CN104586784A - Nitrazepam composition freeze-dried tablets and preparation method thereof - Google Patents

Abstract

The invention provides nitrazepam composition freeze-dried tablets and a preparation method thereof and relates to the technical fields of medicines and medicine production. The nitrazepam composition freeze-dried tablets contain nitrazepam, starch and cane sugar, wherein starch and cane sugar are used as auxiliary materials, common corn starch is subjected to a heating process treatment so that the adhesion and disintegration functions of starch in the tablets can be improved, and the formability of the tablets can be improved, and the nitrazepam composition freeze-dried tablets only need the two auxiliary materials, namely starch and cane sugar. The nitrazepam composition freeze-dried tablets adopt a freeze-drying process of cooling twice and heating twice, the formability of the tablets can be better because of cooling twice and heating twice, and the dissolution rate of the tablets is increased, thus improving the bioavailability of the tablets; the tablets overcome the defects of common nitrazepam tablets, reduce the types and the dosages of the auxiliary materials in the nitrazepam tablets, have a high dissolution rate and a high bioavailability, and ensure the curative effect and the safety of clinical medication.

Description

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

Background technology

This product is Benzodiazepines antianxiety drugs, and mechanism of action and its selectively acting, in cerebral limbic system, are combined, and promote-the release of aminobutyric acid with maincenter benzodiazepine receptors, promotes that betaynaptic transmission function is relevant, has stable, calm and remarkable syngignoscism.This product also has central muscle relaxation effect and anticonvulsant action.

molecular formula C ₁₅h ₁₁n ₃o ₃, molecular weight 281.27

In common nitrazepam sheet containing supplementary product kind and quantity more, generally to use filler, lubricant, disintegrating agent, adhesive, correctives etc., according to Chinese Pharmacopoeia (2010 editions) second nitrazepam tablet quality standard, nitrazepam sheet 60 minutes with stripping quantity when 180 minutes should must not should be mutually respectively more than labelled amount 50% with must not be less than 75% of labelled amount, 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 nitrazepam sheet, improve dissolution and the bioavailability of nitrazepam sheet, 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 nitrazepam 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 nitrazepam 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 nitrazepam composition freeze-drying sheet, does adjuvant with starch and sucrose, produces with freeze-dry process, this tablet overcomes the shortcoming of above-mentioned common nitrazepam sheet, decreases supplementary product kind and consumption in nitrazepam sheet, and this sheet dissolution is large, bioavailability is high, ensure that curative effect and the safety of clinical application.

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

A preparation method for nitrazepam 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 5-7.5, 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 nitrazepam 80 grams, add in 1L Semen Maydis-sucrose solution, stir 25 ~ 35 minutes;

Medicinal liquid is sub-packed in drug-containing dish after measuring nitrazepam 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 nitrazepam 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 nitrazepam 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 nitrazepam composition freeze-drying sheet, dosage of sucrose is 8.5% (W/V), it is the hardness reinforcer of this tablet, and plays flavored action.Nitrazepam composition freeze-drying sheet only needs starch and sucrose two kinds of adjuvants.The freeze-dry process of two liters falls in nitrazepam 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 nitrazepam 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 900ml stirs, and controls at 5-7.5, 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 nitrazepam 80g, add in 1L Semen Maydis-sucrose solution, stir 30 minutes.

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

Embodiment 2

A, take the corn starch of 130g, the purified water adding 900ml stirs, and controls at 5-7.5, 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 nitrazepam 80 grams (by 1000 calculations), add 1L Semen Maydis-sucrose solution, stir 30 minutes.

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

Experimental data

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

1, hardness, friability contrast test

Get nitrazepam composition freeze-drying sheet prepared by above-described embodiment respectively and nitrazepam 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	64	<1％
Execute example 2	65	<1％
			Ordinary tablet	63	<1％

Experimental data shows, nitrazepam 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 nitrazepam sheet (commercially available) and each 6 of nitrazepam composition freeze-drying sheet, No. 4 to No. 6 is embodiment 2), press Chinese Pharmacopoeia (2010 editions) second dissolution method (annex X C first method) respectively, with phosphate buffer (PH8.6) 1000ml for dissolution medium, rotating speed is 150 turns per minute, operate in accordance with the law, respectively through 60min, 100min, 140min, 180min, during 210min, get solution 8ml, filter, and immediately in stripping rotor, supplement phosphate buffer (PH8.6) 8ml, subsequent filtrate is as need testing solution, separately get nitrazepam reference substance and be about 20mg, accurately weighed, put in 250ml measuring bottle, add dissolution medium appropriate, put jolting in tepidarium and nitrazepam is dissolved, let cool, be diluted to scale with dissolution medium, shake up, in contrast product solution.Precision measures need testing solution and each 5ml of reference substance solution, put in 25ml measuring bottle respectively, scale is diluted to dissolution medium, shake up, according to ultraviolet-visible spectrophotometry (annex IV A), measure absorbance respectively at the wavelength place of 278nm, calculate the stripping quantity of every sheet in the above-mentioned time respectively.Result is as follows:

One, nitrazepam sheet (commercially available)

Two, nitrazepam lyophilizing 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.

Three, result judges

Judge according to Chinese Pharmacopoeia (2010 editions) second nitrazepam tablet quality standard, nitrazepam sheet (commercially available) 60 minutes with stripping quantity when 180 minutes should must not should be mutually respectively more than labelled amount 50% with must not be less than 75% of labelled amount for qualified, when actual measurement is 60 minutes, dissolution is 42.3%, when 180 minutes, dissolution is 76.15%, and nitrazepam lyophilizing sheet when 60 minutes time, dissolution is 43.4,100 minutes dissolution be 76.1%.It can thus be appreciated that the time that nitrazepam lyophilizing sheet dissolution reaches 75% decreased for about 44.4% (80 minutes) time than nitrazepam sheet (commercially available).So the nitrazepam lyophilizing sheet blood drug level peaking time is shorter than nitrazepam sheet (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 nitrazepam composition freeze-drying sheet, is characterized in that, is prepared from by following raw material:

2. a preparation method for nitrazepam 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 5-7.5, 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 nitrazepam 80 grams, add in 1L Semen Maydis-sucrose solution, stir 25 ~ 35 minutes;

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