CN101596240A - A kind of two red micropills and preparation method thereof - Google Patents

A kind of two red micropills and preparation method thereof Download PDF

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Publication number
CN101596240A
CN101596240A CNA2009100123744A CN200910012374A CN101596240A CN 101596240 A CN101596240 A CN 101596240A CN A2009100123744 A CNA2009100123744 A CN A2009100123744A CN 200910012374 A CN200910012374 A CN 200910012374A CN 101596240 A CN101596240 A CN 101596240A
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micropill
weight portion
red
chitosan
ball
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CN101596240B (en
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关屹
闫冬
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Beijing Huayao Kechuang Pharmaceutical Technology Development Co., Ltd
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SHENYANG YILING MEDICINE TECHNOLOGY Co Ltd
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Abstract

The present invention relates to a kind of two red micropill, mainly made by crude drug Radix Salviae Miltiorrhizae and Cortex Moutan and microcrystalline cellulose excipients, chitosan and an amount of adhesive, the prepared two red micropills of the present invention have effective ingredient and comprise the rate height, the micropill that makes becomes ball good, characteristics such as disintegrate is fast in vivo.

Description

A kind of two red micropills and preparation method thereof
Technical field
The present invention relates to a kind of two red micropill that is used for cardiovascular disease, belong to field of traditional Chinese.
Background technology
Two red sheets are that Chinese Pharmacopoeia records preparation, are a kind of medicine of the treatment thoracic obstruction, and symptom is as " General Treatise on the Cause and Symptoms of Diseases " thoracic obstruction piece of writing cloud: " time of the thoracic obstruction; width of cloth clothes as full in the heart; dysphagia is unfavorable, breezy as itch, puckery in the larynx; strong at heart shoot; that the bitter numbness strand of muscle skill is as thorn, must not pitching, the front skin is pain all; hands can not be violated, fullness in the chest is losed heart and little person is also ".Modern medicine is used for the treatment of coronary heart disease, the angina pectoris of common pilosity clinically, is that coronary atherosclerosis or spasm cause luminal stenosis, makes coronary insufficiency, acute, the transience ischemia of cardiac muscle, the caused clinical syndrome of anoxia.Shuang dan orally disintegrating tablet is made up of the effective site of Radix Salviae Miltiorrhizae and Cortex Moutan, has activating blood circulation to dissipate blood stasis, and the effect of coronary circulation-promoting pain-relieving is used for the thoracic obstruction due to the congestion impatency.
At present, the two red peroral dosage form on the market has oral liquid, granule, tablet and capsule, and oral liquid carries and stores inconvenience, and granule, tablet and capsular bioavailability are not high yet, can not play quick-acting effects.Micropill is a kind of dosage form with many advantages, is made up of a plurality of dispersal unit as a dosage, but large tracts of land after oral, is evenly dispersed in gastrointestinal tract, improves bioavailability of medicament, is not subjected to the influence of gastric emptying in the gastrointestinal transhipment, absorbs favorable reproducibility; Micropill is wrapped slow controlled release film coat, also can be made into slow controlled release micro pill agent.But Chinese medicine is made micropill, also exists a lot of problems, and especially for some Chinese medical concrete pellet preparations, because the extractum amount is big, stickiness is higher, when making micropill, has limited the development of Chinese medical concrete micropill usually owing to drug loading is little.In the prior art, usually, making the used excipient of micropill is lactose, starch, microcrystalline Cellulose, because microcrystalline Cellulose has dilatancy preferably, the micropill molding of making is better, adopt more.
Adopt microcrystalline Cellulose as the two red micropills of excipient preparation, when the micropill drug loading greater than 30% the time, the micropill balling property is poor, granularity is inhomogeneous.Under the process conditions of same preparation micropill, the problem of solution rounding rate commonly used is suitably to increase the excipient microcrystalline Cellulose, and to reduce the viscosity of extract, this has caused the low problem of drug loading again.Therefore, improving two red micropill drug loading, and make the micropill of qualified profile, is a big problem that needs solution at present.
Summary of the invention
The object of the present invention is to provide a kind of drug loading height, rapid-action, two red micropill that bioavailability is high.
