CN104000789A - Adefovir dipivoxil dispersible tablet and preparation method thereof - Google Patents
Adefovir dipivoxil dispersible tablet and preparation method thereof Download PDFInfo
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- CN104000789A CN104000789A CN201410149196.0A CN201410149196A CN104000789A CN 104000789 A CN104000789 A CN 104000789A CN 201410149196 A CN201410149196 A CN 201410149196A CN 104000789 A CN104000789 A CN 104000789A
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Abstract
The invention relates to an adefovir dipivoxil dispersible tablet for treating hepatitis B and a preparation method thereof. The invention aims to provide a new preparation, i.e. the adefovir dipivoxil dispersible tablet to vast patients and medical workers. The adefovir dipivoxil dispersible tablet has the characteristics of rapid disintegration, fast absorption and convenient taking, and can improve the bioavailability of drugs and the blood concentration, as well as the antiviral effect. Adefovir dipivoxil is adopted as the raw material, and some auxiliary materials of specific types and proportion are added so as to be pressed into tablets according to the conventional technology of pharmaceutics.
Description
Invention field
The present invention relates to a kind of pharmaceutical composition containing adefovir ester, more particularly, the present invention relates to a kind of Adefovir dipivoil dispersion tablet, be used for the treatment of the disease that hepatitis B or hepatitis B infection cause.The invention still further relates to the preparation method of described Adefovir dipivoil dispersion tablet.
Background of invention
(M & M that (HBV) causes in the whole world is one the most serious in liver virus to hepatitis B virus.According to World Health Organization's statistics, global HBV carrier approximately 3.5 hundred million people, cause dead about 100-200 ten thousand people every year.At present, there are two kinds of sensitized vaccine and DNA recombiant vaccinies for preventative; And curative drug conventional be a-interferon, it is expensive tolerance and the effective percentage low (only having the patient of 25%-40% to play mitigation) of being difficult to not only.
Adefovir ester is a kind of new anti-hepatitis B virus (HBV) medicine, is also the oral anti-HBV medicine of another kind after lamivudine.Adefovir ester belongs to AMP phosphoric acid nucleoside acid-like substance, and contestable suppresses HBV polymerase, and ends the prolongation of HBV DNA chain.This medicine is gone on the market in the U.S. by FDA (FDA) approval in JIUYUE, 2002, and Chinese I1, the clinical registration test of III phase also start in December, 2002.Adefovir ester is purines derivant, is the prodrug of adenine phosphate compound adefovirdipivoxil, is novel Acyclic nucleotide class broad-spectrum antiviral medicament, is the nucleoside analog that is used for the treatment of clinically hepatitis B at present.Adefovir ester, because of features such as drug resistance incidence rate are low, evening time, the long-term prescription safety of generation drug resistance are good, is more suitable for for long-term antiviral therapy it.And, adefovir ester is to the YMDD variant sensitivity producing because of long-term taking lamivudine, can significantly reduce YMDD variation patient's serum HBV-DNA titre and ALT level, after oral, be converted into adefovirdipivoxil in vivo and bring into play antivirus action, therefore the appearance of adefovir ester makes different IPs glycoside treated with combined medication become possibility to extend the antiviral therapy time.In a word, under the limited treatment level that can reach when prodrug, how realizing strategy long-term, effectively antiviral therapy is the problem that is worth exploration, and adefovir ester is good a selection of chronic viral hepatitis B Long-term Anti viral therapy, has broad application prospects.
Adefovir ester tablet and capsule etc. are mainly to granulate with wet method to make common oral drugs at present; this method of granulating need to add liquid first major ingredient and adjuvant to be made to wet soft material; then obtain finished product by steps such as dry, tablettings; but in finished product, conventionally can contain more moisture, humidity is larger, and product shelf-stability is bad; non-refractory, high humidity and strong illumination; and complicated process of preparation, cost is larger, is unfavorable for actual production and application.Summary of the invention.
Dispersible tablet was a kind of novel pharmaceutical formulation that development in recent years is got up, and British Pharmacopoeia has recorded this dosage form as far back as 1993.Chinese Pharmacopoeia is until 2000 just set it as a kind of new dosage form and take in wherein.Compare ordinary tablet, dispersible tablet requires tablet in the temperature of disintegrate medium during 20 DEG C of left and right, disintegration time is less than 3 minutes, and granule after disintegrate should be able to whole mistake 710 μ m screen clothes, and said preparation has the advantages such as drug release rate is fast, bioavailability is high, untoward reaction is few.When clinical practice, both can resemble conventional tablet and take, and can put into again after water disperses rapidly and take, in special case, can also chew or buccal, carry with easy to use, have the advantage of solid preparation and liquid preparation concurrently, the patient who is specially adapted to old man, child and dysphagia uses simultaneously.
