CN102100673A - Method for improving direct tabletting content uniformity of medicines with low loading rate - Google Patents
Method for improving direct tabletting content uniformity of medicines with low loading rate Download PDFInfo
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- CN102100673A CN102100673A CN2009102509049A CN200910250904A CN102100673A CN 102100673 A CN102100673 A CN 102100673A CN 2009102509049 A CN2009102509049 A CN 2009102509049A CN 200910250904 A CN200910250904 A CN 200910250904A CN 102100673 A CN102100673 A CN 102100673A
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Abstract
The invention adopts a freeze-drying method to uniformly disperse principal medicines in a certain quantity of carriers and then utilizes the method of direct tabletting of power. The method of the invention solves the problem that the content uniformity is low when the medicines with low loading rate are directly tabletted, and is quite suitable for industrial mass production.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, particularly relate to the method that improves low drug loading medicine direct compression uniformity of dosage units.
Background technology
The preparation technology of tablet mainly contains several methods such as wet granule compression tablet, dry granulation tabletting, direct powder compression.Current, the tablet manufacturing of China still is most widely used with wet granule compression tablet.Wet granulation is to add adhesive in drug powder, powder is coalesced together and prepares particulate method by the crane span structure of adhesive or cohesive action.Made granule may be final products, as granule; May be intermediate products also, as tablet.But with respect to traditional wet granule compression tablet, the direct powder compression technology at home and abroad application in the pharmaceutical manufacturer receives publicity gradually.
Direct powder compression is after the powder of medicine is sieved respectively with suitable adjuvant and mixing, without system granule (wet granular or dried granule) and directly compacting is in blocks.Because its technical process is simple, needn't granulate, drying, the energy-and time-economizing, the protection medicine stability improves drug dissolution, and technology usage degree height and industrial automatization are high, are adopted by the pharmaceutical manufacturer of various countries just more and more.Interrelated data shows, has 40% tablet kind to adopt this explained hereafter abroad approximately.
But direct compression process also has its shortcoming, only is applicable to the medicine of high drug load.Usually be applicable to that drug loading is about 10～15% kind, drug loading can according to circumstances suitably relax to 5～40%.Surpass this scope, too low as drug loading, principal agent just is difficult for being uniformly dispersed; Too high as drug loading, can cause normally direct compression because of shortcomings such as the low compressibility of principal agent and lazy flows again.
But in pharmaceuticals industry, there is the dosage of many medicines all very low, specification as Rezulin repaglinide sheet is the 2mg/ sheet, nootropics huperzine A sheet is the 50ug/ sheet, the depressor Levamlodipine beaylate tablets is the 2.5mg/ sheet, Bendectin Granisetron Hydrochloride sheet is the 1mg/ sheet, and their drug loading separately are respectively 0.5～2.0%, 0.04%, 1.25%, 0.5%.In addition, also have cilazapril, the hydrochloric acid moxonidine, glipizide etc. also belong to this class medicine.Less than 5% medicine, adopting the problem of direct compression technology maximum is exactly that uniformity of dosage units is poor for these drug loading.
Summary of the invention
The object of the present invention is to provide a kind of technical scheme, to solve the problem that causes the uniformity of dosage units difference when low drug loading medicine adopts direct compression process easily.
The alleged low drug loading medicine of the present invention refers in preparation drug loading less than 5% medicine.
The present invention adopts the mixed solution lyophilization of freeze-drying with principal agent and adjuvant, and principal agent is dispersed in certain carrier, adopts the direct powder compression tabletting again.
Technical scheme of the present invention comprises the steps:
(1) principal agent and lyophilizing caffolding agent are fully dissolved with appropriate solvent, lyophilization is pulverized, and obtains containing the freeze-dried mixed powder of principal agent;
(2) the freeze-dried mixed powder that will contain principal agent mixes direct compression with adjuvant.
The weight of the lyophilizing mixed powder that step (1) makes can be that wherein several times of principal agent are to hundred times, and principal agent is dispersed in the mixed powder.The weight that contains the freeze-dried mixed powder of principal agent in the step (2) accounts for 5～40% of whole tabletting weight of material usually, and preferred 10～15%.
