CN102397263A - Valine entecavir controlled-release tablet and preparation method thereof - Google Patents
Valine entecavir controlled-release tablet and preparation method thereof Download PDFInfo
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- CN102397263A CN102397263A CN2010102819014A CN201010281901A CN102397263A CN 102397263 A CN102397263 A CN 102397263A CN 2010102819014 A CN2010102819014 A CN 2010102819014A CN 201010281901 A CN201010281901 A CN 201010281901A CN 102397263 A CN102397263 A CN 102397263A
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- entecavir
- valine
- release tablet
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Abstract
The invention relates to a valine entecavir controlled-release tablet for treating hepatitis B and a preparation method thereof, and aims to provide a novel preparation, i.e., a valine entecavir controlled-release tablet which has the advantages of mild absorption, stable plasma concentration and small side effect. The valine entecavir controlled-release tablet is prepared by adding a diluent and a penetration enhancer into valine entecavir serving as a raw material for preparing a tablet core, coating and punching. The medicament release of the valine entecavir controlled-release tablet is stable and close to grade 0, the plasma concentration is stable, the untoward reaction is reduced, and the compliance of a patient is enhanced.
Description
Technical field
The present invention relates to the new pharmaceutical formulation of valine entecavir, say that further it is valine entecavir controlled release tablet and preparation method thereof.
Background technology
Hepatitis B sickness rate in various hepatitis is the highest, endangers also the most bad.China is high incidence of hepatitis b; HBsAg (HBsAg) carrier has people more than 100,000,000; Account for more than 1/3 of whole world carrier; Have at least every year 1200000 chronic hepatitis B patients to die from hepatitis B relevant disease (comprising liver cirrhosis, hepatocarcinoma etc.), the diseases prevention and treatment task is very heavy.Though vaccine is controlled hepatitis b virus infected performance great role, existing a large amount of needs of patients efficacious therapy with the control source of infection, reduce the case fatality rate of hepatitis B relevant disease, improve patients ' life quality.
Entecavir is a cyclohexanedione hydroxyphenylpyruvate dioxygenase carbon deoxyguanosine, is a kind of deoxyguanosine analog that can effectively suppress hepatitis B virus duplication, has stronger anti-HBV effect.In the in vitro tests, the Entecavir extremely low concentration can suppress duplicating of HBV, and its cytotoxicity is then very low, and very good selective therapy index is arranged.
For a long time, virus has become a difficult problem of puzzlement treating chronic hepatitis B to the drug resistance of medicine.Nucleoside is just controlled the patient that the YMDD virus variation does not take place and is accepted Bo Lu and decide TM (Entecavir sheet) treatment, and the drug resistance phenomenon does not appear in the data show in 144 weeks.These data declarations Bo Lu decides the line medicine of TM (Entecavir sheet) as treating hepatitis B; Have high " drug resistant gene barrier ", make the long term object of this treating hepatitis B of realization " long term inhibition hepatitis B virus duplication or thoroughly remove hepatitis B virus " become possibility.
The Entecavir poorly water-soluble, bioavailability is lower, needs to add a large amount of cosolvents in the preparation prescription to strengthen its absorption, has increased security concern on this part degree.Valine entecavir is the L-valine ester prodrug of Entecavir, absorb to get into human body after, by the rapid hydrolysis of esterase dissociate Entecavir and valine, oral administration biaavailability improves greatly in intestinal and liver cell.The valine entecavir good water solubility, external in simulated gastric fluid the dissolution in 10 minutes reach more than 95%.Beasle dog body giving drugs into nose shows that for dynamics research the valine entecavir absolute bioavailability reaches 70.9%, and is merely 37.2% with the Entecavir of prescription, and the absolute bioavailability of processing after the prodrug has improved one times nearly.
The treatment cycle of chronic viral hepatitis B is long, needs the patient to take medicine continuously for a long time and can reach therapeutic purposes, and patient's compliance is relatively poor usually, also can influence the effect of Drug therapy to a certain extent if be interrupted to take medicine.The valine entecavir water solublity is better, is not easy to control rate of releasing drug, and long-time steadily release of control medicine is its main difficulty.