Adopt the technology of the present invention that adefovir ester is prepared into dispersion sheet, not only expand the dosage form range of application of adefovir ester, particularly through the selection to the present invention's formula, obtain the sense of taste good, disintegrate rapidly, absorb fast, taking convenience, the bioavailability that can improve medicine and blood drug level, improve the novel formulation of antivirus action.
The invention provides a kind of Adefovir dipivoil dispersion tablet, its disintegrate is rapid, rapid-action, and bioavailability is high, improves the curative effect for the treatment of hepatitis B, taking convenience, and also preparation method is simple, is applicable to large-scale production.
Summary of the invention
The object of this invention is to provide a kind of disintegrate fast, absorb rapidly, can effectively improve bioavailability and the blood drug level of medicine, improve adefovir ester peroral dosage form-Adefovir dipivoil dispersion tablet of taste, taking convenience, few side effects and preparation method thereof simultaneously.The concrete technical scheme that the present invention adopts is as follows:
On the one hand, the present invention relates to a kind of Adefovir dipivoil dispersion tablet, wherein, the percentage by weight of adefovir ester is 0.01-10%, and the percentage by weight of adjuvant is 90-99.99%.
Some embodiments therein, dispersible tablet of the present invention, wherein, wherein said adjuvant is selected from disintegrating agent, filler, binding agent, lubricant, wherein the percentage by weight of filler is 20-90%, the percentage by weight of disintegrating agent is 5-40%, and the percentage by weight of binding agent is that the percentage by weight of 1-20%, lubricant is 0.1-5%.
In other embodiments, dispersible tablet of the present invention, wherein, described disintegrating agent is selected from one or more in carboxymethyl starch sodium, polyvinylpolypyrrolidone, low-substituted hydroxypropyl cellulose, carboxymethyl starch sodium, sodium carboxymethyl cellulose, cross-linking sodium carboxymethyl cellulose, carboxymethylcellulose calcium, carboxymethylcellulose calcium, microcrystalline Cellulose, sodium lauryl sulphate, cetyl sulfo-sodium succinate, sodium dioctyl sulfosuccinate, tween 80; Described filler is selected from one or more of lactose, sucrose, sorbitol, mannitol, xylitol, erythritol, pregelatinized Starch, starch; Binding agent is wherein selected from a kind of in ethanol, water, ethanol-water solution, syrup, starch slurry, carboxymethylcellulose sodium solution, povidone solution, Magnesiumaluminumsilicate, sodium alginate or several mixture wherein; Lubricant is wherein selected from one or more the mixture in micropowder silica gel, magnesium stearate, calcium stearate, stearic acid, Pulvis Talci, silicon dioxide, Stepanol MG, PEG4000, PEG6000.
In other embodiments, dispersible tablet of the present invention, wherein, described dispersible tablet also contains correctives, correctives is selected from one or more the mixture in flavoring orange essence, Mint Essence, grape essence, cherry essence, flavoring banana essence, flavoring pineapple essence, vanilla, Fructus Citri Limoniae essence, Aspartame, saccharin sodium, steviol glycosides, and consumption is 0.5-5%.
Some embodiments therein, dispersible tablet of the present invention, wherein, the formula of described dispersible tablet consists of:
Some embodiments therein, dispersible tablet of the present invention, wherein, described dispersible tablet formula consists of:
Some embodiments therein, dispersible tablet of the present invention, wherein, described dispersible tablet formula consists of:
Some embodiments therein, described dispersible tablet of the present invention, wherein, described dispersible tablet formula consists of:
Polyvinylpyrrolidone 50% alcoholic solution 5g (in polyvinylpyrrolidone)
On the other hand, the present invention relates to a kind of preparation method of dispersible tablet of the present invention, it adopts wet granule compression tablet, comprises following steps: medicine and various adjuvant are pulverized, crossed after 80-100 mesh sieve mix homogeneously; With suitable amount of adhesive soft material processed, granulate with 12-24 mesh sieve, 40-80 DEG C of dry 4-5 hour, 18-20 mesh sieve granulate, adds tabletting after other adjuvant mix homogeneously; Wherein disintegrating agent can adopt the method that additional, Nei Jia or inside and outside mixing add, and also can adopt direct powder compression, and medicine and various adjuvant are pulverized, and crosses after 80-100 mesh sieve, and mix homogeneously, regulates pressure, preparation tabletting.
Detailed description of the invention
Following examples have further described and demonstrated embodiment within the scope of the present invention.Embodiment is only used to the object of illustrations and provides, and is not intended to be regarded as limitation of the present invention, and it may exist the multiple variant that does not deviate from spirit and scope of the invention.