Research worker of the present invention is found through a large amount of tests are unexpected, in two red micropills, add an amount of chitosan, can obtain the higher two red micropill of drug loading, but become big, can stop the release of medicine because chitosan is met water viscosity, influence the release of medicine when consumption is big, do not reach quick-acting effects, therefore, when guaranteeing that drug loading is higher relatively, also must control the amount of chitosan, so that the release of the two red compositions of its not obvious influence.
The two red micropills of the present invention are made by acceptable excipient in raw medicinal material and the pharmacy.
Among the present invention, used crude drug is Radix Salviae Miltiorrhizae, Cortex Moutan, and raw medicinal material composition weight proportioning is Radix Salviae Miltiorrhizae 2-8 weight portion, Cortex Moutan 1-4 weight portion.
Among the present invention, the crude drug weight proportion is preferably Radix Salviae Miltiorrhizae 2-4 weight portion, Cortex Moutan 1-2 weight portion.
Among the present invention, the crude drug weight proportion is Radix Salviae Miltiorrhizae 2 weight portions more preferably, Cortex Moutan 1 weight portion.
Among the present invention, raw medicinal material is to get active component through extracting preparation, and the active component of preparation gained is made micropill again, and wherein the preparation method of active component extract is: Cortex Moutan distillation, distillate device are in addition collected; Medicinal residues and Radix Salviae Miltiorrhizae decoct with water secondary, and 2 hours for the first time, 1 hour for the second time, collecting decoction filters, and is concentrated into the clear paste that relative density is 1.14-1.16 under 60 ℃ of conditions of filtrate, adding ethanol makes and contains alcohol amount and reach 60%, mixing, cold preservation 24 hours, filter, relative density is the clear paste of 1.14-1.16 under filtrate recycling ethanol to the 60 ℃ condition, adds the Cortex Moutan distillate, continuing at 60 ℃, to be evaporated to relative density be 1.26,40 ℃ of following evacuation dryings are pulverized, and get activity extract.
Perhaps, raw material activity extract of the present invention can also make in the following way: Cortex Moutan distills with distilled water, and distillate device is in addition collected, and distillate is put in 4 ℃ of refrigerators and placed one day, separates out crystallization, and is standby, filters, and gets crystallization, 40 ℃ of following evacuation dryings; Medicinal residues and Radix Salviae Miltiorrhizae decoct with water secondary, 2 hours for the first time, 1 hour for the second time, collecting decoction, filter, be concentrated into the clear paste that relative density is 1.14-1.16 under 60 ℃ of conditions of filtrate, add ethanol and make and contain the alcohol amount and reach 60%, mixing, cold preservation 24 hours filters, and relative density is the clear paste of 1.14-1.16 under filtrate recycling ethanol to the 60 ℃ condition, continuing at 60 ℃, to be evaporated to relative density be 1.26,40 ℃ of following evacuation dryings are pulverized, and the Cortex Moutan crystal is joined in the extract, mixing gets activity extract.
Among the present invention, used micropill excipient is microcrystalline Cellulose and chitosan; Preparing the used adhesive of micropill of the present invention is the ethanol of 30%-50%.
Suitable amounts for chitosan, research worker draws the scope with the 5%-15% of prescription weight, more preferably the weight range of 8%-12% through experiment sieving, the two red particle drug-loaded amount of gained is also higher relatively, and the two red micropill effective ingredient release of gained is better.
Among the present invention, the recipe quantity proportioning of two red pellet preparations is: the raw medicinal material active component extract is the 20-60 weight portion, microcrystalline Cellulose 20-70 weight portion, chitosan 5-12 weight portion.Being preferably the raw medicinal material active component extract is the 40-60 weight portion, microcrystalline Cellulose 20-50 weight portion, chitosan 8-12 weight portion.
The preparation method of micropill of the present invention comprises the steps: crude drug activity extract, excipient are pulverized, cross 120 mesh sieves, with crude drug activity extract, excipient mixing, ethanol with 30%-50% is that adhesive is mediated evenly system soft material, employing is extruded-round as a ball one-tenth ball legal system micropill, extrude-extruded velocity of spheronization is that 25-35r/min, round as a ball speed are that 800-1000r/min, round as a ball time are 4-8min.