Controlled release tablet can provide the strong dose thing; Scalable surface area and release aperture etc. are to obtain required rate of releasing drug; Release and environment (like pH, stirring, feed situation etc.) are irrelevant, even irrelevant with the character of medicine, and the inside and outside dependency is good, so release situation in the available external release data prediction body; Can be used for regulating blood level; Can be by the different rates multiple medicine of controlled release simultaneously: reduce medicining times, improve compliance; Reduce advantages such as stimulation and untoward reaction, people are used more it pay close attention to.
Valine entecavir is as a brand-new chemical entities medicine, and the research of its new formulation almost is the blank of this area, based on before bibliographical information, do not see the relevant report that the valine entecavir controlled release tablet is arranged.
Summary of the invention
The object of the present invention is to provide a kind of valine entecavir controlled release tablet and preparation method thereof; With control valine entecavir release and blood drug level in vivo; The interior blood drug level of body is steady after making the patient take medicine, and reduces the peak valley fluctuation of blood drug level, to reduce the untoward reaction of medicine; And its can also prolong drug action time in vivo, reduce the administration frequency, increase patient's compliance.
Valine entecavir controlled release tablet provided by the present invention comprises following component:
(1) label composition:
Valine entecavir 200～450 weight portions;
Diluent 100～300 weight portions;
Penetration enhancer 90～300 weight portions;
(2) coating composition:
Filmogen 120～400 weight portions;
Plasticizer 30～100 weight portions;
And, be equipped with the aperture that the aperture is 0.4-0.6mm in a side of this valine entecavir controlled release tablet.
The further preferred valine entecavir controlled release tablet of the present invention comprises following component:
(1) label composition:
Valine entecavir 250～350 weight portions;
Diluent 180～240 weight portions;
Penetration enhancer 170～220 weight portions;
(2) coating composition:
Filmogen 150～300 weight portions;
Plasticizer 50～80 weight portions;
And, be equipped with the aperture that the aperture is 0.45-0.55mm in a side of this valine entecavir controlled release tablet.
Further, above-mentioned core segment also includes the lubricant of 10～20 weight portions and an amount of binding agent.
In the component of above-mentioned valine entecavir controlled release tablet:
Diluent is selected from one or more the mixture in starch, pregelatinized Starch, dextrin, lactose, the microcrystalline Cellulose;
Penetration enhancer is selected from one or more the mixture in sodium chloride, potassium chloride, magnesium sulfate, magnesium chloride, potassium sulfate, sodium sulfate, d-mannitol, carbamide, glucose, sucrose, Magnesium succinate, the tartaric acid;
Filmogen is selected from cellulose acetate, ethyl cellulose, polyacrylic acid tree vinegar, gather phthalein amine or ethylene-vinyl acetate copolymer, polyvinyl chloride, gather phthalein amine, gather one or more the mixture in the carbonic acid vinegar;
Plasticizer is selected from that phthalic acid two hot vinegar, phthalic acid diethyl are cruel, one or more the mixture in the mannitol, Oleum Ricini, glycerol;
Binding agent is selected from the mixed solution of water, water or the alcohol of one or more mixture in polyvinylpyrrolidone, sodium carboxymethyl cellulose, hydroxypropyl emthylcellulose, the methylcellulose;
Lubricant is pharmaceutically useful adjuvant with lubrication, comprises magnesium stearate, Pulvis Talci, sodium lauryl sulphate.
The present invention also provides a kind of method for preparing of above-mentioned valine entecavir controlled release tablet, and the processing step of this method is following:
With sieving behind the valine entecavir of recipe quantity and diluent, the penetration enhancer pulverize separately, behind the mix homogeneously, add binding agent system soft material, 20 mesh sieves are granulated, 50 ± 5 ℃ of dryings, 18 mesh sieve granulate, dried granule add lubricant and are pressed into label; Art for coating: the coating solution flow velocity is 5-10ml/min, and pressure is 0.8kg/cm
2, the coating kettle temperature is 40 ℃, and the coating pan rotating speed is 10-20rpm, and the punching diameter is 0.4-0.6mm, gets product.
The valine entecavir controlled release tablet that utilizes the present invention to prepare, blood drug level is steady in the body of oral back, and side effect reduces, and administration number of times is few, and duration of efficacy is long.Valine entecavir release in gastrointestinal tract is slow, and the concentration that medicine contacts with gastrointestinal mucosa is little, has also alleviated the stimulation that medicine causes gastrointestinal tract.
