CN102552158B - Mei Takawei enteric coated micropill and preparation method thereof - Google Patents
Mei Takawei enteric coated micropill and preparation method thereof Download PDFInfo
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- CN102552158B CN102552158B CN201010603145.2A CN201010603145A CN102552158B CN 102552158 B CN102552158 B CN 102552158B CN 201010603145 A CN201010603145 A CN 201010603145A CN 102552158 B CN102552158 B CN 102552158B
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- 235000010603 pastilles Nutrition 0.000 claims abstract description 29
- 238000000576 coating method Methods 0.000 claims abstract description 28
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- 239000011248 coating agent Substances 0.000 claims abstract description 24
- 238000007789 sealing Methods 0.000 claims abstract description 17
- 239000012055 enteric layer Substances 0.000 claims abstract description 16
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- YKBGVTZYEHREMT-UHFFFAOYSA-N 2-amino-9-[4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-3h-purin-6-one Chemical compound C1=2NC(N)=NC(=O)C=2N=CN1C1CC(O)C(CO)O1 YKBGVTZYEHREMT-UHFFFAOYSA-N 0.000 description 1
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- FJAOCNGVPLTSLD-NKWVEPMBSA-N COc1c2nc[n]([C@@H]3O[C@H](CO)CC3)c2nc(N)n1 Chemical compound COc1c2nc[n]([C@@H]3O[C@H](CO)CC3)c2nc(N)n1 FJAOCNGVPLTSLD-NKWVEPMBSA-N 0.000 description 1
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- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to field of pharmaceutical preparations, relate to a kind of Mei Takawei enteric coated micropill, comprise the pastille micropill be made up of active component Mei Takawei and pharmaceutical excipient, and the enteric layer to be made up of crylic acid resin material and other pharmaceutical excipient, between described enteric layer and main medicament layer, sealing coat is set.Mei Takawei enteric coated micropill of the present invention, includes pastille micropill, sealing coat, enteric layer, components by weight percentage: the Mei Takawei in pastille micropill is 20 ~ 50%, and excipient is 30 ~ 50%; Coating materials in sealing coat is 2 ~ 7%, and antiplastering aid is 0 ~ 2%; Enteric material in enteric layer is 10 ~ 40%, and stabilizing agent is 0 ~ 1%, and plasticizer is 1 ~ 5%, and antiplastering aid is 3 ~ 10%.Mei Takawei enteric coated micropill acid-resistant strength prepared by the present invention is strong, and rate of release is stablized, good stability.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, be specifically related to a kind of chemicals Mei Takawei enteric coated preparation for the treatment of Type B viral hepatitis and preparation method thereof.
Background technology
Hepatitis B (hepatitisB), is called for short hepatitis B, is caused by hepatitis B virus (HBV), take hepatic lesions as the main infectious disease that also can cause multiple organ injury.The whole world has every year dies from primary hepatocarcinoma more than 500,000 people, and wherein nearly the primary hepatocarcinoma of 80% caused by chronic viral hepatitis B.In 400,000,000 Chronic Hepatitis Bs, have 75% to live in Asia, and China is the country that hepatitis B sickness rate is the highest.Latest data shows, and China is every year because the number of hepatopathy death is close to 500,000, and the loss caused to society is up to 1,000 hundred million yuan.
Mei Takawei (6-methocy bideoxy bideoxy guanosine) is a kind of research of nucleosides against hepatitis B virus of novelty, and researched and developed by Chang'ao Pharmacy technology Co., Ltd., Nanjing city, its structural formula is as follows:
Mei Takawei is the derivant of 2,3-dideoxyguanosine, and in 2,3-dideoxyguanosine class medicine, base is all existing list marketing of medicine of adenine, uracil and cytosine, does not only have base to be the ddG class medicine listing of guanine.This is mainly owing to the physicochemical property of ddG, and the water solublity of ddG is very poor, extremely unstable to temperature, and-20 DEG C of preservations of general needs, are also easy to be degraded, so be difficult to become a kind of medicine in vivo.And Mei Takawei is as the derivant of ddG, then have the metastable feature of temperature, simultaneously degraded is in vivo also gentleer than ddG a lot, and drug effect is suitable with lamivudine.Therefore Mei Takawei has compared with ddG good water solubility and more stable feature.
