CN116510026A - Mannitol compound pharmaceutical adjuvant and preparation method thereof - Google Patents
Mannitol compound pharmaceutical adjuvant and preparation method thereof Download PDFInfo
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- CN116510026A CN116510026A CN202310806517.9A CN202310806517A CN116510026A CN 116510026 A CN116510026 A CN 116510026A CN 202310806517 A CN202310806517 A CN 202310806517A CN 116510026 A CN116510026 A CN 116510026A
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- mannitol
- ball milling
- trehalose
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- 229930195725 Mannitol Natural products 0.000 title claims abstract description 82
- 239000000594 mannitol Substances 0.000 title claims abstract description 82
- 235000010355 mannitol Nutrition 0.000 title claims abstract description 82
- -1 Mannitol compound Chemical class 0.000 title claims abstract description 34
- 239000000546 pharmaceutical excipient Substances 0.000 title claims abstract description 33
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims abstract description 49
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims abstract description 48
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 claims abstract description 43
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 claims abstract description 43
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 claims abstract description 43
- 238000000498 ball milling Methods 0.000 claims abstract description 40
- 238000003756 stirring Methods 0.000 claims abstract description 27
- 238000002156 mixing Methods 0.000 claims abstract description 21
- 239000005457 ice water Substances 0.000 claims abstract description 17
- 238000001035 drying Methods 0.000 claims abstract description 12
- JLPULHDHAOZNQI-ZTIMHPMXSA-N 1-hexadecanoyl-2-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/C\C=C/CCCCC JLPULHDHAOZNQI-ZTIMHPMXSA-N 0.000 claims abstract description 11
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 claims abstract description 11
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims abstract description 11
- 229920000161 Locust bean gum Polymers 0.000 claims abstract description 11
- 235000010445 lecithin Nutrition 0.000 claims abstract description 11
- 239000000787 lecithin Substances 0.000 claims abstract description 11
- 229940067606 lecithin Drugs 0.000 claims abstract description 11
- 235000010420 locust bean gum Nutrition 0.000 claims abstract description 11
- 239000000711 locust bean gum Substances 0.000 claims abstract description 11
- 239000000600 sorbitol Substances 0.000 claims abstract description 11
- 235000010356 sorbitol Nutrition 0.000 claims abstract description 11
- 239000008347 soybean phospholipid Substances 0.000 claims abstract description 11
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims abstract description 6
- 238000001914 filtration Methods 0.000 claims abstract description 6
- 238000010438 heat treatment Methods 0.000 claims abstract description 6
- 238000005406 washing Methods 0.000 claims abstract description 6
- 239000000463 material Substances 0.000 claims description 38
- 229940124531 pharmaceutical excipient Drugs 0.000 claims description 17
- 238000007710 freezing Methods 0.000 claims description 11
- 230000008014 freezing Effects 0.000 claims description 11
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 10
- 239000008367 deionised water Substances 0.000 claims description 10
- 229910021641 deionized water Inorganic materials 0.000 claims description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 10
- 238000009777 vacuum freeze-drying Methods 0.000 claims description 6
- 229960000913 crospovidone Drugs 0.000 claims description 5
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 5
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 5
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 5
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 5
- 229940069328 povidone Drugs 0.000 claims description 5
- 238000001694 spray drying Methods 0.000 claims description 5
- 238000000034 method Methods 0.000 abstract description 17
- 239000003826 tablet Substances 0.000 description 22
- 238000011084 recovery Methods 0.000 description 18
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 12
- 230000000052 comparative effect Effects 0.000 description 6
- 235000019359 magnesium stearate Nutrition 0.000 description 6
- 239000004480 active ingredient Substances 0.000 description 3
- 239000002131 composite material Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000007910 chewable tablet Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 210000000214 mouth Anatomy 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 150000005846 sugar alcohols Chemical class 0.000 description 1
- 235000019605 sweet taste sensations Nutrition 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Biochemistry (AREA)
- Medicinal Chemistry (AREA)
- Molecular Biology (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
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- Veterinary Medicine (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention provides a mannitol compound pharmaceutic adjuvant and a preparation method thereof, and is characterized in that the preparation method of the mannitol compound pharmaceutic adjuvant comprises trehalose treatment, mannitol pretreatment and mixing steps; mixing the primarily treated trehalose with acetic acid, placing in an ice water bath, adding sorbitol, lecithin and locust bean gum, stirring, removing the ice water bath, heating to room temperature at a speed of 1.2-1.7 ℃/min, continuing stirring, filtering, washing, drying and crystallizing to obtain the treated trehalose; the mannitol pretreatment step comprises the steps of performing ball milling treatment on mannitol for the first time, adding soybean phospholipid for performing ball milling treatment for the second time, and drying after ball milling is finished to obtain pretreated mannitol. The mannitol compound pharmaceutic adjuvant prepared by the method of the invention enhances the compressibility and the flowability and improves the quality of the mannitol pharmaceutic adjuvant under different pressures.