The valine entecavir controlled release tablet that utilizes the present invention to prepare once-a-day, each 1～3, is applicable to disease patient in various degree.
Theoretically, controlled release preparation is than ordinary preparation, and it is steady to have in the body blood drug level, the effective blood drug concentration length of holding time; Reduce blood drug level " peak valley " phenomenon, thereby alleviate the toxicity of medicine; Reduce administration number of times, characteristics such as make things convenient for administration and take.
Say that from therapeutic complying with former preparation is taken medicine for three times on the one, the patient often forgets easily take medicine daytime; Take medicine for three times on the one; Should be to be administered once in per 8 hours theoretically, but difficulty in fact very, three times the interval of taking medicine daytime be shorter; The back of taking medicine evening long the time in the morning to, cause early morning with morning the time-out blood concentration low.Controlled release tablet was taken medicine once on the 1st, reduced medicining times, took medicine on time easily, keep 24 hours blood drug level steadily, so can overcome above-mentioned contradiction, be beneficial to patient treatment.
Advantage of the present invention is: the valine entecavir controlled release tablet, and once-a-day, blood drug level is steady in the body; Effective blood concentration is held time and is reached 24 hours; Reduce the peak valley phenomenon of blood drug level, alleviated the toxicity of medicine, reduced administration number of times; Improve patient's compliance, adapted to the needs of clinical development.
Description of drawings
Fig. 1 is the interior blood drug level change curve of body behind the oral valine entecavir tablet of beasle dog, wherein ◆ expression valine entecavir controlled release tablet, ■ representes the valine entecavir conventional tablet.
The specific embodiment
In the embodiment below, the present invention is carried out illustrations with the mode of embodiment.It provides purpose and is to understand the present invention, but not intention and can not be interpreted as the appended given scope of the present invention of claim of restriction by any way.
Embodiment 1 valine entecavir controlled release tablet
(1) label prescription:
Valine entecavir 250g;
Mannitol 200g;
Sodium chloride 180g;
(2) coating fluid prescription:
Cellulose acetate 160g;
Polyethylene Glycol 3350 40g;
Dichloromethane 1800ml
Methanol 800ml
Sheet heart preparation: with sieving behind the medicine of recipe quantity and sodium chloride, the mannitol pulverize separately, mix homogeneously uses 95% ethanol to be wetting agent system soft material; 20 mesh sieves are granulated; 50 ± 5 ℃ of dryings of wet granular, 18 mesh sieve granulate, tabletting promptly gets 1000 sheet hearts behind the dried granule mixing.
Art for coating: label is placed in the coating pan, be blown into hot-air, when treating that the label temperature is 40 ℃ of left and right sides; Carry out coating, the coating solution flow velocity is 5-10mL/min, and pressure is 0.8kg/cm2; The coating kettle temperature is about 40 ℃, reaches weightening finish 4.0～4.5% to the thickness of label outer coatings film, continues to be blown into hot-air 0.5h; Then with coated tablet 40 ℃ of following dry 48h in drying baker; Get the coated tablet that above-mentioned drying finishes, use mechanical means to break into the aperture of aperture, get product as 0.45mm in coated tablet one side.
Embodiment 2 valine entecavir controlled release tablets
(1) label prescription:
Valine entecavir 350g;
Microcrystalline Cellulose 240g;
Magnesium sulfate 2200g;
Magnesium stearate 15g
(2) coating fluid prescription:
Cellulose acetate 250g;
Dibutyl phthalate 20ml
Polyethylene Glycol 3350 40g;
Acetone 4500ml
Sheet heart preparation: with sieving behind the medicine of recipe quantity and magnesium sulfate, the microcrystalline Cellulose pulverize separately, mix homogeneously uses 95% alcohol to be wetting agent system soft material; 20 mesh sieves are granulated; Tabletting promptly got 1000 sheet hearts after 50 ± 5 ℃ of dryings of wet granular, 18 mesh sieve granulate, dried granule added the lubricant mixing.