Mei Takawei is as nucleoside medicine, as the prodrug of ddG, in blood plasma, rapid metabolization is 2,3-dideoxyguanosine (ddG), then in cell, be phosphorylated to active triphosphate ddGTP, by suppressing copying of DNA with the natural substrate triphosphoric acid NSC 22837 competition binding of HBV polymerase, causing DNA chain to synthesize and stopping, thus suppress protein translation and the DNA replication dna of virus.Mei Takawei overcomes the defect of interferons curative effect of medication and general toleration difference, and " drug resistance " problem of nucleoside medicine long-term treatment and " drug withdrawal knock-on " phenomenon, will become the new force on anti-hbv drug market.
Chinese patent application CN101147728 provides 6-methocy bideoxy bideoxy guanosine (i.e. Mei Takawei) long circulating liposome preparation and preparation method thereof.Said preparation can change the bioavailability of medicine preferably, the half-life of prolong drug, and reducing the toxicity of medicine, is the newer pharmaceutical dosage form for injecting; The present inventor through more deep research, according to the medicine feature of Mei Takawei itself, invent a kind of be suitable for oral, technique is simple, be easy to the Mei Takawei enteric coated pellets formulation that operates, is a kind of novel excellent enteric coated preparation of Mei Takawei.
Pellet is a kind of dosage decentralized dosage form, and a dosage is often made up of the multiple unit disperseed, and the dosage form be made up of a unit with single dose has the following advantages compared with Tablet and Capsula agent: 1. good looking appearance, good fluidity.When loading capsule, without the need to adding fluidizer, the capsule content uniformity loaded than powder, granule is little, in the preparation of compound preparation, have good advantage; 2. bioavailability is higher, and local irritation is little.Micropill take after can extensively, be evenly distributed in gastrointestinal tract, distribution area is large in vivo, the impact of the transhipment unable to take food thing conveying rhythm and pace of moving things of micropill in gastrointestinal tract simultaneously, namely general not by the impact of gastric emptying, make drug bioavailability improve and reduce or eliminate medicine to gastrointestinal zest.3. micropill release is stablized, and plasma concentration curve is steady, and favorable reproducibility, adverse reaction rate are low.4. take medicine more convenient, except the method that granulate is taken, taking inconvenient patient for granulate can take apart pellet capsule, directly takes little micropill, can not cause the change of drug effect.
Mei Takawei is extremely unstable under strongly acidic conditions, inactivation of degrading rapidly under gastric acid condition, is prepared into the impact that enteric coated preparation can avoid gastric acid, alleviates gastrointestinal zest, improves bioavailability; Mei Takawei is unstable under the high temperature conditions, and more than 58 DEG C, i.e. melting, easily causes character to change, and needs the strict temperature controlling material when preparing micropill.The invention provides a kind of Mei Takawei enteric coated pellets formulation and preparation method thereof.The preparation of this enteric coated micropill adopts adjuvant and the preparation technology of preparation routine, be applicable to suitability for industrialized production, and this enteric coated pellets formulation makes patient's medication convenient, overcomes common enteric coatel tablets preferably, common enteric coated capsule may be broken by the teeth when swallowing, affect the shortcoming of drug effect.
Summary of the invention
The object of the invention is to overcome above-mentioned the deficiencies in the prior art, aim to provide a kind of good stability, side effect is little, determined curative effect, supplementary product consumption are few, production efficiency is high Mei Takawei enteric-coated pellet capsule and preparation method thereof.
Mei Takawei is unstable in acid, and inactivation of degrading rapidly under gastric acid condition, is prepared into the stimulation that enteric-coated pellet capsule can avoid gastric acid, improves bioavailability.
Mei Takawei is unstable to high temperature, and the i.e. melting more than 58 DEG C, face shaping changes.Adopt conventional fluid bed, extrusion spheronization and centrifugal granulating to prepare micropill, in preparation process, all need heat drying; If coating solution solvent is dehydrated alcohol, just need in explosion-proof Workshop Production, and it is relatively high to use dehydrated alcohol to make solvent production cost.For preparing Mei Takawei enteric-coated pellet capsule that is stable, that be applicable to suitability for industrialized production, need to be controlled by special prescription composition and applicable technological parameter.
