CN104490817A - Entecavir composition freeze-dried tablet and preparation method thereof - Google Patents

Abstract

The invention provides an entecavir composition freeze-dried tablet and a preparation method thereof, and relates to the technical fields of medicines and medicine production. The entecavir composition freeze-dried tablet comprises entecavir, starch and sucrose; and the entecavir composition freeze-dried tablet is prepared from the starch and the sucrose as auxiliary materials by a freeze-drying process. According to the tablet, the defects of ordinary entecavir tablet are overcome; the variety and the amount of auxiliary materials in the entecavir tablet are reduced; the tablet is high in dissolution rate, and high in bioavailability; and the curative effect and the safety of clinical medication are ensured.

Description

A kind of entecavir composite lyophilizing sheet and preparation method thereof

Technical field

The present invention relates to medicine and medical production technical field, be specifically related to a kind of entecavir composite lyophilizing sheet and preparation method thereof.

Background technology

Entecavir chemical name: 2-amino-9-[(1S, 3R, 4S)-4-hydroxyl-3-methylol-2-methylenecyclopentyl]-1,9-dihydro-6H-purine-6-one monohydrate, molecular formula: C12H15N5O3H2O, molecular weight: 295.3.Entecavir is applicable to virus replication and enlivens, and the lasting rising of serum alanine aminotransferase (ALT) or liver histological show the treatment of chronic adult's hepatitis B of activeness pathological changes.

In common Entecavir tablet containing supplementary product kind and quantity more, generally to use filler, lubricant, disintegrating agent, adhesive, correctives etc., according to Chinese Pharmacopoeia (2010 editions) second Entecavir tablet quality standard, the dissolution of Entecavir tablet reached more than 75% for qualified 60 minutes time, and increasing research shows that impurity in the incompatibility of the toxic and side effects of adjuvant itself, adjuvant and principal agent, adjuvant etc. all can have an impact to the safety of medicine.

Therefore, provide one can overcome above-mentioned shortcoming, select suitable adjuvant and technique, reduce supplementary product kind and consumption in Entecavir tablet, improve dissolution and the bioavailability of Entecavir tablet, ensure that the safety of clinical application all has positive effect.

Traditional lyophilizing tablet can improve dissolution and bioavailability, but still need use the adjuvant such as mannitol, gelatin.And mannitol has certain biological activity, gelatin resource-constrained and perishable.

Starch is the basic adjuvant of oral solid formulation, it is polymerized by glucose molecule, and be commonly used for adhesive, diluent and disintegrating agent in tablets, it is cheap and easy to get, to human-body safety, but being used alone starch has no report as adjuvant freeze-dry process production Entecavir lyophilizing sheet.

Summary of the invention

Technical problem to be solved by this invention is the defect overcoming prior art, and propose a kind of entecavir composite lyophilizing sheet and preparation method thereof further, said preparation adjuvant is few, good stability, and bioavailability is high.

Technical problem to be solved by this invention realizes by the following technical solutions:

A kind of entecavir composite lyophilizing sheet, comprise Entecavir, starch, sucrose, this entecavir composite lyophilizing sheet starch and sucrose do adjuvant, produce with freeze-dry process, this tablet overcomes the shortcoming of above-mentioned common Entecavir tablet, decreases supplementary product kind and consumption in Entecavir tablet, and this sheet dissolution is large, bioavailability is high, ensure that curative effect and the safety of clinical application.

A kind of entecavir composite lyophilizing sheet, is prepared from by following raw material:

A preparation method for entecavir composite lyophilizing sheet, comprises step as follows:

A, take the starch of component amount, add a certain amount of purified water and stir, by pH adjusting agent, the pH value of solution is controlled between 5-6.5, be then heated to 72 DEG C, be incubated 20 minutes, make the corn starch solution of 5 ~ 15% (W/V);

B, measure purified water 45ml, boil, add 85g sucrose, stir, after dissolving, continue to be heated to 100 DEG C, filter with purified cotton, the appropriate hot distilled water of filter is cleaned, and washing liquid and filtrate merge, and let cool, add appropriate distilled water, make full dose become 100ml, stir evenly, obtain B solution;

The solution that C, the solution and the step B that steps A are obtained obtain mixes, and fully stirs 30 minutes, is down to room temperature and obtains Semen Maydis-sucrose solution;

D, take Entecavir 5 grams, add in 1L Semen Maydis-sucrose solution, stir 25 ~ 35 minutes;

Medicinal liquid is sub-packed in drug-containing dish after measuring Entecavir content by E, medicinal liquid, each drug-containing dish dress 1.0ml;

F, the drug-containing dish that medicinal liquid is housed is put into vacuum freezing drying oven, be cooled to subzero 45 DEG C, keep 2 hours, evacuation, then 0 DEG C is warming up to gradually, keep 2 hours, then be cooled to subzero 45 DEG C, keep 2 hours, be warming up to 0 DEG C gradually again, keep 2 ~ 4 hours, then be warming up to 28 ~ 32 DEG C of dryings 4 ~ 6 hours gradually, whole process vacuum remains on 10 handkerchiefs;

G, finally the drug-containing dish lid of powder charge to be covered tightly, and load aluminium foil bag and carry out sealing and obtain entecavir composite lyophilizing sheet.

