CN105534935B - Pantoprazole microplate, preparation method, multiple unit type Pantoprazole enteric sustained-release preparation and preparation method thereof - Google Patents
Pantoprazole microplate, preparation method, multiple unit type Pantoprazole enteric sustained-release preparation and preparation method thereof Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
- A61K9/2081—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets with microcapsules or coated microparticles according to A61K9/50
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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Abstract
The present invention provides a kind of Pantoprazole microplates, including drug containing label, the drug containing label is made by the composite auxiliary material of the Pantoprazole of 12.5wt%~25wt%, the lubricant of 1wt%~10wt% and 65wt%~86.5wt% through dry method vertical compression, and the composite auxiliary material is spray-dried obtained by the pH adjusting agent of the filler of 45wt%~95wt%, the adhesive of 2wt%~25wt%, the disintegrant of 2wt%~25wt% and 1wt%~5wt%.The present invention also provides a kind of preparation methods of Pantoprazole microplate.The present invention also provides a kind of multiple unit type Pantoprazole enteric sustained-release preparations.The present invention prepares composite auxiliary material using spray drying process, then is mixed with drug and lubricant, and the microplate press sheet mixture uniformity obtained by dry method direct tablet compressing is good, it is less prone to auxiliary material layering, electrostatic is reduced, and mobility and compressibility are good, and powder bullet output also meets the requirements.
Description
Technical field
The present invention relates to technical field of pharmaceuticals, more particularly, to a kind of Pantoprazole microplate, preparation method, multiple unit type
Pantoprazole enteric sustained-release preparation and preparation method thereof.
Background technology
Proton pump inhibitor (proton pump inhibitors, PPIs) is used to treat hydrochloric acid in gastric juice exceptional relevance disease,
It is the drug that clinical application in recent ten years is extensive, curative effect is best.First generation PPIs Omeprazoles were listed in 1989 in the U.S.,
Pantoprazole is the third generation proton pump inhibitor after Omeprazole, Lansoprazole, is researched and developed by the pharmaceutical factories German Byk Gulden,
Most listed in Germany earlier than 1994.Pantoprazole is first water-soluble proton pump inhibitor, is clinically used to treat each
Kind gastric acid related disease, such as peptic ulcer, gastroesophageal reflux disease, to pylorus when being applied alone or being combined with other drugs
The disease of helicobacter infection is also largely effective.
In the Protonix listed, mainly use its sodium salt as raw material.Pantoprazole Sodium is benzimidazole sulphur
Acyl derivative, chemical constitution are 5- (difluoro-methoxy) -2- { [3,4- dimethoxy -2- pyridines]-methyl sulfinyl } -
1H- benzimidazoles, chemical structural formula are：C16H14F2N3NaO4S, structural formula are as follows：
Pantoprazole Sodium is white or off-white color crystalline powder, and soluble easily in water, the atomic phosphate for being dissolved in pH 7.4 is slow
Fliud flushing is practically insoluble in n-hexane.Pantoprazole is unstable in acidic environment, and stability is related to pH in aqueous solution,
It is reduced with the reduction of pH, it is unstable under conditions of pH ＜ 6, it is degradable.At ambient temperature, Pantoprazole pH 1.25,
50% time of degrading under the conditions of pH 5 and pH 7.8 is respectively：5 minutes, 2.8 hours, 220 hours.As it can be seen that Pantoprazole is in acid
Property medium in it is sensitive, fast degradation is easily catalyzed by acid compound, but be stable under alkaline condition.Therefore, in order to avoid
Pantoprazole is degraded in gastric acid environment, must just take effective measures, active material is enable completely to be transmitted to pH value
The enteron aisle position that can be rapidly absorbed close to neutral and drug.Currently, the Pantoprazole Sodium oral preparation listed both at home and abroad is main
For enteric-coated micro-pill or particles filled capsule and enteric coatel tablets.
According to the existing way of drug dose, oral preparation can be divided into multiple unit type drug-delivery preparation and single unit type administration system
Agent.Although the drug release behavior of the two entirety is similar, compared with multiple unit dosage form, single unit type preparation has certain
Limitation cannot such as be broken into two with one's hands and take, and drug release is influenced by vivo environment, and there are risks of burst drug release etc..Currently, domestic
The outer pantoprazole sodium enteric tablet listed is the single unit matrix agent wrapped up using single layer enteric coating, sees such as United States Patent (USP)
5997903, which describes the oral form Pantoprazole being made of core, middle layer and outer layer.