Embodiment 1
Prescription:
Preparation method: first above-mentioned each material was pulverized respectively to 100 mesh sieves, by after adefovir ester, mannitol, microcrystalline Cellulose, abundant mix homogeneously, add appropriate starch slurry to make soft material, 16 mesh sieves are granulated, and 60 DEG C after dry 3-4 hour, 16 mesh sieve granulate, add disintegrating agent crosslinked carboxymethyl fecula sodium, crospolyvinylpyrrolidone outward, correctives grape essence, and magnesium stearate lubricant, after mixing, be pressed into Adefovir dipivoil dispersion tablet.
Embodiment 2:
Prescription:
Preparation method: first above-mentioned each material was pulverized respectively to 100 mesh sieves, by after adefovir ester, mannitol, microcrystalline Cellulose, abundant mix homogeneously, add appropriate starch slurry to make soft material, 16 mesh sieves are granulated, and 80 DEG C dry after 3 hours, 16 mesh sieve granulate, add disintegrating agent crosslinked carboxymethyl fecula sodium outward, correctives aspartame, lubricant Pulvis Talci, after mixing, be pressed into Adefovir dipivoil dispersion tablet.
Embodiment 3:
Prescription:
Preparation method: first above-mentioned each material was pulverized respectively to 100 mesh sieves, by after adefovir ester, lactose, pregelatinized Starch, the abundant mix homogeneously of microcrystalline Cellulose, add appropriate low-substituted hydroxypropyl cellulose to make soft material, 24 mesh sieves are granulated, and 60 DEG C after dry 2-3 hour, 20 mesh sieve granulate, add disintegrating agent low-substituted hydroxypropyl cellulose outward, correctives Fructus Citri Limoniae essence, lubricant micropowder silica gel, after mixing, be pressed into Adefovir dipivoil dispersion tablet.
Embodiment 4:
Prescription:
Polyvinylpyrrolidone 50% alcoholic solution 5g (in polyvinylpyrrolidone)
Preparation method: first above-mentioned each material was pulverized respectively to 100 mesh sieves, by after adefovir ester, xylitol, the abundant mix homogeneously of microcrystalline Cellulose, add polyvinylpyrrolidone 50% alcoholic solution to make soft material, 24 mesh sieves are granulated, and 60 DEG C after dry 1-2 hour, 20 mesh sieve granulate, add disintegrating agent crospolyvinylpyrrolidone, L-HPC outward, correctives steviol glycosides, cherry essence, lubricant PEG6000, after mixing, be pressed into Adefovir dipivoil dispersion tablet.
Embodiment 5
Prescription:
Preparation method: first above-mentioned each material was pulverized respectively to 100 mesh sieves, by after adefovir ester, lactose, pregelatinized Starch, microcrystalline Cellulose, low-substituted hydroxypropyl cellulose, Aspartame, Fructus Citri Limoniae essence, the abundant mix homogeneously of micropowder silica gel, regulate pressure, be pressed into Adefovir dipivoil dispersion tablet.
Biologic test
pharmaceutical formulation dissolution of the present invention and stability study
With reference to dissolution method (2010 editions two annex XC bis-methods of Chinese Pharmacopoeia).
Adefovir dipivoil dispersion tablet accelerated stability test: by the Adefovir dipivoil dispersion tablet of the present invention of blister package with
Commercially available ordinary tablet (excellent He Ding, Shanghai YSY Pharmaceutical Co., Ltd.) is put under 2 DEG C of 40 DEG C of scholars of temperature, relative humidity 75% scholar's 5% condition and is placed six months, and outcome quality is stable, and indices is as shown in table 1.
Table 1 pharmaceutical formulation dissolution of the present invention and results of stability
Above-mentioned data show, Adefovir dipivoil dispersion tablet disintegrate of the present invention is rapid, is obviously better than ordinary tablet, and dissolution is high, steady quality, and impurity and content all meet standards of pharmacopoeia.
Claims (9)
1. an Adefovir dipivoil dispersion tablet, wherein, the percentage by weight of adefovir ester is 0.01-10%, the percentage by weight of adjuvant is 90-99.99%.
2. dispersible tablet according to claim 1, wherein, wherein said adjuvant is selected from disintegrating agent, filler, binding agent, lubricant, wherein the percentage by weight of filler is 20-90%, the percentage by weight of disintegrating agent is 5-40%, and the percentage by weight of binding agent is that the percentage by weight of 1-20%, lubricant is 0.1-5%.
