CN104546673A - Clonazepam composition freeze-dried tablet and preparation method thereof - Google Patents

Abstract

The invention provides a clonazepam composition freeze-dried tablet and a preparation method thereof, and relates to the technical field of medicines and medicine production. The clonazepam composition freeze-dried tablet is prepared from clonazepam, starch and cane sugar, starch and cane sugar are used as auxiliary materials, and heating process treatment is performed on the ordinary corn starch, so that the bonding and disintegration functions of starch in the tablet are improved, the formability of the tablet is improved, and the clonazepam composition freeze-dried tablet only needs the two auxiliary materials namely starch and cane sugar. The clonazepam composition freeze-dried tablet is prepared by the freeze-drying process that the temperature is increased and decreased for two times; the process that the temperature is increased and decreased for two times enables the formability of the tablet to be better and increases the dissolution rate of the tablet, so as to improve the bioavailability of the tablet; the tablet overcomes the defect of the common clonazepam, is high in dissolution rate and high in bioavailability, and ensures the curative effect and the safety of the clinical medication; the varieties and the dosage of the auxiliary materials in clonazepam are reduced.

Description

A kind of clonazepam composition 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 clonazepam composition lyophilizing sheet and preparation method thereof.

Background technology

Clonazepam is Benzodiazepines Kang epilepsy anticonvulsant.This medicine has antagonism to many animals epilepsy model, especially good to the clonism model antagonism caused by pentylenetetrazole, all has stronger antagonism to maximal electroshock convulsions, strychnine and Picrotoxin convulsions etc.Inhibitory action is had to various types of epilepsy.Clonazepam had both suppressed the seizure discharge of epilepsy focus, also suppressed the diffusion that discharge activities is organized towards periphery.This medicine acts on the benzodiazepine receptors (BZR) of central nervous system, strengthen the combination of CNS inhibition neurotransmitter γ-aminobutyric acid (GABA) and GABAA receptor, promote that chloride channel is open, cell hyperpolarization, strengthen the synapse suppression that GABA serotonergic neuron mediates, neuronic irritability is reduced.Clonazepam may cause dependency.

In common clonazepam 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 clonazepam tablet quality standard, the dissolution of clonazepam sheet reached more than 75% 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 clonazepam sheet, improve dissolution and the bioavailability of clonazepam 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 clonazepam 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 clonazepam composition 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 clonazepam composition lyophilizing sheet, adjuvant is done with starch and sucrose, produce with freeze-dry process, this tablet overcomes the shortcoming of above-mentioned common clonazepam sheet, decrease supplementary product kind and consumption in clonazepam sheet, this sheet dissolution is large, and bioavailability is high, ensure that curative effect and the safety of clinical application.

A kind of clonazepam composition lyophilizing sheet, is prepared from by following raw material:

A preparation method for clonazepam composition 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 5.5-7.5, 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 100m L, 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 clonazepam 0.25 gram, add in 1L Semen Maydis-sucrose solution, stir 25 ~ 35 minutes;

Medicinal liquid is sub-packed in drug-containing dish after measuring clonazepam 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 clonazepam composition lyophilizing 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 clonazepam composition lyophilizing 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 clonazepam lyophilizing compounded plate, dosage of sucrose is 8.5% (W/V), it is the hardness reinforcer of this tablet, and plays flavored action.Clonazepam lyophilizing compounded plate only needs starch and sucrose two kinds of adjuvants.The freeze-dry process of two liters falls in clonazepam lyophilizing compounded plate 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 clonazepam 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 5.5-7.5, 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 100m L, 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 clonazepam 0.25g, add in 1L Semen Maydis-sucrose solution, stir 30 minutes.

Medicinal liquid is sub-packed in drug-containing dish after measuring clonazepam 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 clonazepam composition lyophilizing sheet.

Embodiment 2

A, take the corn starch of 130g, the purified water adding 900m l stirs, and controls at 5.5-7.5, 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 100m L, 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 clonazepam 0.25 gram (by 1000 calculations), add 1L Semen Maydis-sucrose solution, stir 30 minutes.

Medicinal liquid is sub-packed in drug-containing dish after measuring clonazepam 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 clonazepam composition lyophilizing sheet.

Experimental data

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

1, hardness, friability contrast test

Get clonazepam composition lyophilizing sheet prepared by above-described embodiment respectively and clonazepam 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	65	<1％
Execute example 2	68	<1％
			Ordinary tablet	73	<1％

Experimental data shows, clonazepam composition 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 clonazepam sheet (commercially available) and each 6 of clonazepam composition 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 water 900mL for dissolution medium, rotating speed is 75 turns per minute, operate in accordance with the law, respectively through 10min, 20min, 30min, 45min, during 75min, get solution to filter, getting subsequent filtrate is need testing solution, according to Chinese Pharmacopoeia (2010 editions) second annex V D high performance liquid chromatography, be filler with octadecylsilane chemically bonded silica, with acetonitrile-methanol-water (30:30:40) for mobile phase, determined wavelength 254nm.Theoretical tray calculates by clonazepam and is not less than 1000.Precision measures test solution 100ul, injection liquid chromatography, record chromatogram, separately get clonazepam reference substance, accurately weighed, add dissolve with methanol and be quantitatively diluted to the solution about containing 50ug in 1ml, measure in right amount in precision, quantitatively dilute the solution made about containing 0.25ug in every 1ml with water, 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, clonazepam sheet (commercially available)

Two, clonazepam 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.

Four, result judges

Judge according to Chinese Pharmacopoeia (2010 editions) second clonazepam tablet quality standard, the dissolution of clonazepam sheet (commercially available) reached more than 75% for qualified 45 minutes time, actual measurement is 77.5%, and clonazepam lyophilizing sheet dissolution 20 minutes time reaches 77.3%.It can thus be appreciated that the time that clonazepam lyophilizing sheet dissolution reaches 75% decreased for about 55.6% (25 minutes) time than clonazepam sheet (commercially available).So the clonazepam lyophilizing sheet blood drug level peaking time is shorter than clonazepam 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 clonazepam composition lyophilizing sheet, is characterized in that, is prepared from by following raw material:

2. a preparation method for clonazepam composition 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 5.5-7.5, 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 clonazepam 0.25 gram, add in 1L Semen Maydis-sucrose solution, stir 25 ~ 35 minutes;

Medicinal liquid is sub-packed in drug-containing dish after measuring clonazepam 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 clonazepam composition lyophilizing sheet.