Multi-unit drug delivery system (Multiple Unit Particulates systems, MUPs) refers to will have spy
The miniature compartment systems dispersal unit for determining release rule combines and reaches the system of ideal drug release behavior.These dispersal units master
To include pellet, microplate, crystal, ion exchange resin particle, particle and powder etc., and release rule can be by using film packet
The preparation techniques such as clothing, skeleton and ion exchange resin are adjusted.MUPs can fill dispersal unit to Capsules to obtain
Can also be that pellet is tabletted to capsule, the MUPs listed belongs to capsule mostly, such as pantoprazole sodium enteric-coated
Pellet or particles filled capsule, such asBut the uniformity of dosage units for dissolving vertical Soviet Union is poor, and in super Acceleration study
Afterwards and unstable, single miscellaneous and total impurities increasing degrees are larger.
Invention content
In view of this, the purpose of the present invention is to provide a kind of Pantoprazole microplate, preparation method, Pantoprazole enterics
Sustained-release preparation and preparation method thereof, Pantoprazole enteric sustained-release preparation provided by the invention have higher acid-resistant strength, compared with
High uniformity of dosage units, and after super Acceleration study, stability is preferable, maximum single miscellaneous and total impurities incrementss are well below existing
There is Protonix.
Microplate (mini-tablets) refers to through diameter made of special tablet press machine stamping compacting between the miniature of 2-3mm
Tablet is similar to pellet on clinical effectiveness, belongs to the dispersal unit of MUPs.Patient, can be equal in gastrointestinal tract after oral microplate
Even dispersion, individual difference is small, is less prone to burst release.Compared with pellet, microplate removes the Common advantages with dispersal unit preparation
Outside, also there are its particular advantages.Since microplate is suppressed through fixing mould, micro unit piece weight and size all accurately may be used
Control produces favorable reproducibility, and medicament contg is accurate, and homogeneity is good and industrial production efficiency higher.Microplate technique can evade
The damp and hot step of pellet core is added medicine to or prepared to pellet, contributes to the stability of product.
Microplate, to uniformity requirements height, will realize the big production of the continuous industryization of microplate, mold since weight and size are small
Durability and the mobility of press sheet mixture be crucial influence factor.Tabletting particle or having for powder are flowed well
Dynamic property and compressibility, while being protection sheeting equipment, increase microplate mold durability, also require tabletting particle or powder have compared with
Small pop-up power.Wet granulation may be used in microplate or prepared by the mode of dry method vertical compression, for the drug of hydrothermal stability difference, such as
Pantoprazole, dry method direct tablet compressing are then a kind of simpler, economic and suitable preparation methods.But dry method vertical compression requires auxiliary material must
Must have good mobility and compressibility, dry jet mixing pile that should be able to meet the requirement of dry powder vertical compression, this, which becomes, restricts dry powder
An important factor for direct tablet compressing.Therefore, how to make powder that there is good mobility and compressibility to be whether microplate obtained has
There is the key of superperformance.
The present invention provides a kind of Pantoprazole microplate, including drug containing label, the drug containing label by 12.5wt%~
The composite auxiliary material of the Pantoprazole of 25wt%, the lubricant of 1wt%~10wt% and 65wt%~86.5wt% is through dry method vertical compression
It is made, the composite auxiliary material is by the filler of 45wt%~95wt%, the adhesive of 2wt%~25wt%, 2wt%~25wt%
Disintegrant and 1wt%~5wt% pH adjusting agent it is spray-dried be made.
The present invention prepares composite auxiliary material using spray drying process, by the filler of 45wt%~95wt%, 2wt%~
The pH adjusting agent of the adhesive of 25wt%, the disintegrant of 2wt%~25wt% and 1wt%~5wt% mixes, spray-dried place
It after reason, then is mixed with drug and lubricant, the microplate press sheet mixture uniformity obtained by dry method direct tablet compressing is good, is not easy out
Existing auxiliary material layering, electrostatic are reduced, and mobility and compressibility are good, and powder bullet output also meets the requirements.Method provided by the invention is straight
It is pressed into microplate, gained microplate surface is smooth, and piece shape is complete, and homogeneity is good.