Described starch selects corn starch, preferably the corn starch solution of 10% (W/V).

Beneficial effect of the present invention is:

A kind of entecavir composite lyophilizing sheet provided by the invention and preparation method thereof, it adopts unique processing step, heating process process is carried out to common corn starch, starch bonding in tablets, disintegration can be improved, improve the mouldability of tablet, in entecavir composite lyophilizing sheet, dosage of sucrose is 8.5% (W/V), and it is the hardness reinforcer of this tablet, and plays flavored action.Entecavir composite lyophilizing sheet only needs starch and sucrose two kinds of adjuvants.The freeze-dry process of two liters falls in entecavir composite lyophilizing sheet employing two, and twice cooling, twice intensification can make sheet mouldability better, which increase the dissolution of tablet, thus improve the bioavailability of tablet.

Detailed description of the invention

The technological means realized to make the present invention, creation characteristic, reaching object and effect is easy to understand, below in conjunction with specific embodiment, set forth the present invention further, but following embodiment being only the preferred embodiments of the present invention, and not all.Based on the embodiment in embodiment, those skilled in the art under the prerequisite not making creative work obtain other embodiment, all belong to the protection domain of this patent.

Entecavir content is for 5mg/ sheet.

Embodiment 1

A, take the corn starch of 100g, the purified water adding 900ml stirs, and is controlled then to be heated to 72 DEG C 6.0 by the pH value of solution, keep 120 minutes, make the corn starch solution of 9% (W/V) by pH adjusting agent.

B, measure purified water 45ml, boil, add 85g sucrose, stir, after dissolving, continue to be heated to 100 DEG C, filter with purified cotton, the appropriate hot distilled water of filter is cleaned, and washing liquid and filtrate merge, and let cool, add appropriate distilled water, make full dose become 100ml, stir evenly, obtain B solution.

The solution that C, the solution and the step B that steps A are obtained obtain mixes, and fully stirs 30 minutes, after solution be down to room temperature obtain Semen Maydis-sucrose solution.

D, take Entecavir 5g, add in 1L Semen Maydis-sucrose solution, stir 30 minutes.

Medicinal liquid is sub-packed in drug-containing dish after measuring Entecavir content by E, medicinal liquid, each drug-containing dish dress 1.0ml.

F, the drug-containing dish that medicinal liquid is housed is put into vacuum freezing drying oven, be cooled to subzero 45 DEG C, keep 2 hours, evacuation, then 0 DEG C is warming up to gradually, keep 2 hours, then be cooled to subzero 45 DEG C, keep 2 hours, be warming up to 0 DEG C gradually again, keep 2 ~ 4 hours, then be warming up to 28 ~ 32 DEG C of dryings 4 ~ 6 hours gradually, whole process vacuum remains on 10 handkerchiefs; Finally the drug-containing dish lid of powder charge is covered tightly, and load aluminium foil bag and carry out sealing and obtain entecavir composite lyophilizing sheet.

Embodiment 2

A, take the corn starch of 130g, the purified water adding 900ml stirs, and controls 6.0, is then heated to 72 DEG C, keep 120 minutes, make the corn starch solution of 13% (W/V) by pH adjusting agent by the pH value of solution.

B, measure purified water 45ml, boil, add 85g sucrose, stir, after dissolving, continue to be heated to 100 DEG C, filter with purified cotton, the appropriate hot distilled water of filter is cleaned, and washing liquid and filtrate merge, and let cool, add appropriate distilled water, make full dose become 100ml, stir evenly, obtain B solution.

The solution that C, the solution and the step B that steps A are obtained obtain mixes, and fully stirs 30 minutes, after solution be down to room temperature obtain Semen Maydis-sucrose solution.

D, take Entecavir 5 grams (by 1000 calculations), add 1L Semen Maydis-sucrose solution, stir 30 minutes.

Medicinal liquid is sub-packed in drug-containing dish after measuring Entecavir content by E, medicinal liquid, each drug-containing dish dress 1.0ml.

F, the drug-containing dish that medicinal liquid is housed is put into vacuum freezing drying oven, be cooled to subzero 45 DEG C, keep 2 hours, evacuation, then 0 DEG C is warming up to gradually, keep 2 hours, then be cooled to subzero 45 DEG C, keep 2 hours, be warming up to 0 DEG C gradually again, keep 2 ~ 4 hours, then be warming up to 28 ~ 32 DEG C of dryings 4 ~ 6 hours gradually, whole process vacuum remains on 10 handkerchiefs; Finally the drug-containing dish lid of powder charge is covered tightly, and load aluminium foil bag and carry out sealing and obtain entecavir composite lyophilizing sheet.

