and the percentage by weight of adjuvant is 80-99.999%.Described entecavir granule preferably contains Entecavir 0.01-5mg for every dose.
3, as claim 1 and 2 described granules, it is characterized in that: wherein said adjuvant is selected from: filler, binding agent, correctives, sweeting agent, food coloring.
4, as claim 1,2 and 3 described granules, it is characterized in that: wherein filler can be: one or more in mannitol, sugar alcohol, Sorbitol (higher alcohol), lactose, sucrose, maltose (hydrocolloid), dextrin, starch, the edible cellulose.The content of filler in every entecavir granule is the 5-70% of weight per package, is preferably the 10-50% of weight per package.
5, as claim 1,2 and 3 described granules, it is characterized in that: binding agent can be: the alcoholic solution of dehydrated alcohol, Different concentrations of alcohol solution, crospolyvinylpyrrolidone, polyvinylpyrrolidone, sodium carboxymethyl cellulose, sugar and polyhydric alcohol, in the glycine one or more.The content of binding agent in every bag entecavir granule is the 0.01-15% of weight per package, is preferably 0.1-15%.
6, as claim 1,2 and 3 described granules, it is characterized in that: sweeting agent can be: one or more in protein sugar, aspartame, cyclamate, saccharin sodium, Calcium o-benzolsulfimide, cyclohexane sulfamic acid, cyclohexane sulfamic acid sodium, cyclohexane sulfamic acid potassium, agedoite, glycyrrhizin, the pure sugar.The content of sweeting agent in every entecavir granule is the 0.01-5% of weight per package.And protein sugar, aspartame, sweet close element, saccharin sodium, Calcium o-benzolsulfimide, cyclohexane sulfamic acid, cyclohexane sulfamic acid sodium, the content of cyclohexane sulfamic acid potassium in every bag entecavir granule are the 0.01-1% of weight per package.Agedoite, glycyrrhizin, the content of alcohol sugar in every bag entecavir granule are the 0.5-5% of weight per package.
7, as claim 1,2 and 3 described granules, it is characterized in that: correctives can be: one or more in citric acid, Oleum menthae, various edible essence, Cortex Cinnamomi, the various fruity material.The content of correctives in every bag of entecavir granule is the 0.1-3% of weight per package, is preferably 0.5-2%.
8, a kind of method for preparing entecavir granule is characterized in that: raw material, adjuvant were all placed under 60 ℃ of conditions dry 4 hours, and it is standby to cross 80 mesh sieves; Get Entecavir and mix, must mix powder with other adjuvants except that binding agent; After mixed powder adds binding agent, add 20% ethanol and mediate the system soft material, the wet grain of the 20 mesh sieve systems of crossing; The grain that will wet place 50 ℃～60 ℃ oven drying 3-4 hour, cross 18 mesh sieve granulate after, must do granule; With dried granule packaging, maybe, promptly get entecavir granule of the present invention with packing behind dried granule and the food coloring mixing.
9, a kind of method for preparing entecavir granule is characterized in that: raw material, adjuvant were all placed under 60 ℃ of conditions dry 4 hours, and it is standby to cross 80 mesh sieves; Get Entecavir and mix, must mix powder with other adjuvants; To mix that powder adds or not with the food coloring dry granulation, packing promptly gets entecavir granule of the present invention.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200610152510 CN1931138A (en) | 2006-09-28 | 2006-09-28 | Entecavir granule and its prepn process |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200610152510 CN1931138A (en) | 2006-09-28 | 2006-09-28 | Entecavir granule and its prepn process |
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| CN1931138A true CN1931138A (en) | 2007-03-21 |
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| CN 200610152510 Pending CN1931138A (en) | 2006-09-28 | 2006-09-28 | Entecavir granule and its prepn process |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102389400A (en) * | 2011-11-02 | 2012-03-28 | 谢安云 | Entecavir granule formulation and preparation method thereof |
| CN102525967A (en) * | 2010-12-16 | 2012-07-04 | 重庆药友制药有限责任公司 | Entecavir oral solid composition and preparation method thereof |
| CN103301071A (en) * | 2013-06-03 | 2013-09-18 | 北京阜康仁生物制药科技有限公司 | Stable entecavir sugarless granules and preparation method thereof |
| CN108159004A (en) * | 2018-03-20 | 2018-06-15 | 李益香 | A kind of pharmaceutical composition and its preparation process of the Entecavir for treating chronic adult's hepatitis B |
-
2006
- 2006-09-28 CN CN 200610152510 patent/CN1931138A/en active Pending
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102525967A (en) * | 2010-12-16 | 2012-07-04 | 重庆药友制药有限责任公司 | Entecavir oral solid composition and preparation method thereof |
| CN102525967B (en) * | 2010-12-16 | 2015-04-15 | 重庆药友制药有限责任公司 | Entecavir oral solid composition and preparation method thereof |
| CN102389400A (en) * | 2011-11-02 | 2012-03-28 | 谢安云 | Entecavir granule formulation and preparation method thereof |
| CN103301071A (en) * | 2013-06-03 | 2013-09-18 | 北京阜康仁生物制药科技有限公司 | Stable entecavir sugarless granules and preparation method thereof |
| CN108159004A (en) * | 2018-03-20 | 2018-06-15 | 李益香 | A kind of pharmaceutical composition and its preparation process of the Entecavir for treating chronic adult's hepatitis B |
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Application publication date: 20070321 |