In Pantoprazole microplate provided by the invention, the active constituent of the drug containing label is Pantoprazole, including dissolves support
Draw azoles or its in the salt of pharmaceutical formulation, preferably sodium sesquihydrate.The content of the Pantoprazole is
12.5wt%~25wt%, preferably 18wt%~22wt%.In the present invention, the grain size of the Pantoprazole or its salt is preferred
Less than 450 μm.
In the drug containing label, lubricant includes but not limited to magnesium stearate, calcium stearate, stearic acid, stearyl fumarate
It is one or more in sodium, talcum powder, sodium stearyl fumarate, colloidal silicon dioxide, preferably magnesium stearate, colloidal silica
One or both of silicon.The content of the lubricant is 1wt%~10wt%, preferably 3wt%~6wt%.In the present invention
In, the grain size of the lubricant is preferably smaller than 450 μm.
In the drug containing label, the composite auxiliary material by the filler of 45wt%~95wt%, 2wt%~25wt% it is viscous
The pH adjusting agent of mixture, the disintegrant of 2wt%~25wt% and 1wt%~5wt% is spray-dried to be made.Contain tablet described
In core, the content of the composite auxiliary material is 65wt%~86.5wt%, preferably 72wt%~80wt%.
The filler includes but not limited to microcrystalline cellulose, lactose, starch, modified starch, pregelatinized starch, sweet dew
It is one or more in alcohol, dextrin, sucrose, one or both of preferably microcrystalline cellulose, lactose.The content of the filler
For 45wt%~95wt%, preferably 70wt%~80wt%.
Described adhesive includes but not limited to polyvinylpyrrolidone, chitosan, starch, converted starch, dextrin, ethyl fibre
It is dimension element, one or more in hydroxypropyl methyl cellulose, preferred starch, ethyl cellulose one or two.The bonding
The content of agent is 2wt%~25wt%, preferably 8wt%~15wt%.
The disintegrant includes but not limited to crosslinked polyvinylpyrrolidone, low-substituted hydroxypropyl cellulose, ethoxy fibre
Tie up one kind or more of element, sodium carboxymethyl starch, croscarmellose sodium, microcrystalline cellulose, alginic acid, pregelatinized starch
Kind, preferably one or both of crosslinked polyvinylpyrrolidone, low-substituted hydroxypropyl cellulose.The content of the disintegrant is
2wt%~25wt%, preferably 10wt%~15wt%.
The pH adjusting agent include but not limited to aluminium hydroxide, potassium hydroxide, sodium hydroxide, magnesium hydroxide, sodium citrate,
It is one or more in potassium citrate, sodium carbonate, sodium bicarbonate, saleratus, calcium carbonate, preferably sodium carbonate, calcium carbonate, preferably
One or both of calcium carbonate, sodium carbonate.The content of the pH adjusting agent is 1wt%~5wt%, more preferably 5wt%.
The composite auxiliary material is made by spray drying, includes the following steps：
It is spray-dried after filler, adhesive, disintegrant, pH adjusting agent are mixed with water, obtains composite auxiliary material.
Specifically, being first uniformly mixed filler, adhesive, disintegrant and pH adjusting agent, then mix, obtains with water
To suspension.The solid content of the suspension is 10%~30%.Preferably 10%~20%.
Then the suspension is spray-dried, technological parameter is：Sample size is 10mL/min~30mL/min, excellent
It is selected as 10mL/min~20mL/min；Spray dryer centrifugal energy nozzle rotating speed is 250r/min~500r/min, preferably 300r/
Min~400r/min；Inlet air temperature is 150 DEG C~190 DEG C, preferably 170 DEG C~190 DEG C；Leaving air temp is 30 DEG C~60 DEG C,
Preferably 50 DEG C~60 DEG C.
In one embodiment of the invention, Pantoprazole, 1wt% of the drug containing label by 12.5wt%~25wt%
The magnesium stearate of~10wt% and the composite auxiliary material of 65wt%~86.5wt% are made through dry method vertical compression, the composite auxiliary material by
The poly- second of crosslinking of the microcrystalline cellulose of 45wt%~95wt%, the ethyl cellulose of 2wt%~25wt%, 2wt%~25wt%
The sodium carbonate of alkene pyrrolidone and 1wt%~5wt% are spray-dried to be made.