The described solvent of step (1) can be selected according to the physicochemical property of principal agent itself, can be water, also can be organic solvent.For the medicine of slightly solubility,, can also add pH regulator agent and/or solubilizing agent for reaching abundant dissolved purpose.Solubilizing agent comprises: polyethylene castor oil hydrogenated, Polyethylene Glycol, Tween 80 etc.The pH regulator agent comprises: meglumine, sodium hydroxide, hydrochloric acid etc.
The described lyophilizing caffolding agent of step (1) comprises mannitol, glucose, lactose etc.Those skilled in the art can select as required.
The described adjuvant of step (2) comprises direct compression adjuvant, disintegrating agent and lubricant.Wherein the direct compression adjuvant comprises: mannitol, starch, lactose, microcrystalline Cellulose etc.Disintegrating agent comprises: cross-linking sodium carboxymethyl cellulose, crospolyvinylpyrrolidone, crosslinked carboxymethyl fecula sodium, low-substituted hydroxypropyl cellulose etc.Lubricant comprises: micropowder silica gel, magnesium stearate, Pulvis Talci etc.
The present invention has remedied the shortcoming that low drug loading medicine is unsuitable for direct compression, to hang down the fully dissolving earlier of drug loading medicine and lyophilizing caffolding agent, lyophilizing again, principal agent is dispersed in the lyophilizing mixed powder, the high compressibility and the high fluidity of direct compression requirement had both been satisfied, also have good uniformity of dosage units, be suitable for the big production of industry.
The specific embodiment
Embodiment 1
Take by weighing repaglinide 2g, mix, add 2% meglumine solution 50ml dissolving again, add 5g caffolding agent mannitol again with 2g solubilizing agent polyethylene castor oil hydrogenated, after the thorough dissolving evenly, lyophilization.Collect the powder after lyophilization is pulverized, cross 60 mesh sieves, behind 62g microcrystalline Cellulose, pre-paying of 25g starch, 2g cross-linking sodium carboxymethyl cellulose mix homogeneously, mix with 0.5g micropowder silica gel, 0.5g magnesium stearate more at last, with 100mg is target patch weight sheet, records drug content and is about the 2mg/ sheet.
Measure the uniformity of dosage units of 30 repaglinide sheets: RSD=1.5%.
Embodiment 2
Take by weighing huperzine A 0.05g,, add 10g caffolding agent lactose again with the dissolving of 100ml pure water, after the thorough dissolving evenly, lyophilization.Collect the powder after lyophilization is pulverized, cross 60 mesh sieves, behind 40g microcrystalline Cellulose, 50g mannitol, 16.4g starch and 2.4g cross-linking sodium carboxymethyl cellulose mix homogeneously, mix with 0.6g micropowder silica gel, 0.6g magnesium stearate more at last, with 120mg is target patch weight sheet, records drug content and is about 50 μ g/ sheets.
Measure the uniformity of dosage units of 30 huperzine A sheets: RSD=1.8%.
Embodiment 3
Take by weighing Levamlodipine besylate 250g,, add 7.75kg caffolding agent glucose again with the dissolving of 40L pure water, after the thorough dissolving evenly, lyophilization.Collect the powder after lyophilization is pulverized, cross 60 mesh sieves, behind 9.2kg mannitol, 2kg starch and 0.6kg low-substituted hydroxypropyl cellulose mix homogeneously, mix with 100g micropowder silica gel, 100g magnesium stearate more at last, with 200mg is target patch weight sheet, records drug content and is about the 2.5mg/ sheet.
Measure the uniformity of dosage units of 30 Levamlodipine beaylate tablets: RSD=1.7%.