Description
Technical Field
The invention relates to the technical field of pharmaceutical excipients, in particular to a mannitol compound pharmaceutical excipient and a preparation method thereof.
Background
The pharmaceutical auxiliary materials comprise excipient, disintegrating agent, corrigent, lubricant, adhesive and the like, are indispensable components in the pharmaceutical preparation, can ensure that the pharmaceutical active ingredients are selectively transported to tissue parts in a certain program, prevent the pharmaceutical active ingredients from being deactivated before being released from a main body, can enable the medicine to be released in vivo according to certain kinetic factors, and play a key role in the practical application and the curative effect of the pharmaceutical active ingredients.
Mannitol is sugar alcohol of natural source, has very wide application in the medical field, can be used as excipient for tablets, has no hygroscopicity and good chemical stability, has the characteristics of tasty and refreshing property, good granulation property and the like, and is suitable for most tablets; mannitol absorbs heat when dissolved and has sweet taste and comfortable feeling to the oral cavity, so mannitol is widely used for manufacturing chewable tablets.
However, mannitol is poor in compressibility when used as a tablet filling agent, and problems of poor material flowability, uneven filling in a tabletting process, large weight deviation difference and the like can occur, so that the mannitol is limited to be used in tablets;
therefore, the mannitol compound pharmaceutical auxiliary material is provided, and the improvement of fluidity and compressibility is a technical problem to be solved in the prior art.
Disclosure of Invention
In order to solve the technical problems in the prior art, the invention provides a mannitol compound pharmaceutical excipient and a preparation method thereof, which improve fluidity and compressibility.
In order to solve the technical problems, the invention adopts the following technical scheme:
1. trehalose treatment
Mixing the primarily treated trehalose with acetic acid, placing in an ice water bath, controlling the temperature of the ice water bath at 1.8-2.2 ℃, adding sorbitol, lecithin and locust bean gum, stirring for 43-47min, controlling the stirring speed at 265-275rpm, removing the ice water bath, heating to room temperature at a speed of 1.2-1.7 ℃/min, continuously stirring for 0.8-1.2h, and filtering, washing, drying and crystallizing to obtain the treated trehalose;
the mass concentration of the acetic acid is 3.8-4.2%;
the mass volume ratio of the trehalose to the acetic acid is 1:3-5;
the mass ratio of the trehalose, the sorbitol, the lecithin and the locust bean gum is 24-26:0.3-0.5:0.4-0.6:0.1-0.3.
2. Mannitol pretreatment
Performing first ball milling treatment on mannitol, wherein the ball-material ratio is 6-10:1, the ball milling speed is 290-310rpm, the ball milling time is 1.8-2.2h, adding soybean phospholipid for performing second ball milling treatment, the ball-material ratio is 10-14:1, the ball milling speed is 380-420rpm, the ball milling time is 2.4-2.6h, and drying after ball milling is finished to obtain pretreated mannitol;
the mass ratio of mannitol to soybean phospholipid is 10:1-2.