In one embodiment of the invention, Pantoprazole, 1wt% of the drug containing label by 12.5wt%~25wt%
The magnesium stearate of~10wt% and the composite auxiliary material of 65wt%~86.5wt% are made through dry method vertical compression, the composite auxiliary material by
The lactose of 45wt%~95wt%, the ethyl cellulose of 2wt%~25wt%, the low substituted hydroxy-propyl of 2wt%~25wt% are fine
The calcium carbonate of dimension element and 1wt%~5wt% are spray-dried to be made.
In one embodiment of the invention, Pantoprazole, 1wt% of the drug containing label by 12.5wt%~25wt%
The magnesium stearate of~10wt% and the composite auxiliary material of 65wt%~86.5wt% are made through dry method vertical compression, the composite auxiliary material by
The lactose of 45wt%~95wt%, the starch of 2wt%~25wt%, 2wt%~25wt% low-substituted hydroxypropyl cellulose and
The calcium carbonate of 1wt%~5wt% is spray-dried to be made.
In one embodiment of the invention, Pantoprazole, 1wt% of the drug containing label by 12.5wt%~25wt%
The magnesium stearate of~10wt% and the composite auxiliary material of 65wt%~86.5wt% are made through dry method vertical compression, the composite auxiliary material by
The crosslinked polyethylene pyrroles of the lactose of 45wt%~95wt%, the ethyl cellulose of 2wt%~25wt%, 2wt%~25wt%
The sodium carbonate of alkanone and 1wt%~5wt% are spray-dried to be made.
In one embodiment of the invention, Pantoprazole, 1wt% of the drug containing label by 12.5wt%~25wt%
The magnesium stearate of~10wt% and the composite auxiliary material of 65wt%~86.5wt% are made through dry method vertical compression, the composite auxiliary material by
The microcrystalline cellulose of 45wt%~95wt%, the starch of 2wt%~25wt%, the low substituted hydroxy-propyl of 2wt%~25wt% are fine
The calcium carbonate of dimension element and 1wt%~5wt% are spray-dried to be made.
Pantoprazole microplate provided by the invention further includes the separation layer for wrapping up the drug containing label, wraps up the separation layer
Enteric delay controlled release layer and wrap up the coatings that the enteric delays controlled release layer.
Wherein, the separation layer is prepared by spacer layer coating liquid.The spacer layer coating liquid is by adhesive, antiplastering aid
It is formulated with basic matterial and solvent.
In spacer layer coating liquid, described adhesive can be hydroxypropyl methyl cellulose, hydroxypropyl cellulose, Methyl cellulose
It is one or more in element, ethyl cellulose, sodium carboxymethylcellulose, povidone, preferably hydroxypropyl methyl cellulose, hydroxypropyl
The one or two of cellulose.The content of described adhesive is 1.5wt%~4wt%, preferably 2.8wt%.
In spacer layer coating liquid, the antiplastering aid can be one kind of talcum powder, magnesium stearate, glycerin monostearate
Or two kinds, preferably talc powder.The content of the antiplastering aid is 2wt%~5wt%, preferably 4wt%.
In spacer layer coating liquid, the basic matterial can be aluminium hydroxide, potassium hydroxide, sodium hydroxide, hydroxide
It is one or more in magnesium, calcium carbonate, magnesium carbonate, sodium carbonate, magnesia, aluminium oxide, preferred calcium carbonate.The basic matterial
Content is 0.5wt%~2.0wt%, preferably 0.8wt%.
In spacer layer coating liquid, the solvent can be one or more in water, ethyl alcohol, isopropanol.The solvent
Content be 89wt%~95wt%, preferably 92wt%.
The spacer layer coating increases weight in terms of drug containing label weight as 20%~40%, and preferably 20%~30%.
The slow controlled release of the enteric delays controlled release layer coating solution by enteric layer by layer and is prepared.The enteric delays controlled release layer coating solution
Delay controlled-release material, plasticizer, antiplastering aid, emulsifier and solvent by enteric to be formulated.
The enteric delays in controlled release layer coating solution, the enteric delay controlled-release material can be methacrylic acid copolymer,
Cellacefate, Hydroxypropyl Methylcellulose Phathalate, hydroxypropylmethylcellulose acetate succinate, carboxylic
It is one or more in methylethylcellulose, preferred methacrylic acid copolymer.The enteric delay controlled-release material content be
17wt%~28wt%, preferably 22wt%.
