CN104490832A - Lyophilized tablet prepared from warfarin composition and preparation method thereof - Google Patents

Abstract

The invention provides a lyophilized tablet prepared from a warfarin composition and a preparation method thereof and belongs to the technical of medicines and medicine production. The lyophilized tablet is prepared from warfarin, starch and sucrose, wherein the starch and the sucrose serve as adjuvants. By heating the common corn starch, the binding and disintegrating effects of the starch in the lyophilized tablet can be improved, and the formability of the lyophilized tablet can be improved. The adjuvants for preparing the lyophilized tablet only comprise the starch and the sucrose. The lyophilized tablet is prepared by decreasing temperature twice and increasing temperature twice, and the twice temperature decrease and twice temperature increase can ensure that the lyophilized tablet can be well formed, the dissolution rate of the lyophilized tablet can be increased and the bioavailability of the lyophilized tablet can be improved. The lyophilized tablet overcomes the defects of the ordinary tablet prepared from warfarin, is prepared by adopting a few kinds of and a small amount of adjuvants compared with the tablet prepared from warfarin, has high dissolution rate and high bioavailability, has a good clinical treatment effect and can be used for clinical treatment safely.

Description

A kind of warfarin composition freeze-drying 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 warfarin composition freeze-drying sheet and preparation method thereof.

Background technology

This product is the one of coumarin anticoagulant, has the effect to antivitamin K in vivo.The factor Ⅱ that vitamin K can be suppressed to participate in, VII, Ⅸ, the synthesis at liver of Ⅹ.Be mainly used in preventing and treating thrombotic disease.

molecular weight: 330.31

In common warevan 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 warevan tablet quality standard, the dissolution sending out forest tract magnificent reached more than 70% for qualified 45 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 warevan tablet, improve dissolution and the bioavailability of warevan 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 warevan tablet 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 warfarin composition freeze-drying 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 warfarin composition freeze-drying sheet, does adjuvant with starch and sucrose, produces with freeze-dry process, this tablet overcomes the shortcoming of above-mentioned common warfarin sheet, decreases supplementary product kind and consumption in warfarin sheet, and this sheet dissolution is large, bioavailability is high, ensure that curative effect and the safety of clinical application.

A kind of warfarin composition freeze-drying sheet, is prepared from by following raw material:

A preparation method for warfarin composition freeze-drying 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 7.2-8.3, 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 warfarin 2.5 grams, add in 1L Semen Maydis-sucrose solution, stir 25 ~ 35 minutes;

Medicinal liquid is sub-packed in drug-containing dish after measuring warfarin 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 warfarin composition freeze-drying sheet.

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

Beneficial effect of the present invention is:

The preparation method of a kind of warfarin composition freeze-drying sheet of the present invention, heating process process is carried out to common corn starch, starch bonding in tablets, disintegration can be improved, improve the mouldability of tablet, in warfarin composition freeze-drying sheet, dosage of sucrose is 8.5% (W/V), it is the hardness reinforcer of this tablet, and plays flavored action.Warfarin composition freeze-drying sheet only needs starch and sucrose two kinds of adjuvants.The freeze-dry process of two liters falls in warfarin composition freeze-drying 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.

Accompanying drawing explanation

Fig. 1 is the dissolution correlation curve figure of warfarin in experiment.

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.

Embodiment 1

A, take the corn starch of 100g, the purified water adding 900m l stirs, and controls 7.2-8.3, is then heated to 72 DEG C, keep 120 minutes, make the corn starch solution of 9% (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 warfarin 2.5g, add in 1L Semen Maydis-sucrose solution, stir 30 minutes.

Medicinal liquid is sub-packed in drug-containing dish after measuring warfarin 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 warfarin composition freeze-drying sheet.

Embodiment 2

A, take the corn starch of 130g, the purified water adding 900m l stirs, and controls 7.2-8.3, 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 warfarin 2.5 grams (by 1000 calculations), add 1L Semen Maydis-sucrose solution, stir 30 minutes.

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

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 warfarin composition freeze-drying sheet.

Experimental data

The warfarin composition freeze-drying sheet that above-described embodiment is obtained carries out following quality research test:

1, hardness, friability contrast test

Get warfarin composition freeze-drying sheet prepared by above-described embodiment respectively and warfarin 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	67.4	<1％
Execute example 2	65.5	<1％
			Ordinary tablet (commercially available)	69.5	<1％

Experimental data shows, warfarin composition freeze-drying 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 warevan tablet (commercially available) and each 6 of warfarin composition freeze-drying sheet, No. 4 to No. 6 is embodiment 2), this product, according to dissolution method (annex X C first method), with phthalate buffer of seeing (pH6.8) 500ml for dissolution medium, rotating speed is 100 turns per minute, operate in accordance with the law, through 45 minutes time, get solution and be about 10ml, filter, according to the chromatographic condition under assay item, precision measures subsequent filtrate 20fzl and notes people's chromatograph of liquid, record chromatogram; Separately get warfarin sodium reference substance appropriate, accurately weighed, add phosphate buffer (pH6.8) dissolve and quantitatively dilute the solution made about containing 5ug (2.5mg specification) in every 1ml, be measured in the same method, by external standard method with the stripping quantity of the every sheet of calculated by peak area.Result is as follows:

One, warevan tablet (commercially available)

Two, warfarin composition freeze-drying sheet (No. 1 to No. 3 is embodiment 1, and No. 4 to No. 6 is embodiment 2)

Respectively with catch cropping Dissolution profiles during average dissolution pair, as Fig. 1.

Four, result judges

Judge according to Chinese Pharmacopoeia (2010 editions) second warevan tablet quality standard, the dissolution of warevan tablet (commercially available) reached more than 70% for qualified 45 minutes time, actual measurement is 73.5%, and warfarin lyophilizing sheet dissolution 30 minutes time reaches 75.35%.It can thus be appreciated that the time that warfarin lyophilizing sheet dissolution reaches 70% is than the time decreasing about 15 minutes of warfarin (commercially available).So the warfarin lyophilizing sheet blood drug level peaking time is shorter than warfarin (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. a warfarin composition freeze-drying sheet, is characterized in that, is prepared from by following raw material:

2. a preparation method for warfarin composition freeze-drying 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 7.2-8.3, 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 warfarin 2.5 grams, add in 1L Semen Maydis-sucrose solution, stir 25 ~ 35 minutes;

Medicinal liquid is sub-packed in drug-containing dish after measuring warfarin 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 warfarin composition freeze-drying sheet.