3. Mixing
Mixing the treated trehalose, the pretreated mannitol and the crosslinked povidone, adding deionized water, controlling the stirring speed to be 280-320rpm, stirring for 95-105min, and then spray-drying at 78-82 ℃ to obtain a pre-auxiliary material;
reducing the pre-auxiliary material to room temperature at the speed of 2.8-3.2 ℃/min, then placing the pre-auxiliary material at the temperature of minus 27 ℃ to minus 23 ℃ for vacuum freeze drying treatment, wherein the freezing time is 1.2-1.4h, the freezing vacuum degree is 26-30Pa, and naturally recovering the pre-auxiliary material to room temperature to prepare the mannitol compound pharmaceutical auxiliary material;
the mass ratio of the trehalose after treatment to the mannitol after pretreatment to the crospovidone to the deionized water is 0.8-1.2:1.9-2.2:0.15-0.25:28-32.
Compared with the prior art, the invention has the following beneficial effects:
1. according to the invention, the trehalose is treated by adopting a specific method, so that the surface activity of the trehalose is improved; the mannitol is pretreated by adopting a specific method, so that the mannitol and the trehalose are mixed more uniformly, the compatibility with other components is improved, the compressibility and the flowability are enhanced, and the quality of mannitol pharmaceutic adjuvant under different pressures is improved;
2. the mannitol compound pharmaceutic adjuvant prepared by the method has the yield of 95.7-96.1 percent and the repose angle of 20-23 degrees;
3. adding 1% magnesium stearate into the mannitol compound medicinal auxiliary material prepared by the invention, and tabletting under different pressures respectively;
under 1400kg pressure, the tablet hardness is 184-187N, elastic recovery is 1.0-1.3%, friability is 0.17-0.20%, and disintegration time is 15-18s;
under the pressure of 1000kg, the hardness of the tablet is 174-179N, the elastic recovery rate is 1.1-1.5%, the friability is 0.19-0.22%, and the disintegration time is 12-16s;
under 800kg pressure, the tablet hardness is 166-170N, elastic recovery is 1.2-1.8%, friability is 0.22-0.27%, and disintegration time is 11-13s.
Detailed Description
For a clearer understanding of the technical features, objects and effects of the present invention, specific embodiments of the present invention will be described.
Example 1 mannitol composite pharmaceutical adjuvant and preparation method thereof
1. Trehalose treatment
Mixing the primarily treated trehalose with acetic acid, placing in an ice water bath, controlling the temperature of the ice water bath at 2 ℃, adding sorbitol, lecithin and locust bean gum, stirring for 45min, controlling the stirring speed at 270rpm, removing the ice water bath, heating to room temperature at a speed of 1.5 ℃/min, continuing stirring for 1h, and filtering, washing, drying and crystallizing to obtain the treated trehalose;
the mass concentration of the acetic acid is 4%;
the mass volume ratio of the trehalose to the acetic acid is 1:4;
the mass ratio of the trehalose, the sorbitol, the lecithin and the locust bean gum is 25:0.4:0.5:0.2.
2. Mannitol pretreatment
Performing first ball milling treatment on mannitol, wherein the ball material ratio is 8:1, the ball milling speed is 300rpm, the ball milling time is 2 hours, then adding soybean phospholipid for performing second ball milling treatment, the ball material ratio is 12:1, the ball milling speed is 400rpm, the ball milling time is 2.5 hours, and drying after ball milling is finished to obtain pretreated mannitol;
the mass ratio of mannitol to soybean phospholipid is 10:1.5.
3. mixing
Mixing the treated trehalose, the pretreated mannitol and the crosslinked povidone, adding deionized water, controlling the stirring speed to be 300rpm, stirring for 100min, and then spray-drying at 80 ℃ to obtain a pre-auxiliary material;
reducing the pre-auxiliary material to room temperature at a speed of 3 ℃/min, then placing the pre-auxiliary material at-25 ℃ for vacuum freeze-drying treatment, wherein the freezing time is 1.3h, the freezing vacuum degree is 28Pa, and naturally recovering the pre-auxiliary material to room temperature to prepare the mannitol compound medicinal auxiliary material;
the mass ratio of the trehalose after treatment to the mannitol after pretreatment to the crospovidone to the deionized water is 1:2:0.2:30.
