CN104586743A - Clozapine compound freeze-dried tablet and preparation method thereof - Google Patents
Clozapine compound freeze-dried tablet and preparation method thereof Download PDFInfo
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- CN104586743A CN104586743A CN201410826964.1A CN201410826964A CN104586743A CN 104586743 A CN104586743 A CN 104586743A CN 201410826964 A CN201410826964 A CN 201410826964A CN 104586743 A CN104586743 A CN 104586743A
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Abstract
The invention provides a clozapine compound freeze-dried tablet and a preparation method thereof and relates to the field of pharmaceuticals and pharmaceutical production technology. The clozapine compound freeze-dried tablet comprises clozapine, starch and sucrose, wherein the starch and the sucrose are used as accessories. The preparation method is characterized by a heating process to ordinary corn starch, which can improve agglutinating and disintegrating functions of the starch in the tablet so as to improve shaping property of the tablet, and the clozapine compound freeze-dried tablet only include starch and sucrose as the accessories. The clozapine compound freeze-dried tablet is prepared by a two-cooling two-heating freeze-drying process. The shaping property of the tablet can be improved by the two-time cooling and two-time heating process, so as to improve dissolution rate of the tablet to increase bioavailability of the tablet. The clozapine compound freeze-dried tablet dislcosed by the invention overcomes defects of ordinary clozapine tablet and reduces accessory types and dosages used therein. The tablet is characterized by large dissolution rate and high bioavailability and ensures efficacy and safety of the tablet in clinical medication.
Description
Technical field
The present invention relates to medicine and medical production technical field, be specifically related to a kind of clozapine composition freeze-drying sheet and preparation method thereof.
Background technology
Clozapine is atypical antipsychotic agents, can be used for schizoid acute stages treated and long term maintenance therapy, also can be used for treating the restless and hallucination vain hope of the excitement of mania or other psychotic disorders.Not only effective to psychosis positive symptom, also there is certain effect to negative symptoms.Be applicable to each hypotype that is acute and chronic schizophrenia, effective to hallucinatory paranoid form, hebephrenictype.
Molecular weight: 326.84
In common clozapine containing supplementary product kind and quantity more, generally to use filler, lubricant, disintegrating agent, adhesive, correctives etc., according to Chinese Pharmacopoeia (2010 editions) second clozapine quality standard, the dissolution of clozapine reached more than 80% for qualified 30 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 clozapine, improve dissolution and the bioavailability of clozapine, 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 clozapine 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 clozapine 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 clozapine composition freeze-drying sheet, does adjuvant with starch and sucrose, produces with freeze-dry process, this tablet overcomes the shortcoming of above-mentioned common clozapine, decreases supplementary product kind and consumption in clozapine, and this sheet dissolution is large, bioavailability is high, ensure that curative effect and the safety of clinical application.
A kind of clozapine composition freeze-drying sheet, is prepared from by following raw material:
A preparation method for clozapine 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 5.0-6.5, 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 clozapine 25 grams, add in 1L Semen Maydis-sucrose solution, stir 25 ~ 35 minutes;
Medicinal liquid is sub-packed in drug-containing dish after measuring clozapine 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 clozapine 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 clozapine 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 clozapine composition freeze-drying sheet, dosage of sucrose is 8.5% (W/V), it is the hardness reinforcer of this tablet, and plays flavored action.Clozapine composition freeze-drying sheet only needs starch and sucrose two kinds of adjuvants.The freeze-dry process of two liters falls in clozapine 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 clozapine 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 5.0-6.5, 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 clozapine 25g, add in 1L Semen Maydis-sucrose solution, stir 30 minutes.
Medicinal liquid is sub-packed in drug-containing dish after measuring clozapine 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 clozapine composition freeze-drying sheet.
Embodiment 2
A, take the corn starch of 130g, the purified water adding 900ml stirs, and controls at 5.0-6.5, 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 clozapine 25 grams (by 1000 calculations), add 1L Semen Maydis-sucrose solution, stir 30 minutes.
Medicinal liquid is sub-packed in drug-containing dish after measuring clozapine 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 clozapine composition freeze-drying sheet.
Experimental data
The clozapine composition freeze-drying sheet that above-described embodiment is obtained carries out following quality research test:
1, hardness, friability contrast test
Get clozapine composition freeze-drying sheet prepared by above-described embodiment respectively and clozapine ordinary tablet (commercially available) detects friability and hardness by " Chinese Pharmacopoeia " version in 2010 two annex XG 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 | 66 | <1% |
Ordinary tablet | 69 | <1% |
Experimental data shows, clozapine 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 clozapine (commercially available) and each 6 of clozapine composition freeze-drying sheet, No. 4 to No. 6 is embodiment 2), press Chinese Pharmacopoeia (2010 editions) second dissolution method annex XC second method respectively, with hydrochloric acid (9 → 1000) 1000mL for dissolution medium, rotating speed is 100 turns per minute, operate in accordance with the law, respectively through 5min, 10min, 20min, 30min, during 60min, get solution 10ml, filter, it is appropriate that precision measures worry liquid, with being quantitatively diluted to dissolution medium in every 1ml about containing 5ug, according to Chinese Pharmacopoeia (2010 editions) second annex IV A ultraviolet visible spectrophotometry, absorbance is measured at the wavelength place of 240nm, separately get clozapine reference substance, accurately weighed, quantitatively be diluted in every 1ml with dissolution medium and be about measured in the same method containing 5ug, calculate the stripping quantity of every sheet.Limit is 80 ℅ of labelled amount, should conform with the regulations.
One, clozapine (commercially available)
Two, clozapine 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 clozapine quality standard, the dissolution of clozapine (commercially available) reached more than 80% for qualified 30 minutes time, actual measurement is 81.9%, and clozapine lyophilizing sheet dissolution 20 minutes time reaches 86.4%.It can thus be appreciated that the time that clozapine lyophilizing sheet dissolution reaches 80% decreased for about 33.3% (10 minutes) time than clozapine (commercially available).So the clozapine lyophilizing sheet blood drug level peaking time is shorter than clozapine (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 clozapine composition freeze-drying sheet, is characterized in that, is prepared from by following raw material:
2. a preparation method for clozapine 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 5.0-6.5, 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 clozapine 25 grams, add in 1L Semen Maydis-sucrose solution, stir 25 ~ 35 minutes;
Medicinal liquid is sub-packed in drug-containing dish after measuring clozapine 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 clozapine composition freeze-drying sheet.
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Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
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JPS61242556A (en) * | 1985-04-19 | 1986-10-28 | Hatoya Seika:Kk | Preparation of snack using fruits |
US20020173016A1 (en) * | 2001-03-27 | 2002-11-21 | Helmut Wurst | High-throughput nucleic acid polymerase devices and methods for their use |
CN1806805A (en) * | 2005-01-20 | 2006-07-26 | 马晶 | Leponex orally disintegrating tablet and preparation method thereof |
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- 2014-12-25 CN CN201410826964.1A patent/CN104586743A/en active Pending
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS61242556A (en) * | 1985-04-19 | 1986-10-28 | Hatoya Seika:Kk | Preparation of snack using fruits |
US20020173016A1 (en) * | 2001-03-27 | 2002-11-21 | Helmut Wurst | High-throughput nucleic acid polymerase devices and methods for their use |
CN1806805A (en) * | 2005-01-20 | 2006-07-26 | 马晶 | Leponex orally disintegrating tablet and preparation method thereof |
Non-Patent Citations (1)
Title |
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刘晓睿: "《口腔速溶片的研究进展》", 《中南药学》 * |
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Application publication date: 20150506 |