One, single microcrystalline Cellulose of using mixes controlled trial with microcrystalline Cellulose, chitosan
Choose microcrystalline Cellulose, microcrystalline Cellulose mixes with chitosan, is divided into totally 8 groups of Testing Team in the following table 1.
Microsphere and its preparation is: take by weighing an amount of crude drug activity extract, pulverize, cross 120 mesh sieves, respectively with the different tests group in used mixed with excipients, the ethanol with 30% is that adhesive is mediated evenly system soft material, adopts and extrudes round as a ball legal system micropill, the extruded velocity of extruding spheronization is that 30r/min, round as a ball speed are that 900r/min, round as a ball time are 5min, collect the molding micropill, the micropill that makes is sieved out micropill in 18-24 order scope, weigh.
Test method: measure total ball weight, roundness, 18-24 order ball yield, specifically see Table 1
Table 1 test grouping
The test group numbering Extract weight part The microcrystalline Cellulose weight portion The chitosan weight portion Total ball is heavy The rounding rate (Φ/°) 18-24 order ball yield (%)
1 20 80 - 48.4±0.26 11.0±0.21 87.3±0.12
2 30 70 - 45.7±0.19 12.2±0.18 85.8±0.15
3 40 60 - 30.7±0.12 16.3±0.32 57.6±0.16
4 50 50 - - - -
5 40 50 10 46.6±0.17 10.2±0.23 88.9±0.23
6 50 40 10 44.9±0.20 11.4±0.31 86.7±0.19
7 60 30 10 40.5±0.16 12.3±0.35 83.1±0.15
8 65 25 10 34.7±0.14 14.8±.37 80.2±0.19
In test, we find, are using excipient only under the situation as microcrystalline Cellulose, when two red micropill drug loading are 40%, the micropill balling-up is poor, receive total ball heavily few, the granularity of the two red micropills of gained is also inhomogeneous, micropill (the micropill particle diameter is less than the 1mm) proportion in the 18-24 order scope is also few, and when medicine carrying is 50%, the two red micropill of making basically can not balling-up, is strip or irregular shape, and granularity is very big.In excipient, add an amount of chitosan, reach at 60% o'clock at medicine carrying, the total ball of finished product micropill is heavy, the interior micropill yield of 18-24 order scope is all higher, and its even particle size distribution, the rounding rate is good, therefore, adds an amount of chitosan, can effectively change two insufficient problems of red micropill drug loading, improve the medicine carrying ratio of the two red micropills of unit.
Measured the above-mentioned accumulation dissolution of gained micropill in 15min of respectively organizing respectively, the stripping of 1,2,3,5,6,7,8 group of accumulative total all can reach more than 70%.
Two, chitosan proportion screening test in prescription
Establishing chitosan successively, to account for the prescription gross weight in prescription be 3%, 5%, 10%, 12%, 15%, 20% totally 6 groups, and activity extract is fixed as and accounts for 50% of micropill prescription total amount.Measure the accumulation dissolution in total ball weight, roundness, 18-24 order ball yield and the 15min respectively, concrete outcome sees Table 2.
Table 2 different content chitosan is to the influence of micropill
The test group numbering Extract weight part The microcrystalline Cellulose weight portion The chitosan weight portion Total ball is heavy The rounding rate (Φ/°) 18-24 order ball yield (%) 15min accumulates stripping (%)
1 50 47 3 22.3±0.15 20.1±0.21 32.5±0.12 86.2
2 50 45 5 35.7±0.19 16.2±0.28 72.8±0.21 85.9
3 50 40 10 45.8±0.18 10.5±0.31 88.7±0.29 85.3
4 50 38 12 44.3±0.26 11.3±0.27 85.3±0.27 82.4
5 50 35 15 41.6±0.17 13.2±0.23 71.2±0.26 70.5
6 50 30 20 27.9±0.21 18.4±0.33 45.7±0.17 49.7
It for medicine carrying 50% micropill prescription, when chitosan was lower than 5%, molding micropill yield was low, and the micropill in the 18-24 order scope is also less, the micropill skewness, and when chitosan content improved, to 20%, the accumulation dissolution of micropill in 15min was less relatively, the effect that its performance of impression is quick-acting, at chitosan is that 5%-15% is advisable, and is preferably 5%-12%, more preferably 8%-12%.