The present inventor is through a large amount of experimentatioies, find that the dissolubility of Mei Takawei has very large association with solvent temperature, slightly molten in water under room temperature condition, be heated to 30 DEG C of dissolubility and be increased to 4% (g/100ml), be heated to 40 DEG C of dissolubility and be increased to 10% (g/100ml).Investigate the stability of Mei Takawei under condition of different temperatures simultaneously, got appropriate Mei Takawei respectively at 20 DEG C, 30 DEG C, 40 DEG C, 50 DEG C and 60 DEG C of placements, investigate its appearance character and related substance, investigate result as follows:
The stability of Mei Takawei under table 1 condition of different temperatures
Show according to above-mentioned experimental result, Mei Takawei is unstable to temperature, is mainly reflected in appearance character and changes, and related substance there is no significance change, but character change can cause micropill that the migration of moisture and material occurs between different layers in preparation process, affects the stability of finished product.Comprehensive Mei Takawei dissolubility at different temperatures, controls temperature of charge within 50 DEG C, is more preferably 40 DEG C in the process preparing micropill.
Mei Takawei enteric coated micropill components by weight percentage provided by the invention is as follows:
A. pastille micropill
Mei Takawei 20 ~ 50%
Excipient 30 ~ 50%
B. sealing coat
Coating materials 2 ~ 7%
Antiplastering aid 0 ~ 2%
C. enteric layer
Enteric material 10 ~ 40%
Stabilizing agent 0 ~ 1%
Plasticizer 1 ~ 5%
Antiplastering aid 3 ~ 10%
Described excipient is microcrystalline Cellulose, lactose or its compositions;
Described antiplastering aid is Pulvis Talci, magnesium stearate, silicon dioxide, titanium dioxide, is preferably Pulvis Talci;
Described coating materials is hydroxypropyl methylcellulose class, polyvidone, copolyvidone;
Described enteric material is crylic acid resin enteric material, polyvinyl acetate phthalic acid ester, Hydroxypropyl Methyl Cellulose Phthalate, is preferably crylic acid resin, is more preferably EudragitL30D-55, and it is 30% containing curing acrylic resin;
Described stabilizing agent is sodium hydroxide, potassium hydroxide etc.;
Described plasticizer is triethyl citrate, polyethylene glycol 6000, diethyl phthalate etc.
Pastille micropill refers to the micropill that Mei Takawei and one or more above-mentioned pharmaceutically useful excipient are prepared by extrusion spheronization, centrifugal granulating, high-efficiency coating pot or fluid bed, by medicated layer preparation coated on celphere, also can mix powder by medicine and directly prepare.As adopted extrusion spheronization legal system for pastille micropill, just do not need celphere.The standby micropill of extrusion spheronization legal system we select microcrystalline Cellulose, lactose as excipient, preferably microcrystalline cellulose.Because microcrystalline Cellulose (MCC) is a kind of balling-up promoter, can retain a large amount of moisture content and make material have plasticity, compared with other adjuvant, the micropill smooth surface obtained by MCC, roundness are better.Preparation method: by Mei Takawei and mixed with excipients even, with the ethanol water of 0%-90% for binding agent prepares soft material, above-mentioned soft material is put extruding → extrudate in extruder and to add in spheronizator → round as a ball 5min → 40 DEG C drying → screening (selecting the micropill of 0.5 ~ 1.0mm), according to the needs of final capsule fill, can again sieve.
Sealing coat coating mainly plays buffer action, and Mei Takawei is unstable under acidic condition, and the general slant acidity of enteric coating liquid, directly can not contact enteric-coating material, need at pastille micropill outer cladding sealing coat, then bag enteric layer; Sealing coat can improve the roundness of pastille micropill, crisp Magnum degree simultaneously, and then improves the effect of final enteric coating.Coating material and antiplastering aid are mixed with suspension, and spray, with on pastille micropill, can adopt centrifugal granulating, fluid bed, high-efficiency coating machine to prepare.Sealing coat increases weight 6%, 8%, 10% respectively by experiment, and micropill smooth in appearance when finding weightening finish 8%, yield are higher, and coating process produces without adhesion and electrostatic phenomenon, preferred sealing coat coating weight gain 8%.