Art for coating: label is placed in the coating pan, be blown into hot-air, when treating that the label temperature is 40 ℃ of left and right sides; Carry out coating, the coating solution flow velocity is 5-10mL/min, and pressure is 0.8kg/cm2; The coating kettle temperature is about 40 ℃, reaches weightening finish 4.0～4.5% to the thickness of label outer coatings film, continues to be blown into hot-air 0.5h; Then with coated tablet 40 ℃ of following dry 48h in drying baker; Get the coated tablet that above-mentioned drying finishes, use mechanical means to break into the aperture of aperture, get product as 0.5mm in coated tablet one side.
Embodiment 3 valine entecavir conventional tablets
Valine entecavir 350g;
Microcrystalline Cellulose 240g;
Magnesium sulfate 2200g;
Magnesium stearate 15g
With sieving behind the medicine of recipe quantity and magnesium sulfate, the microcrystalline Cellulose pulverize separately; Mix homogeneously; Use 95% ethanol to be wetting agent system soft material, 20 mesh sieves are granulated, 50 ± 5 ℃ of dryings of wet granular; Tabletting promptly got 1000 valine entecavir conventional tablets after 18 mesh sieve granulate, dried granule added the lubricant mixing.
Embodiment 4 valine entecavir tablet release in vitro/stripping experiment
According to external stripping/release experiment that " Pharmacopoeia of People's Republic of China version in 2005 " carried out valine entecavir about the pertinent regulations and the condition of medicinal tablet dissolution in vitro/release degree.
Valine entecavir controlled release tablet and 6 of the valine entecavir conventional tablets of respectively getting embodiment 2,3 preparations experimentize; Adopt the basket method of changeing; The mensuration medium is a simulated gastric fluid; Respectively at experiment beginning sampling in back 10 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, 16 hours, 24 hours, measure the content of valine entecavir in the medium.The valine entecavir Determination on content adopts ultraviolet spectrophotometry.Experimental result such as table 1 are represented in release and stripping with the percent of labelled amount:
Experimental result shows; The release in vitro of the valine entecavir controlled release tablet that the present invention is prepared has reached the requirement of controlled release preparation preferably near 0 grade of release, postpones to have controlled the release of valine entecavir; Make medicine within 24 hours, constantly to discharge, play consistently effect.And the stripping result of valine entecavir conventional tablet shows, medicine can cause medicine to form the apparent in view peak valley effect that gets blood drug level in vivo promptly near stripping fully, and weaken the therapeutical effect of medicine in external quick stripping in 4 hours like this.
The monitoring of blood drug level in the embodiment 5 valine entecavir tablet bodies
Through the valine entecavir controlled release tablet and the valine entecavir conventional tablet of embodiment 2,3 preparations of feeding to beasle dog,, monitor the variation of blood drug level in its body in the present embodiment through the timing blood sampling.
12 male beasle dogs are divided into 2 groups at random; Every group 6; Respectively at when beginning experiment feed 1 of the prepared valine entecavir controlled release tablet of embodiment 2,3 and valine entecavir conventional tablet; Respectively at the 0.5th, 2,6,12,24 hour blood sampling after the experiment beginning, detect the content of valine entecavir in the blood then.Because valine entecavir is the prodrug of Entecavir, it generates Entecavir performance drug effect via enzymes metabolism in vivo, and the concentration of Entecavir in the said blood sample is detected on the historical facts or anecdotes border.Detect and adopt HPLC, detection and chromatographic condition are the normal condition of Entecavir.
Experimental result is as shown in Figure 1.
Experimental result shows; The prepared valine entecavir controlled release tablet of the present invention has been stablized the blood drug level of Entecavir well than conventional tablet; Avoided the peak valley fluctuation; Effectively prolong the action time of medicine, improved the therapeutic index of medicine, avoided the untoward reaction of medicine more to a certain extent.
Claims (10)
1. valine entecavir controlled release tablet, it is characterized in that: it comprises following component:
(1) label composition:
Valine entecavir 200～450 weight portions;
Diluent 100～300 weight portions;
Penetration enhancer 90～300 weight portions;
(2) coating composition:
Filmogen 120～400 weight portions;
Plasticizer 30～100 weight portions;
And, be equipped with the aperture that the aperture is 0.4-0.6mm in a side of this valine entecavir controlled release tablet.