Embodiment 4
Take by weighing Granisetron Hydrochloride 1g, the dissolve with hydrochloric acid solution with 200ml 0.1% adds 20g lyophilizing caffolding agent mannitol again, after the thorough dissolving evenly, and lyophilization.Collect the powder after lyophilization is pulverized, cross 60 mesh sieves, mix with 50g microcrystalline Cellulose, 90g lactose, 32g calcium hydrogen phosphate, again with 5g cross-linking sodium carboxymethyl cellulose mix homogeneously after, mix with 1g micropowder silica gel, 1g magnesium stearate more at last, with 200mg is target patch weight sheet, records drug content and is about the 1mg/ sheet.
Measure the uniformity of dosage units of 30 Granisetron Hydrochloride sheets: RSD=2.0%.
Embodiment 5
Take by weighing repaglinide 0.5kg, mix, add 1% meglumine solution 300L dissolving again, add 36kg caffolding agent mannitol again with 0.5kg solubilizing agent polyethylene castor oil hydrogenated, after the thorough dissolving evenly, lyophilization.Collect the powder after lyophilization is pulverized, cross 60 mesh sieves, behind 40kg mannitol, pre-paying of 17kg starch, 2kg cross-linking sodium carboxymethyl cellulose mix homogeneously, mix with 0.5kg micropowder silica gel, 0.5kg magnesium stearate more at last, with 100mg is target patch weight sheet, records drug content and is about the 0.5mg/ sheet.
Measure the uniformity of dosage units of 30 repaglinide sheets: RSD=1.6%.
Embodiment 6
Take by weighing huperzine A 0.05g,, add 15g caffolding agent lactose again with the dissolving of 100ml pure water, after the thorough dissolving evenly, lyophilization.Collect the powder after lyophilization is pulverized, cross 60 mesh sieves, behind 40g lactose, 50g mannitol, 10g calcium hydrogen phosphate and 3.6g crosslinked carboxymethyl fecula sodium mix homogeneously, mix with 0.8g micropowder silica gel, 0.6g magnesium stearate more at last, with 120mg is target patch weight sheet, records drug content and is about 50 μ g/ sheets.
Measure the uniformity of dosage units of 30 huperzine A sheets: RSD=1.4%.
Embodiment 7
Take by weighing Levamlodipine besylate 2.5g,, add 27.5g caffolding agent glucose again with the dissolving of 200ml pure water, after the thorough dissolving evenly, lyophilization.Collect the powder after lyophilization is pulverized, cross 60 mesh sieves, behind 92g microcrystalline Cellulose, 50g lactose, 20g starch and 6g crospolyvinylpyrrolidone mix homogeneously, mix with 1g micropowder silica gel, 1g magnesium stearate more at last, with 200mg is target patch weight sheet, records drug content and is about the 2.5mg/ sheet.
Measure the uniformity of dosage units of 30 Levamlodipine beaylate tablets: RSD=1.2%.
Embodiment 8
Take by weighing Granisetron Hydrochloride 1g,, add 9g lyophilizing caffolding agent glucose again with the dissolving of 100ml pure water, after the thorough dissolving evenly, lyophilization.Collect the powder after lyophilization is pulverized, cross 60 mesh sieves, mix with 56g microcrystalline Cellulose, 100g mannitol, 25g starch, again with 5g cross-linking sodium carboxymethyl cellulose mix homogeneously after, mix with 2g micropowder silica gel, 2g magnesium stearate more at last, with 200mg is target patch weight sheet, records drug content and is about the 1mg/ sheet.
Measure the uniformity of dosage units of 30 Granisetron Hydrochloride sheets: RSD=1.7%.
Embodiment 9
Take by weighing cilazapril 1g, with 2g poloxamer 188 in 60 ℃ of mixed meltings, reuse 100ml pure water dissolving adds 17g lyophilizing caffolding agent glucose again, thoroughly after the dissolving evenly, lyophilization.Collect the powder after lyophilization is pulverized, cross 60 mesh sieves, mix with 50g lactose, 85g microcrystalline Cellulose, 37g starch, again with 5g crospolyvinylpyrrolidone mix homogeneously after, mix with 1g micropowder silica gel, 2g magnesium stearate more at last, with 200mg is target patch weight sheet, records drug content and is about the 1mg/ sheet.
Measure the uniformity of dosage units of 30 cilazapril sheets: RSD=2.2%.