3. dispersible tablet according to claim 2, wherein, described disintegrating agent is selected from one or more in carboxymethyl starch sodium, polyvinylpolypyrrolidone, low-substituted hydroxypropyl cellulose, carboxymethyl starch sodium, sodium carboxymethyl cellulose, cross-linking sodium carboxymethyl cellulose, carboxymethylcellulose calcium, carboxymethylcellulose calcium, microcrystalline Cellulose, sodium lauryl sulphate, cetyl sulfo-sodium succinate, sodium dioctyl sulfosuccinate, tween 80; Described filler is selected from one or more of lactose, sucrose, sorbitol, mannitol, xylitol, erythritol, pregelatinized Starch, starch; Binding agent is wherein selected from a kind of in ethanol, water, ethanol-water solution, syrup, starch slurry, carboxymethylcellulose sodium solution, povidone solution, Magnesiumaluminumsilicate, sodium alginate or several mixture wherein; Lubricant is wherein selected from one or more the mixture in micropowder silica gel, magnesium stearate, calcium stearate, stearic acid, Pulvis Talci, silicon dioxide, Stepanol MG, PEG4000, PEG6000.
4. dispersible tablet according to claim 3, wherein, described dispersible tablet also contains correctives, correctives is selected from one or more the mixture in flavoring orange essence, Mint Essence, grape essence, cherry essence, flavoring banana essence, flavoring pineapple essence, vanilla, Fructus Citri Limoniae essence, Aspartame, saccharin sodium, steviol glycosides, and consumption is 0.5-5%.
5. according to the dispersible tablet described in claim 1-4 any one, wherein, the formula of described dispersible tablet consists of:
6. according to the dispersible tablet described in claim 1-4 any one, wherein, described dispersible tablet formula consists of:
7. according to the dispersible tablet described in claim 1-4 any one, wherein, described dispersible tablet formula consists of:
8. according to the dispersible tablet described in claim 1-4 any one, wherein, described dispersible tablet formula consists of:
Polyvinylpyrrolidone 50% alcoholic solution 5g (in polyvinylpyrrolidone)
9. a preparation method for dispersible tablet described in claim 1-8 any one, it adopts wet granule compression tablet, comprises following steps: medicine and various adjuvant are pulverized, crossed after 80-100 mesh sieve mix homogeneously; With suitable amount of adhesive soft material processed, granulate with 12-24 mesh sieve, 40-80 DEG C of dry 4-5 hour, 18-20 mesh sieve granulate, adds tabletting after other adjuvant mix homogeneously; Wherein disintegrating agent can adopt the method that additional, Nei Jia or inside and outside mixing add, and also can adopt direct powder compression, and medicine and various adjuvant are pulverized, and crosses after 80-100 mesh sieve, and mix homogeneously, regulates pressure, preparation tabletting.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106880610A (en) * | 2015-12-15 | 2017-06-23 | 北大方正集团有限公司 | A kind of ramelteon dispersible tablet and preparation method thereof |
| CN106880600A (en) * | 2015-12-15 | 2017-06-23 | 北大方正集团有限公司 | A kind of Topiroxostat dispersible tablet and preparation method thereof |
| CN106880609A (en) * | 2015-12-15 | 2017-06-23 | 北大方正集团有限公司 | A kind of Suo Feibuwei dispersible tablets and preparation method thereof |
| CN106880608A (en) * | 2015-12-15 | 2017-06-23 | 北大方正集团有限公司 | A kind of teriflunomide dispersible tablet and preparation method thereof |
| CN106890146A (en) * | 2015-12-18 | 2017-06-27 | 上海星泰医药科技有限公司 | A kind of Oseltamivir phosphate dispersible tablet and preparation method thereof |
| CN114224858A (en) * | 2021-12-29 | 2022-03-25 | 辰欣药业股份有限公司 | Adefovir dipivoxil tablet and preparation method thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1546046A (en) * | 2003-12-08 | 2004-11-17 | 杨喜鸿 | Adefovir dipivoxil dispersing tablet and its preparation |
-
2014
- 2014-04-15 CN CN201410149196.0A patent/CN104000789A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1546046A (en) * | 2003-12-08 | 2004-11-17 | 杨喜鸿 | Adefovir dipivoxil dispersing tablet and its preparation |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106880610A (en) * | 2015-12-15 | 2017-06-23 | 北大方正集团有限公司 | A kind of ramelteon dispersible tablet and preparation method thereof |
| CN106880600A (en) * | 2015-12-15 | 2017-06-23 | 北大方正集团有限公司 | A kind of Topiroxostat dispersible tablet and preparation method thereof |
| CN106880609A (en) * | 2015-12-15 | 2017-06-23 | 北大方正集团有限公司 | A kind of Suo Feibuwei dispersible tablets and preparation method thereof |
| CN106880608A (en) * | 2015-12-15 | 2017-06-23 | 北大方正集团有限公司 | A kind of teriflunomide dispersible tablet and preparation method thereof |
| CN106890146A (en) * | 2015-12-18 | 2017-06-27 | 上海星泰医药科技有限公司 | A kind of Oseltamivir phosphate dispersible tablet and preparation method thereof |
| CN114224858A (en) * | 2021-12-29 | 2022-03-25 | 辰欣药业股份有限公司 | Adefovir dipivoxil tablet and preparation method thereof |
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Application publication date: 20140827 |