Specific embodiment
Below further specify the present invention from specific embodiment, need to prove that each listed embodiment is not in order to limit the present invention, those skilled in the art can make any change at an easy rate in admissible scope.
The preparation of embodiment 1 extract
Radix Salviae Miltiorrhizae 2000g Cortex Moutan 1000g
Cortex Moutan distills with distilled water, and distillate device is in addition collected; Medicinal residues and Radix Salviae Miltiorrhizae add water and add 8 times of water gagings decoction secondaries, 2 hours for the first time, 1 hour for the second time, collecting decoction filters, and is concentrated into relative density under 60 ℃ of conditions of filtrate and is 1.14 clear paste, adding ethanol makes and contains alcohol amount and reach 60%, mixing, cold preservation 24 hours, filter, relative density is 1.14 clear paste under filtrate recycling ethanol to the 60 ℃ condition, adds the Cortex Moutan distillate, continuing at 60 ℃, to be evaporated to relative density be 1.26,40 ℃ of following evacuation dryings are pulverized, and get activity extract.
Perhaps, Cortex Moutan distills with distilled water, and distillate device is in addition collected, and distillate is put in 4 ℃ of refrigerators and placed one day, separates out crystallization, and is standby, filters, and gets crystallization, 40 ℃ of following evacuation dryings; Medicinal residues and Radix Salviae Miltiorrhizae add 8 times of water gagings and decoct secondary, 2 hours for the first time, 1 hour for the second time, collecting decoction, filter, be concentrated into relative density under 60 ℃ of conditions of filtrate and be 1.14 clear paste, add ethanol and make and contain the alcohol amount and reach 60%, mixing, cold preservation 24 hours filters, and relative density is 1.14 clear paste under filtrate recycling ethanol to the 60 ℃ condition, continuing at 60 ℃, to be evaporated to relative density be 1.26,40 ℃ of following evacuation dryings are pulverized, and the Cortex Moutan crystal is joined in the extract, mixing gets activity extract.
The preparation of embodiment 2 extracts
Radix Salviae Miltiorrhizae 8000g Cortex Moutan 2000g
Cortex Moutan distills with distilled water, and distillate device is in addition collected; Medicinal residues and Radix Salviae Miltiorrhizae add water and add 10 times of water gagings decoction secondaries, 2 hours for the first time, 1 hour for the second time, collecting decoction filters, and is concentrated into relative density under 60 ℃ of conditions of filtrate and is 1.16 clear paste, adding ethanol makes and contains alcohol amount and reach 60%, mixing, cold preservation 24 hours, filter, relative density is 1.16 clear paste under filtrate recycling ethanol to the 60 ℃ condition, adds the Cortex Moutan distillate, continuing at 60 ℃, to be evaporated to relative density be 1.26,40 ℃ of following evacuation dryings are pulverized, and get activity extract.
3 pairs of red micropill prescriptions of embodiment and preparation
Raw medicinal material activity extract 20g
Microcrystalline Cellulose 25g
Chitosan 5g
30% ethanol 20mL
Get crude drug, pulverize, cross 120 mesh sieves, with the extract after pulverizing and microcrystalline Cellulose, chitosan mix homogeneously, ethanol with 30% is that adhesive is mediated evenly, the system soft material, the soft material that makes adopted extrude-spheronization prepares micropill, extruded velocity is 30r/min, round as a ball speed is 900r/min, and the round as a ball time is 5min, collects qualified molding micropill, 60 ℃ of following vacuum dryings, dried micropill with the classification of 18-24 mesh sieve, is got the micropill between the 18-24 mesh sieve, weigh, get 42.1g, the micropill yield is 84.1% between the 18-24 order.