The mannitol compound pharmaceutical excipients prepared by the method of example 1 have a yield of 96.1% and an angle of repose of 20 °;
adding 1% magnesium stearate into the mannitol compound pharmaceutic adjuvant prepared in the method of the example 1, tabletting under different pressures respectively, wherein the tablet hardness is 187N, the elastic recovery rate is 1.0%, the friability is 0.17% and the disintegration time is 15s under 1400kg pressure; under the pressure of 1000kg, the hardness of the tablet is 179N, the elastic recovery rate is 1.1%, the friability is 0.19%, and the disintegration time is 12s; the tablet hardness was 170N, the elastic recovery was 1.2%, the friability was 0.22% and the disintegration time was 11s under 800kg pressure.
Example 2 mannitol composite pharmaceutical excipients and preparation method thereof
1. Trehalose treatment
Mixing the primarily treated trehalose with acetic acid, placing in an ice water bath, controlling the temperature of the ice water bath at 2.2 ℃, adding sorbitol, lecithin and locust bean gum, stirring for 43min, controlling the stirring speed at 265rpm, removing the ice water bath, heating to room temperature at a speed of 1.7 ℃/min, continuing stirring for 1.2h, and filtering, washing, drying and crystallizing to obtain the treated trehalose;
the mass concentration of the acetic acid is 4.2%;
the mass volume ratio of the trehalose to the acetic acid is 1:5;
the mass ratio of the trehalose, the sorbitol, the lecithin and the locust bean gum is 24:0.5:0.4:0.3.
2. Mannitol pretreatment
Performing first ball milling treatment on mannitol, wherein the ball material ratio is 10:1, the ball milling speed is 310rpm, the ball milling time is 1.8 hours, then adding soybean phospholipid for performing second ball milling treatment, the ball material ratio is 14:1, the ball milling speed is 420rpm, the ball milling time is 2.4 hours, and drying after ball milling is finished to obtain pretreated mannitol;
the mass ratio of mannitol to soybean phospholipid is 10:2.
3. mixing
Mixing the treated trehalose, the pretreated mannitol and the crosslinked povidone, adding deionized water, controlling the stirring speed to be 320rpm, stirring for 105min, and then spray-drying at 82 ℃ to obtain a pre-auxiliary material;
reducing the pre-auxiliary material to room temperature at a speed of 3.2 ℃/min, then placing the pre-auxiliary material at-27 ℃ for vacuum freeze-drying treatment, wherein the freezing time is 1.2h, the freezing vacuum degree is 30Pa, and naturally recovering the pre-auxiliary material to room temperature to prepare the mannitol compound medicinal auxiliary material;
the mass ratio of the trehalose after treatment to the mannitol after pretreatment to the crospovidone to the deionized water is 1:2.2:0.15:32.
The mannitol compound pharmaceutical excipients prepared by the method of example 2 have a yield of 95.9% and an angle of repose of 22 °;
adding 1% magnesium stearate into the mannitol compound pharmaceutic adjuvant prepared in the method of the example 2, tabletting under different pressures respectively, wherein the tablet hardness is 185N, the elastic recovery rate is 1.2%, the friability is 0.18% and the disintegration time is 16s under 1400kg pressure; under the pressure of 1000kg, the hardness of the tablet is 176N, the elastic recovery rate is 1.4%, the friability is 0.21%, and the disintegration time is 14s; the tablet hardness was 168N, the elastic recovery was 1.5%, the friability was 0.25% and the disintegration time was 13s under 800kg pressure.