The enteric delays in controlled release layer coating solution, the plasticizer can be triethyl citrate, triacetyl glycerine,
It is one or more in phthalic acid ester, sebacic acid dibutyl ester, cetanol, polyethylene glycol, optimization citric acid triethyl, three vinegar
The one or two of acid glyceride.The content of the plasticizer is 3.5wt%~5wt%, preferably 4.5wt%.
The enteric delays in controlled release layer coating solution, and the antiplastering aid can be that talcum powder, magnesium stearate, monostearate are sweet
The one or two of grease, preferably glycerin monostearate.The content of the antiplastering aid is preferably 1.5wt%~3wt%,
Preferably 2wt%.
The enteric delays in controlled release layer coating solution, the emulsifier be one kind in PLURONICS F87, Tween-80 or
Two kinds, preferably Tween-80.The content of the emulsifier is 0.1wt%~1wt%, preferably 0.2wt%.
The enteric delays in controlled release layer coating solution, and the solvent can be one kind or more in water, ethyl alcohol, isopropanol
Kind, preferably water.The content of the solvent is 65wt%~75wt%, preferably 70wt%.
The enteric delays controlled release layer coating weight gain in terms of the drug containing label weight comprising separation layer for 35%~50%, preferably
It is 35%~45%.
The coatings are prepared by coating solution.The coating solution is formulated by adhesive, antiplastering aid and solvent.
In the coating solution, described adhesive can be hydroxypropyl methyl cellulose, hydroxypropyl cellulose, Methyl cellulose
It is one or more in element, ethyl cellulose, sodium carboxymethylcellulose, preferably hydroxypropyl methyl cellulose, hydroxypropyl cellulose
One or two.The content of described adhesive is 1wt%~5.5wt%, preferably 3.5wt%.
In the coating solution, the antiplastering aid can be talcum powder, magnesium stearate, glycerin monostearate one kind or
It is a variety of, preferred magnesium stearate.The content of the antiplastering aid is 0.1wt%~0.5wt%, preferably 0.2wt%.
In the coating solution, the solvent can be one or more in water, ethyl alcohol, isopropanol, preferably water.Institute
The content for stating solvent is 94wt%~98.9wt%, preferably 96wt%.
The coatings increase weight in terms of the drug containing label weight for delaying controlled release layer and separation layer comprising enteric as 1%~8%, excellent
Select 3%~5%.
Pantoprazole microplate described in above-mentioned technical proposal preparation method in accordance with the following methods：
It is spray-dried after filler, adhesive, disintegrant, pH adjusting agent are mixed with water, obtains composite auxiliary material；
By direct tablet compressing after the composite auxiliary material, Pantoprazole or its salt and mix lubricant.
Specifically, being first uniformly mixed filler, adhesive, disintegrant and pH adjusting agent, then mix, obtains with water
To suspension.The solid content of the suspension is 10%~30%.Preferably 10%~20%.
Then the suspension is spray-dried, technological parameter is：Sample size is 10mL/min~30mL/min, excellent
It is selected as 10mL/min~20mL/min；Spray dryer centrifugal energy nozzle rotating speed is 250r/min~500r/min, preferably 300r/
Min~400r/min；Inlet air temperature is 150 DEG C~190 DEG C, preferably 170 DEG C~190 DEG C；Leaving air temp is 30 DEG C~60 DEG C,
Preferably 50 DEG C~60 DEG C.
It is after obtaining composite auxiliary material, composite auxiliary material, Pantoprazole or its salt and mix lubricant is uniform, obtain mixed powder
The mixed-powder direct tablet compressing can be obtained Pantoprazole microplate by end.
The present invention prepares composite auxiliary material using spray drying process, by the filler of 45wt%~95wt%, 2wt%~
The pH adjusting agent of the adhesive of 25wt%, the disintegrant of 2wt%~25wt% and 1wt%~5wt% mixes, spray-dried place
It after reason, then is mixed with drug and lubricant, the microplate press sheet mixture uniformity obtained by dry method direct tablet compressing is good, is not easy out
Existing auxiliary material layering, electrostatic are reduced, and mobility and compressibility are good, and powder bullet output also meets the requirements, especially with microcrystalline cellulose
With one or both of lactose as one or both of filler, starch and ethyl cellulose as adhesive, crosslinking
One or both of polyvinylpyrrolidone and low-substituted hydroxypropyl cellulose are as in disintegrant, sodium carbonate and calcium carbonate
When one or two are used as pH adjusting agent, it is compound auxiliary that the mobility and compressibility of obtained Pantoprazole microplate are significantly larger than other
Expect the mobility and compressibility of obtained Pantoprazole microplate.