Experimental data

The entecavir composite lyophilizing sheet that above-described embodiment is obtained carries out following quality research test:

1, hardness, friability contrast test

Get entecavir composite lyophilizing sheet prepared by above-described embodiment respectively and Entecavir ordinary tablet (commercially available) detects friability and hardness by " Chinese Pharmacopoeia " version in 2010 two annex X G inspection techniques, carried out comparative study, the results are shown in following table:

Sample	Hardness/N	Friability
			Execute example 1	61	<1％
Execute example 2	67	<1％
			Ordinary tablet (commercially available)	70	<1％

Experimental data shows, entecavir composite lyophilizing sheet and ordinary tablet (commercially available) without significant difference, meet " Chinese Pharmacopoeia " version in 2010 to the requirement of tablet on friability and hardness.

2, dissolution contrast test

(No. 1 to No. 3 is embodiment 1 to get Entecavir tablet (commercially available) and each 6 of entecavir composite lyophilizing sheet, No. 4 to No. 6 is embodiment 2), press Chinese Pharmacopoeia (2010 editions) second dissolution method annex X C second method respectively, with 0.1mol/L hydrochloric acid solution-ethanol (70:30) 900mL for dissolution medium, rotating speed is 120 turns per minute, operate in accordance with the law, respectively through 10min, 20min, 40min, 60min, during 90min, get solution to filter, get continuous worry liquid, with high effective liquid chromatography for measuring Entecavir content: chromatographic column is Luna C18, mobile phase is acetonitrile-water (4:96), flow velocity is 1.0mlmin ^-1, determined wavelength is 254nm, and column temperature is 25 DEG C, and sample size is 20 μ L, another precision takes Entecavir reference substance and is about 13mg, puts in 25mL measuring bottle, and add dissolve with ethanol and be diluted to scale, shaking up, precision measures 2mL, puts in 100mL measuring bottle, adds stripping medium to scale, shakes up, be measured in the same method, calculate the stripping quantity of every sheet.Result is as follows:

One, Entecavir tablet (commercially available)

Two, Entecavir lyophilizing sheet (No. 1 to No. 3 is embodiment 1, and No. 4 to No. 6 is embodiment 2)

Three, result judges

Judge according to Entecavir tablet quality standard, the dissolution of Entecavir tablet (commercially available) reached more than 80% for qualified 40 minutes time, and actual measurement is 80.3%, and Entecavir lyophilizing sheet dissolution 20 minutes time reaches 81.5%.It can thus be appreciated that the time that Entecavir lyophilizing sheet dissolution reaches 80% decreased for about 50% (20 minutes) time than Entecavir tablet (commercially available).So the Entecavir lyophilizing sheet blood drug level peaking time is shorter than Entecavir tablet (commercially available), and bioavailability is higher, better efficacy.

More than show and describe ultimate principle of the present invention, principal character and advantage of the present invention.The technical staff of the industry should understand; the present invention is not restricted to the described embodiments; what describe in above-described embodiment and description is only preference of the present invention; be not used for limiting the present invention; without departing from the spirit and scope of the present invention; the present invention also has various changes and modifications, and these changes and improvements all fall in the claimed scope of the invention.Application claims protection domain is defined by appending claims and equivalent thereof.

Claims (2)

1. an entecavir composite lyophilizing sheet, is characterized in that, is prepared from by following raw material:

2. a preparation method for entecavir composite lyophilizing sheet according to claim 1, is characterized in that, comprise step as follows:

A, take the starch of component amount, add a certain amount of purified water and stir, by pH adjusting agent, the pH value of solution is controlled between 5-6.5, be then heated to 72 DEG C, be incubated 20 minutes, make the corn starch solution of 5 ~ 15% (W/V);

B, measure purified water 45ml, boil, add 85g sucrose, stir, after dissolving, continue to be heated to 100 DEG C, filter with purified cotton, the appropriate hot distilled water of filter is cleaned, and washing liquid and filtrate merge, and let cool, add appropriate distilled water, make full dose become 100ml, stir evenly, obtain B solution;

The solution that C, the solution and the step B that steps A are obtained obtain mixes, and fully stirs 30 minutes, is down to room temperature and obtains Semen Maydis-sucrose solution;

D, take Entecavir 5 grams, add in 1L Semen Maydis-sucrose solution, stir 25 ~ 35 minutes;

Medicinal liquid is sub-packed in drug-containing dish after measuring Entecavir content by E, medicinal liquid, each drug-containing dish dress 1.0ml;

F, the drug-containing dish that medicinal liquid is housed is put into vacuum freezing drying oven, be cooled to subzero 45 DEG C, keep 2 hours, evacuation, then 0 DEG C is warming up to gradually, keep 2 hours, then be cooled to subzero 45 DEG C, keep 2 hours, be warming up to 0 DEG C gradually again, keep 2 ~ 4 hours, then be warming up to 28 ~ 32 DEG C of dryings 4 ~ 6 hours gradually, whole process vacuum remains on 10 handkerchiefs;

G, finally the drug-containing dish lid of powder charge to be covered tightly, and load aluminium foil bag and carry out sealing and obtain entecavir composite lyophilizing sheet.