Example 3 mannitol composite pharmaceutical excipients and preparation method thereof
1. Trehalose treatment
Mixing the primarily treated trehalose with acetic acid, placing in an ice water bath, controlling the temperature of the ice water bath at 1.8 ℃, adding sorbitol, lecithin and locust bean gum, stirring for 47min, controlling the stirring speed at 275rpm, then removing the ice water bath, heating to room temperature at a speed of 1.2 ℃/min, continuing stirring for 0.8h, and filtering, washing, drying and crystallizing to obtain the treated trehalose;
the mass concentration of the acetic acid is 3.8%;
the mass volume ratio of the trehalose to the acetic acid is 1:3;
the mass ratio of the trehalose, the sorbitol, the lecithin and the locust bean gum is 26:0.3:0.6:0.1.
2. Mannitol pretreatment
Performing first ball milling treatment on mannitol, wherein the ball material ratio is 6:1, the ball milling speed is 290rpm, the ball milling time is 2.2 hours, then adding soybean phospholipid for performing second ball milling treatment, the ball material ratio is 10:1, the ball milling speed is 380rpm, the ball milling time is 2.6 hours, and drying after ball milling is finished to obtain pretreated mannitol;
the mass ratio of mannitol to soybean phospholipid is 10:1.
3. mixing
Mixing the treated trehalose, the pretreated mannitol and the crosslinked povidone, adding deionized water, controlling the stirring speed to be 280rpm, stirring for 95min, and then spray-drying at 78 ℃ to obtain a pre-auxiliary material;
reducing the pre-auxiliary material to room temperature at the speed of 2.8 ℃/min, then placing the pre-auxiliary material at the temperature of-23 ℃ for vacuum freeze-drying treatment, wherein the freezing time is 1.4h, the freezing vacuum degree is 26Pa, and naturally recovering the pre-auxiliary material to room temperature to prepare the mannitol compound medicinal auxiliary material;
the mass ratio of the trehalose after treatment to the mannitol after pretreatment to the crospovidone to the deionized water is 0.8:1.9:0.25:28.
The mannitol compound pharmaceutical excipients prepared by the method of example 3 have a yield of 95.7% and an angle of repose of 23 °;
adding 1% magnesium stearate into the mannitol compound pharmaceutic adjuvant prepared in the method of the example 3, tabletting under different pressures respectively, wherein the tablet hardness is 184N, the elastic recovery rate is 1.3%, the friability is 0.20% and the disintegration time is 18s under 1400kg pressure; under the pressure of 1000kg, the tablet hardness is 174N, the elastic recovery rate is 1.5%, the friability is 0.22%, and the disintegration time is 16s; the tablet hardness was 166N, the elastic recovery was 1.8%, the friability was 0.27% and the disintegration time was 12s under 800kg pressure.
Comparative example 1
The procedure was changed on the basis of example 1, except that the trehalose treatment step was omitted and trehalose not subjected to any treatment was directly used in the mixing step, and the rest of the operations were the same.
The mannitol compound pharmaceutical excipients prepared by the method of comparative example 1 have a yield of 82.4% and an angle of repose of 36 °; adding 1% magnesium stearate into the mannitol compound pharmaceutic adjuvant prepared by the method of comparative example 1 for tabletting, wherein the tablet hardness is 142N, the elastic recovery rate is 2.7%, the friability is 1.7% and the disintegration time is 54s under 1400kg pressure; under the pressure of 1000kg, the hardness of the tablet is 130N, the elastic recovery rate is 2.1%, the friability is 2.0%, and the disintegration time is 45s; the tablet hardness was 111N, the elastic recovery was 1.9%, the friability was 2.5% and the disintegration time was 37s under 800kg pressure.
Comparative example 2
The procedure was the same as in example 1 except that the pretreatment step for mannitol was omitted and mannitol without any treatment was directly used in the mixing step.