4 pairs of red micropill prescriptions of embodiment and preparation
Raw medicinal material activity extract 20g
Microcrystalline Cellulose 15.2g
Chitosan 4.8g
40% ethanol 25mL
Get crude drug, pulverize, cross 120 mesh sieves, with the extract after pulverizing and microcrystalline Cellulose, chitosan mix homogeneously, ethanol with 40% is that adhesive is mediated evenly, the system soft material, the soft material that makes adopted extrude-spheronization prepares micropill, extruded velocity is 30r/min, round as a ball speed is 800r/min, and the round as a ball time is 6min, collects qualified molding micropill, 60 ℃ of following vacuum dryings, dried micropill with the classification of 18-24 mesh sieve, is got the micropill between the 18-24 mesh sieve, weigh, get 32.8g, the micropill yield is 82.0% between the 18-24 order.
5 pairs of red micropill prescriptions of embodiment and preparation
Raw medicinal material activity extract 20g
Microcrystalline Cellulose 26g
Chitosan 4g
50% ethanol 30mL
Get crude drug, pulverize, cross 120 mesh sieves, with the extract after pulverizing and microcrystalline Cellulose, chitosan mix homogeneously, ethanol with 50% is that adhesive is mediated evenly, the system soft material, the soft material that makes adopted extrude-spheronization prepares micropill, extruded velocity is 30r/min, round as a ball speed is 1000r/min, and the round as a ball time is 5min, collects qualified molding micropill, 60 ℃ of following vacuum dryings, dried micropill with the classification of 18-24 mesh sieve, is got the micropill between the 18-24 mesh sieve, weigh, get 44.2g, the micropill yield is 88.4% between the 18-24 order.
Embodiment 6 micropills prescription and preparation method
Raw medicinal material activity extract 30g
Microcrystalline Cellulose 16g
Chitosan 4g
30% ethanol 30mL
Get crude drug, pulverize, cross 120 mesh sieves, with the extract after pulverizing and microcrystalline Cellulose, chitosan mix homogeneously, ethanol with 50% is that adhesive is mediated evenly, the system soft material, the soft material that makes adopted extrude-spheronization prepares micropill, extruded velocity is 30r/min, round as a ball speed is 900r/min, and the round as a ball time is 5min, collects qualified molding micropill, 60 ℃ of following vacuum dryings, dried micropill with the classification of 18-24 mesh sieve, is got the micropill between the 18-24 mesh sieve, weigh, get 36.6g, the micropill yield is 73.2% between the 18-24 order.
Embodiment 3-6 accumulative total discharges the dissolution determination employing, and " Chinese pharmacopoeia version II in 2000 the appendix XC of portion stripping uceding changes blue laws, and dissolution medium is 500ml simulated gastric fluid (pH=1.2), and temperature is 37 ℃, and changeing blue rotating speed is 100r/min.Get among the embodiment 3-6 the two red micropill 0.3g of gained respectively, put and change in the basket, change blue contact medium and pick up counting, respectively at 2,5,10,15,20,30,45min, precision is measured and is discharged liquid 5ml, replenishes 5ml equality of temperature medium immediately.Filtrate is put to room temperature, crosses microporous filter membrane (0.45um), as need testing solution, accurate respectively need testing solution and each 10ul of reference substance solution (danshensu sodium solution) of drawing injects high performance liquid chromatograph, measures the content of danshensu, parallel assay is six groups altogether, calculates average accumulated and discharges dissolution rate.The results are shown in Table 3.
The cumulative release dissolution of table 3 embodiment 3-6
Figure A20091001237400111

Claims (6)

1, a kind of two red micropill is made by acceptable excipient in crude drug and the pharmacy, it is characterized in that:
(1) raw materials used medical material composition weight proportioning is: Radix Salviae Miltiorrhizae 2-8 weight portion, and Cortex Moutan 1-4 weight portion, the preparation method of raw medicinal material active component extract is: Cortex Moutan distillation, distillate device are in addition collected; Medicinal residues and Radix Salviae Miltiorrhizae decoct with water secondary, and 2 hours for the first time, 1 hour for the second time, collecting decoction filters, and is concentrated into the clear paste that relative density is 1.14-1.16 under 60 ℃ of conditions of filtrate, adding ethanol makes and contains alcohol amount and reach 60%, mixing, cold preservation 24 hours, filter, relative density is the clear paste of 1.14-1.16 under filtrate recycling ethanol to the 60 ℃ condition, adds the Cortex Moutan distillate, continuing at 60 ℃, to be evaporated to relative density be 1.26,40 ℃ of following evacuation dryings are pulverized, and get activity extract;
(2) used excipient is microcrystalline Cellulose and chitosan, and used adhesive is the ethanol of 30%-50%;
(3) in the micropill prescription, the raw medicinal material active component extract is the 20-60 weight portion, microcrystalline Cellulose 20-70 weight portion, chitosan 5-15 weight portion.