The good hydroxypropyl methylcellulose of the preferred film property of the present invention is as the coating material of sealing coat, and as adopted centrifugal granulation preparation, its formulation and technology is:
(1) hydroxypropyl methylcellulose 10.0
Pulvis Talci 2.0
75% ethanol 100.0g
(2) hydroxypropyl methylcellulose is first scattered in dehydrated alcohol, is then dissolved in water, then add Pulvis Talci and constantly stir, for subsequent use;
(3) centrifugal granulator is started, engine speed 200r.min
-1, whiff pressure 0.5 ~ 0.6Mpa, air blast flux 15*20L.min
-1,, spray air flow 15 ~ 20L.min
-1,, start hydrojet after adding the first preheating 5min of pastille micropill, hydrojet flow-control is at 15 ~ 25L.min
-1, sprayed to coating solution, 40 DEG C of dry 5min, screening.
Enteric-coating material develops very fast at home and abroad, be widely used, synthesize till now from natural, single Cultivar development, semisynthetic multi items macromolecular material, for guarantee medicine stability, reduce adverse effect, make medicine give full play to curative effect and play an important role.Mainly contain Lac, Cellulose Acetate Phthalate (CPA), polyvinyl acetate phthalate (PVAP), acrylic resin (AcrylicResin), hydroxypropyl emthylcellulose titanate esters (HPMCP).Wherein acrylic resin is current domestic application enteric-coating material the most widely, acrylic resin is a kind of excellent enteric-coating material, there is safe, simple to operate, fast drying, make medicine be subject to damp and hotly to affect little, the advantages such as a large amount of adjuvant, cost is low, quality is good can be reduced.Apply that the more Eudragit1L30D-55 aqueous dispersion for German Degussa and Shanghai Ka Lekang develop gather compound, plasticizer and coloring agent in one, can in water-based system refined gram of the enteric-coating material of coating
(Acryl-
).Eudragit1L30D-55 often need add plasticizer, antiplastering aid as enteric-coating material, sometimes also need to add stabilizing agent; Ya Ke
(Acryl-
) preparation, simple to operate, and have the enteric coating powder especially for micropill and PPI (proton pump inhibitor) class medicine.
Enteric layer coating weight gain directly affects the enteric effect of micropill, carry out test coating weight gain 20%, 30%, 40% (in acrylic polymer) respectively, investigate different coating weight gain micropill outward appearance, and carry out acid-resistant strength and drug release determination according to China's coastal port, result is as follows:
| Coating weight gain % | Outward appearance | Acid-resistant strength % | Release % |
| 20 | Clothing film is complete, smooth surface | 94.8 | 97.1 |
| 30 | Clothing film is complete, smooth surface | 98.4 | 99.7 |
| 40 | Clothing film is complete, smooth surface | 98.6 | 99.8 |
Analyzing above result, for ensureing the quality of the pharmaceutical preparations, reaching good enteric effect, preferred enteric layer coating weight gain 30% (in acrylic polymer).
Another aspect of the present invention provides a kind of Mei Takawei enteric-coated pellet capsule, and its capsule 's content is above-mentioned Mei Takawei enteric coated micropill, containing Mei Takawei 20 ~ 120mg.
Preparation method of the present invention, major ingredient and the direct pill of adjuvant mixture, do not need blank pill, simple to operate, only containing one or both excipient in the few pastille micropill of supplementary product consumption, adds Pulvis Talci, well avoid Electrostatic Absorption phenomenon in enteric layer.
Detailed description of the invention
Further illustrate the present invention by the following examples, but not as limitation of the present invention.
Embodiment 1
A. pastille micropill
Mei Takawei 70g
Microcrystalline Cellulose 105g
25% ethanol water 140ml
Preparation technology:
(1) Mei Takawei and microcrystalline Cellulose are crossed 100 mesh sieves respectively, mix homogeneously, prepares soft material with 25% ethanol water;
(2) above-mentioned soft material is put in extrusion spheronization machine, through extruding-round as a ball-be dried to micropill.Extruded velocity 15Hz, round as a ball speed 26Hz (18 minutes), the most rearmounted 40 DEG C of dry 2h, obtain 0.6mm pastille micropill.
B. sealing coat
Pastille micropill 175g
Hydroxypropyl emthylcellulose 14g
70% ethanol water 105ml
Preparation technology:
(1) above-mentioned hydroxypropyl methylcellulose is scattered in dehydrated alcohol, is then dissolved in water;
(2) start centrifugal granulator, by first for pastille micropill preheating 10min, spray into binding agent, whole process control temperature of charge about 30 DEG C, dry 10min, for subsequent use.