Embodiment 10
Take by weighing hydrochloric acid moxonidine 0.2g,, add 19.8g lyophilizing caffolding agent glucose again with the dissolving of 100ml pure water, after the thorough dissolving evenly, lyophilization.Collect the powder after lyophilization is pulverized, cross 60 mesh sieves, mix with 50g microcrystalline Cellulose, 25g starch, again with 4g cross-linking sodium carboxymethyl cellulose mix homogeneously after, mix with 0.5g micropowder silica gel, 0.5g magnesium stearate more at last, with 100mg is target patch weight sheet, records drug content and is about the 0.2mg/ sheet.
Measure the uniformity of dosage units of 30 hydrochloric acid moxonidine sheets: RSD=1.5%.
Embodiment 11
Take by weighing glipizide 2.5kg, mix, add pure water 300L dissolving again, add 36kg caffolding agent glucose again with 5.0kg solubilizing agent polyethylene castor oil hydrogenated, after the thorough dissolving evenly, lyophilization.Collect the powder after lyophilization is pulverized, cross 60 mesh sieves, behind 80kg microcrystalline Cellulose, pre-paying of 20kg starch, 4kg cross-linking sodium carboxymethyl cellulose mix homogeneously, mix with 1kg micropowder silica gel, 1.5kg magnesium stearate more at last, with 150mg is target patch weight sheet, records drug content and is about the 2.5mg/ sheet.
Measure the uniformity of dosage units of 30 glipizide tablets: RSD=1.6%.
Claims (2)
1. one kind increases the method for hanging down drug loading medicine direct compression uniformity of dosage units, it is characterized in that comprising following steps:
(1) with principal agent and lyophilizing caffolding agent dissolution with solvents, lyophilization is pulverized, and obtains containing the freeze-dried mixed powder of principal agent;
(2) the freeze-dried mixed powder that will contain principal agent mixes direct compression with adjuvant.
2. method according to claim 1 is characterized in that principal agent is a kind of in repaglinide, huperzine A, Levamlodipine besylate, Granisetron Hydrochloride, cilazapril, hydrochloric acid moxonidine or the glipizide.
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| Application Number | Priority Date | Filing Date | Title |
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| CN2009102509049A CN102100673A (en) | 2009-12-18 | 2009-12-18 | Method for improving direct tabletting content uniformity of medicines with low loading rate |
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| CN2009102509049A CN102100673A (en) | 2009-12-18 | 2009-12-18 | Method for improving direct tabletting content uniformity of medicines with low loading rate |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103860502A (en) * | 2014-04-15 | 2014-06-18 | 白玲强 | Tablet containing moxonidine hydrochloride and preparation method thereof |
| CN104644446A (en) * | 2013-11-25 | 2015-05-27 | 北京万生药业有限责任公司 | Preparing method of repaglinide medicinal preparation |
| CN117482057A (en) * | 2023-11-30 | 2024-02-02 | 福安药业集团宁波天衡制药有限公司 | Stable granisetron hydrochloride tablet and preparation method thereof |
-
2009
- 2009-12-18 CN CN2009102509049A patent/CN102100673A/en active Pending
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104644446A (en) * | 2013-11-25 | 2015-05-27 | 北京万生药业有限责任公司 | Preparing method of repaglinide medicinal preparation |
| CN104644446B (en) * | 2013-11-25 | 2018-02-09 | 北京万生药业有限责任公司 | A kind of preparation method of Repaglinide pharmaceutical preparation |
| CN103860502A (en) * | 2014-04-15 | 2014-06-18 | 白玲强 | Tablet containing moxonidine hydrochloride and preparation method thereof |
| CN103860502B (en) * | 2014-04-15 | 2015-12-30 | 张绪伟 | A kind of tablet containing moxonidine hydrochloride and preparation method thereof |
| CN117482057A (en) * | 2023-11-30 | 2024-02-02 | 福安药业集团宁波天衡制药有限公司 | Stable granisetron hydrochloride tablet and preparation method thereof |
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Application publication date: 20110622 |