The mannitol compound pharmaceutic adjuvant prepared by adopting the method of the comparative example 2 has the yield of 83.7 percent and the repose angle of 34 degrees; adding 1% magnesium stearate into mannitol compound medicinal auxiliary material prepared by the method of comparative example 2 for tabletting, wherein the tablet hardness is 147N, the elastic recovery rate is 2.5%, the friability is 1.4%, and the disintegration time is 47s under 1400kg pressure; under the pressure of 1000kg, the hardness of the tablet is 138N, the elastic recovery rate is 1.9%, the friability is 1.7%, and the disintegration time is 42s; the tablet hardness was 123N, the elastic recovery was 1.6%, the friability was 1.9% and the disintegration time was 35s under 800kg pressure.
The percentages used in the present invention are mass percentages unless otherwise indicated.
Finally, it should be noted that: the foregoing description is only a preferred embodiment of the present invention, and the present invention is not limited thereto, but it is to be understood that modifications and equivalents of some of the technical features described in the foregoing embodiments may be made by those skilled in the art, although the present invention has been described in detail with reference to the foregoing embodiments. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (8)
1. The preparation method of the mannitol compound pharmaceutical excipients is characterized by comprising trehalose treatment, mannitol pretreatment and mixing;
mixing the primarily treated trehalose with acetic acid, placing in an ice water bath, controlling the temperature of the ice water bath to be 1.8-2.2 ℃, adding sorbitol, lecithin and locust bean gum, stirring for 43-47min, controlling the stirring speed to be 265-275rpm, removing the ice water bath, heating to room temperature at the speed of 1.2-1.7 ℃/min, continuously stirring for 0.8-1.2h, and filtering, washing, drying and crystallizing to obtain the treated trehalose;
the mannitol pretreatment step comprises the steps of performing ball milling treatment on mannitol for the first time, adding soybean phospholipid for performing ball milling treatment for the second time, and drying after ball milling is finished to obtain pretreated mannitol.
2. The mannitol compound pharmaceutical excipients and the preparation method thereof according to claim 1, wherein,
the mass concentration of the acetic acid is 3.8-4.2%;
the mass volume ratio of the trehalose to the acetic acid is 1:3-5;
the mass ratio of the trehalose, the sorbitol, the lecithin and the locust bean gum is 24-26:0.3-0.5:0.4-0.6:0.1-0.3.
3. The mannitol compound pharmaceutical excipients and the preparation method thereof according to claim 1, wherein,
the ball milling treatment is carried out for the first time, the ball-material ratio is 6-10:1, the ball milling speed is 290-310rpm, and the ball milling time is 1.8-2.2h;
and ball milling is carried out for the second time, the ball-material ratio is 10-14:1, the ball milling speed is 380-420rpm, and the ball milling time is 2.4-2.6h.
4. The mannitol compound pharmaceutical excipients and the preparation method thereof according to claim 1, wherein,
the mass ratio of mannitol to soybean phospholipid is 10:1-2.
5. The mannitol compound pharmaceutical excipients and the preparation method thereof according to claim 1, wherein,
the mixing step comprises the steps of mixing the treated trehalose, the pretreated mannitol and the crosslinked povidone, adding deionized water, controlling the stirring speed to be 280-320rpm, stirring for 95-105min, and then spray-drying at 78-82 ℃ to obtain the pre-auxiliary material.
6. The mannitol compound pharmaceutical excipients and the preparation method thereof according to claim 5, wherein,
the mass ratio of the trehalose after treatment to the mannitol after pretreatment to the crospovidone to the deionized water is 0.8-1.2:1.9-2.2:0.15-0.25:28-32.
7. The mannitol compound pharmaceutical excipients and the preparation method thereof according to claim 1, wherein,
the mixing step further comprises the steps of reducing the pre-auxiliary material to room temperature at a speed of 2.8-3.2 ℃/min, then performing vacuum freeze drying treatment, and naturally recovering to room temperature to obtain the mannitol compound pharmaceutical auxiliary material.
8. The mannitol compound pharmaceutical excipients and the preparation method thereof according to claim 7, wherein,
the vacuum freeze drying treatment is carried out, the freezing temperature is-27 to-23 ℃, the freezing time is 1.2 to 1.4 hours, and the freezing vacuum degree is 26 to 30Pa.
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