C. enteric layer
Isolation micropill 189g
EudragitL30D-55154g
4%NaOH solution 8g
Triethyl citrate 4g
Pulvis Talci 16g
Water 190g
Preparation technology:
(1) enteric coating liquid preparation: 4%NaOH solution slowly adds in the L30D-55 that stirred, and stirs and makes neutralization even in 15 minutes; Pulvis Talci and triethyl citrate are added to the water, high shear homogenize 10 minutes; Merged by above-mentioned two kinds of solution, be uniformly mixed, sieve, coating process keeps constantly stirring;
(2) centrifugal granulator is started, preheating isolation micropill, enteric coated, dry, get Mei Takawei enteric coated micropill;
(3) incapsulate by standard quantity, i.e. get Mei Takawei enteric-coated pellet capsule.
Embodiment 2
A. pastille micropill
Mei Takawei 65g
Lactose 30g
Microcrystalline Cellulose 90g
50% ethanol water 200ml
Preparation technology:
(1) Mei Takawei, lactose, microcrystalline Cellulose to be progressively increased method mix homogeneously by equivalent, cross 80 mesh sieves, for subsequent use;
(2) using 50% ethanol water as binding agent
(3) start centrifugal granulator, prepare pastille micropill.Spouting velocity changes with granulation time, and initial 2min is 100r.min
-1, make powder wetted at short notice, avoid dust from flying → hydrojet speed to be adjusted to 40r.min
-1,, continue to material and be cotton-shaped flow regime → confession powder, control powder slurry ratio, making material be cotton-shaped flow regime → to growing up to the core → drying → screening of target ball, obtaining pastille micropill;
B. sealing coat
Pastille micropill 185g
Hydroxypropyl methylcellulose 15g
Pulvis Talci 3g
75% ethanol water 150g
Preparation technology:
(1) above-mentioned hydroxypropyl methylcellulose is scattered in dehydrated alcohol, is then dissolved in water, add Pulvis Talci, high-speed shearing machine homogenize;
(2) start centrifugal granulator, by first for pastille micropill preheating 10min, spray into coating solution, whole process control temperature of charge about 30 DEG C, dry 10min, for subsequent use.
C. enteric layer
Isolation micropill 203g
Hydroxypropyl Methyl Cellulose Phthalate 30g
Polyvinyl acetate phthalic acid ester 30g
Magnesium stearate 12g
Triethyl citrate 8g
Water 400g
Preparation technology:
(1) add in the water of high speed shear by above-mentioned Hydroxypropyl Methyl Cellulose Phthalate, polyvinyl acetate phthalic acid ester, magnesium stearate, triethyl citrate, stir 20min, cross 80 mesh sieves, for subsequent use, coating process does not stop to stir;
(2) centrifugal granulator is started, first preheating isolation micropill → enteric coated → dry, screening, get Mei Takawei enteric coated micropill
(3) incapsulate by standard quantity, i.e. get Mei Takawei enteric-coated pellet capsule.
Embodiment 3
A. pastille micropill
Mei Takawei 50g
Microcrystalline Cellulose 50g
Water 85g
Preparation technology:
(1) Mei Takawei, microcrystalline Cellulose being progressively increased method mix homogeneously by equivalent, is that binding agent prepares soft material with water;
(2) above-mentioned soft material is put in extrusion spheronization machine, through extruding-round as a ball-be dried to micropill.Extruded velocity 15Hz, round as a ball speed 26Hz (18 minutes), the most rearmounted 40 DEG C of dry 2h, screening 0.6mm pastille micropill.