2, two red micropill according to claim 1 is characterized in that
(1) raw materials used medical material composition weight proportioning is: Radix Salviae Miltiorrhizae 2-4 weight portion, and Cortex Moutan 1-2 weight portion, the preparation method of raw medicinal material active component extract is: Cortex Moutan distillation, distillate device are in addition collected; Medicinal residues and Radix Salviae Miltiorrhizae decoct with water secondary, and 2 hours for the first time, 1 hour for the second time, collecting decoction filters, and is concentrated into the clear paste that relative density is 1.14-1.16 under 60 ℃ of conditions of filtrate, adding ethanol makes and contains alcohol amount and reach 60%, mixing, cold preservation 24 hours, filter, relative density is the clear paste of 1.14-1.16 under filtrate recycling ethanol to the 60 ℃ condition, adds the Cortex Moutan distillate, continuing at 60 ℃, to be evaporated to relative density be 1.26,40 ℃ of following evacuation dryings are pulverized, and get activity extract;
(2) used excipient is microcrystalline Cellulose and chitosan, and used adhesive is the ethanol of 30%-50%;
(3) in the micropill prescription, the raw medicinal material active component extract is the 20-60 weight portion, microcrystalline Cellulose 20-70 weight portion, chitosan 5-15 weight portion.
3, two red micropill according to claim 1 and 2 is characterized in that the raw medicinal material active component extract is the 20-60 weight portion, microcrystalline Cellulose 20-70 weight portion, chitosan 5-15 weight portion in the described micropill prescription.
4, two red micropill according to claim 3 is characterized in that the raw medicinal material active component extract is the 40-60 weight portion, microcrystalline Cellulose 20-50 weight portion, chitosan 8-12 weight portion in the described micropill prescription.
5, a kind of method for preparing the described two red micropills of arbitrary claim in the claim 1,2 or 4, comprise: crude drug activity extract, excipient are pulverized, cross 120 mesh sieves, with crude drug activity extract, excipient mixing, ethanol with 30%-50% is that adhesive is mediated evenly system soft material, employing is extruded-round as a ball one-tenth ball legal system micropill, and the extruded velocity of extruding spheronization is that 25-35r/min, round as a ball speed are that 800-1000r/min, round as a ball time are 4-8min.
6, a kind of method for preparing the described two red micropills of claim 3, comprise: crude drug activity extract, excipient are pulverized, cross 120 mesh sieves, with crude drug activity extract, excipient mixing, ethanol with 30%-50% is that adhesive is mediated evenly system soft material, employing is extruded-round as a ball one-tenth ball legal system micropill, and the extruded velocity of extruding spheronization is that 25-35r/min, round as a ball speed are that 800-1000r/min, round as a ball time are 4-8min.
CN2009100123744A 2009-07-06 2009-07-06 Shuangdan micro pill and preparation method thereof Active CN101596240B (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104224727A (en) * 2013-06-17 2014-12-24 天士力制药集团股份有限公司 Preparation method of traditional Chinese medicine pellet
CN111228224A (en) * 2018-11-28 2020-06-05 鲁南制药集团股份有限公司 Aloe-containing constipation-relieving pellet preparation and preparation method thereof

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104224727A (en) * 2013-06-17 2014-12-24 天士力制药集团股份有限公司 Preparation method of traditional Chinese medicine pellet
CN104224727B (en) * 2013-06-17 2018-04-03 天士力医药集团股份有限公司 A kind of preparation method of traditional Chinese medicine pellet
CN111228224A (en) * 2018-11-28 2020-06-05 鲁南制药集团股份有限公司 Aloe-containing constipation-relieving pellet preparation and preparation method thereof
CN111228224B (en) * 2018-11-28 2022-05-20 鲁南制药集团股份有限公司 Aloe-containing constipation-relieving pellet preparation and preparation method thereof

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