2. valine entecavir controlled release tablet according to claim 1 is characterized in that: said each constituent content is preferred:
(1) label composition:
Valine entecavir 250～350 weight portions;
Diluent 180～240 weight portions;
Penetration enhancer 170～220 weight portions;
(2) coating composition:
Filmogen 150～300 weight portions;
Plasticizer 50～80 weight portions;
And, be equipped with the aperture that the aperture is 0.45-0.55mm in a side of this valine entecavir controlled release tablet.
3. valine entecavir controlled release tablet according to claim 1 and 2 is characterized in that: said core segment also includes the lubricant of 10～20 weight portions and an amount of binding agent.
4. according to any described valine entecavir controlled release tablet of claim 1 to 3, it is characterized in that: diluent is selected from one or more the mixture in starch, pregelatinized Starch, dextrin, lactose, the microcrystalline Cellulose.
5. according to any described valine entecavir controlled release tablet of claim 1 to 4, it is characterized in that: penetration enhancer is selected from one or more the mixture in sodium chloride, potassium chloride, magnesium sulfate, magnesium chloride, potassium sulfate, sodium sulfate, d-mannitol, carbamide, glucose, sucrose, Magnesium succinate, the tartaric acid.
6. according to any described valine entecavir controlled release tablet of claim 1 to 5, it is characterized in that: filmogen is selected from cellulose acetate, ethyl cellulose, polyacrylic acid tree vinegar, gather phthalein amine or ethylene-vinyl acetate copolymer, polyvinyl chloride, gather phthalein amine, gather one or more the mixture in the carbonic acid vinegar.
7. according to any described valine entecavir controlled release tablet of claim 1 to 6, it is characterized in that: plasticizer is selected from that phthalic acid two hot vinegar, phthalic acid diethyl are cruel, one or more the mixture in the mannitol, Oleum Ricini, glycerol.
8. according to any described valine entecavir controlled release tablet of claim 1 to 7, it is characterized in that: binding agent is selected from the mixed solution of water, water or the alcohol of one or more mixture in polyvinylpyrrolidone, sodium carboxymethyl cellulose, hydroxypropyl emthylcellulose, the methylcellulose.
9. according to any described valine entecavir controlled release tablet of claim 1 to 8, it is characterized in that: lubricant is pharmaceutically useful adjuvant with lubrication, comprises magnesium stearate, Pulvis Talci, sodium lauryl sulphate.
10. method for preparing like the described valine entecavir controlled release tablet of claim 1～9; It is characterized in that:, behind the mix homogeneously, add binding agent system soft material sieving behind the valine entecavir of recipe quantity and diluent, the penetration enhancer pulverize separately; 20 mesh sieves are granulated; 50 ± 5 ℃ of dryings, 18 mesh sieve granulate, dried granule add lubricant and are pressed into label; Art for coating: the coating solution flow velocity is 5-10ml/min, and pressure is 0.8kg/cm2, and the coating kettle temperature is 40 ℃, and the coating pan rotating speed is 10-20rpm, and the punching diameter is 0.4-0.6mm, gets product.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2010102819014A CN102397263A (en) | 2010-09-15 | 2010-09-15 | Valine entecavir controlled-release tablet and preparation method thereof |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2010102819014A CN102397263A (en) | 2010-09-15 | 2010-09-15 | Valine entecavir controlled-release tablet and preparation method thereof |
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| CN102397263A true CN102397263A (en) | 2012-04-04 |
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| CN2010102819014A Pending CN102397263A (en) | 2010-09-15 | 2010-09-15 | Valine entecavir controlled-release tablet and preparation method thereof |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103864791A (en) * | 2014-03-18 | 2014-06-18 | 福建天泉药业股份有限公司 | Entecavir derivative and preparation method thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1712002A (en) * | 2004-06-24 | 2005-12-28 | 中国医学科学院药物研究所 | Osmotic pumping sustained preparation of ropinirole hydrochloride and its preparing method |
-
2010
- 2010-09-15 CN CN2010102819014A patent/CN102397263A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1712002A (en) * | 2004-06-24 | 2005-12-28 | 中国医学科学院药物研究所 | Osmotic pumping sustained preparation of ropinirole hydrochloride and its preparing method |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103864791A (en) * | 2014-03-18 | 2014-06-18 | 福建天泉药业股份有限公司 | Entecavir derivative and preparation method thereof |
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Application publication date: 20120404 |