B. micropill is isolated
Pastille micropill 100g
Hydroxypropyl methylcellulose 8g
75% ethanol 80g
Preparation technology:
(1) hydroxypropyl methylcellulose is first scattered in dehydrated alcohol, is then dissolved in water;
(2) start fluid bed, inlet temperature is 35 DEG C, leaving air temp is 27 DEG C, temperature of charge is 30 DEG C, hydrojet speed is 18g/min/kg, atomizing pressure is 0.9bar, and first preheating pastille micropill 10min → hydrojet is complete → dry to coating solution, to obtain final product;
C. enteric layer
Sealing coat 108g
EudragitL30D-5580g
4%NaOH solution 5g
Polyethylene glycol 6000 3g
Pulvis Talci 8g
Water 127g
Preparation technology:
(1) enteric coating liquid preparation: 4%NaOH solution slowly adds in the L30D-55 that stirred, and stirs and makes neutralization even in 15 minutes; Pulvis Talci and polyethylene glycol 6000 are added to the water, high shear homogenize 10 minutes; Merged by above-mentioned two kinds of solution, be uniformly mixed, sieve, coating process keeps constantly stirring;
(2) fluid bed is started, inlet temperature 37 DEG C, leaving air temp 29 DEG C, temperature of charge 31 DEG C, air quantity 23m
3/ h, hydrojet speed 13g/min/kg, atomizing pressure 1bar, first preheating 5min, enteric coated, the complete drying of coating, get Mei Takawei enteric coated micropill;
(3) incapsulate by standard quantity, i.e. get Mei Takawei enteric-coated pellet capsule.
Comparative example
A. pastille micropill
Mei Takawei 30g
Celphere (0.3 ~ 0.5mm) 80g
Polyvinylpyrrolidone 5g
50% ethanol water 100g
B. sealing coat
Pastille micropill 115g
Hydroxypropyl methylcellulose 9g
Water 62g
C. enteric layer
Isolation micropill 124g
EudragitL30D-55183g
Water 175g
Preparation technology:
(1) same above-described embodiment of the configuration of coating solution;
(2) on centrifugal granulating, high-efficiency coating machine or fluid bed, prepare pastille micropill, bag sealing coat, finally bag enteric layer successively; Incapsulate by standard quantity, i.e. get Mei Takawei enteric-coated pellet capsule.
Embodiment 4 Acceleration study
The Mei Takawei enteric-coated pellet capsule prepared according to above-described embodiment, aluminum-plastic packaged, carry out accelerated test, result shows the change of comparatively comparing that there are no significant for 0 day of its outward appearance of capsule, related substance, acid-resistant strength and the release prepared by embodiment 1-3, display this product is more stable, and capsule prepared by comparative example is in study on the stability process, related substance and other all have a greater change.
Embodiment 5 long-time stability are tested
According to Rabeprazole sodium enteric-coated micro-pellet capsule prepared by patent of invention, aluminum-plastic packaged, in 25 ± 2 DEG C, investigate 24 months in the climatic chamber of relative humidity 60 ± 5%, investigate and the results are shown in following table:
Above result shows, the enteric-coated pellet capsule prepared by embodiment of the present invention 1-3 is significantly more stable than what prepare by comparative example.
Claims (3)
1. Yi Zhong Mei Takawei enteric coated micropill, includes pastille micropill, sealing coat, enteric layer, it is characterized in that components by weight percentage is as follows:
A. pastille micropill
Mei Takawei 20 ~ 50%
Filler 30 ~ 50%
B. sealing coat
Coating materials 2 ~ 7%
Antiplastering aid 0 ~ 2%
C. enteric layer
Described filler is one in microcrystalline Cellulose, lactose or its combination;
Described antiplastering aid is one or more in Pulvis Talci, magnesium stearate, silicon dioxide, titanium dioxide;
Described coating materials is hydroxypropyl methylcellulose;
Described enteric material is one or more in crylic acid resin enteric material, polyvinyl acetate phthalic acid ester, Hydroxypropyl Methyl Cellulose Phthalate;
Described stabilizing agent is one or more in sodium hydroxide, potassium hydroxide; Described plasticizer is one or more in triethyl citrate, polyethylene glycol 6000, diethyl phthalate;
Temperature of charge controls within 50 DEG C by described micropill in preparation process.
2. Mei Takawei enteric coated micropill as claimed in claim 1, is characterized in that described antiplastering aid is Pulvis Talci.
3. Mei Takawei enteric coated micropill as claimed in claim 1, is characterized in that described enteric material is acrylic resin.
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|---|---|---|---|
| CN201010603145.2A CN102552158B (en) | 2010-12-22 | 2010-12-22 | Mei Takawei enteric coated micropill and preparation method thereof |
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| CN1883459A (en) * | 2006-07-11 | 2006-12-27 | 杨喜鸿 | Enteric coated preparation of entecavir and preparation method thereof |
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