The present invention also provides a kind of multiple unit type Pantoprazole enteric sustained-release preparations, including multiple above-mentioned technical proposals
The Pantoprazole microplate.
The multiple unit type Pantoprazole enteric sustained-release preparation can be capsule, can also be tablet.It will be multiple above-mentioned
Pantoprazole microplate described in technical solution is filled in capsule, you can obtains capsule.Described in multiple above-mentioned technical proposals
Pantoprazole microplate is mixed with auxiliary material re-compacted can be prepared by Pantoprazole enteric slow-release tablet.
Specifically, the multiple unit type Pantoprazole enteric slow-release tablet is by the Pantoprazole described in above-mentioned technical proposal
The additional auxiliary material of microplate is suppressed.Relative to capsule, the industrial production efficiency higher of tablet.It is micro- using Pantoprazole enteric
Multiple unit type tablet prepared by piece should be disintegrated in gastrointestinal tract into independent microplate after taking, and Pantoprazole is in gastrointestinal tract acidity
Under the conditions of it is unstable, therefore, when preparing multiple unit type pantoprazole, in tableting processes, the enteric clothing film of microplate is not
Rupture or fusion, the microplate after tabletting, which can occur, should remain to keep its drug release feature.Tuo La is dissolved described in the above-mentioned technical proposal
Azoles microplate and the weight ratio of additional auxiliary material are preferably 1:3~1:When 7, the multiple unit type Pantoprazole piece content being prepared is uniform
Degree is qualified, and acid-resistant strength is good, and Pantoprazole microplate and the weight ratio of additional auxiliary material are more preferably 1:3~1:4.
In the multiple unit type Pantoprazole enteric slow-release tablet, the additional auxiliary material includes filling out for 75wt%~90wt%
Fill agent, the disintegrant of 8wt%~21wt% and 2wt%~5wt% lubricant.
In the additional auxiliary material, the filler is selected from microcrystalline cellulose Vivapur200 and microcrystalline cellulose Avicel
The mixture of PH102 arbitrary proportions, preferably 50:The mixture of 50 ratios.
In the additional auxiliary material, the lubricant includes but not limited to magnesium stearate, calcium stearate, stearic acid, stearic richness
One or more in horse acid sodium, talcum powder, sodium stearyl fumarate, colloidal silicon dioxide, preferably magnesium stearate, tristearin are rich
Horse acid sodium, it is one or more in colloidal silicon dioxide.
In the additional auxiliary material, the disintegrant includes but not limited to crosslinked polyvinylpyrrolidone, low substituted hydroxy-propyl
Cellulose, hydroxyethyl cellulose, sodium carboxymethyl starch, croscarmellose sodium, microcrystalline cellulose, alginic acid, pregelatinated
Starch it is one or more, one preferably in crosslinked polyvinylpyrrolidone, low-substituted hydroxypropyl cellulose and microcrystalline cellulose
Kind is a variety of.
The present invention by described in above-mentioned technical proposal Pantoprazole microplate and additional auxiliary material mix, dry method direct tablet compressing
Obtain multiple unit type Pantoprazole enteric slow-release tablet.
Acid unstable Pantoprazole and the composite auxiliary material dry method vertical compression of spray-dried processing are made first by the present invention
Microplate；Suitable clothing film material is used again, and Pantoprazole enteric microplate is made after being coated to microplate；Obtained dissolves Tuo La
Azoles enteric microplate can be used for fill capsule also can additional auxiliary material be pressed into multiple unit type tablet.Pantoprazole intestines provided by the invention
Molten sustained-release preparation has acid resistance qualified, preparation stabilization, homogeneity is good and can compared with the Protonix listed
The advantages of dosage is adjusted flexibly, and multiple unit type Pantoprazole enteric sustained-release preparation preparation process is simple and easy to do, it is raw
Efficient, process stabilizing is produced, industrialized production is suitble to.The experimental results showed that Pantoprazole enteric provided by the invention delays controlled release
Preparation acid-resistant strength is all higher than 90%, and uniformity of dosage units is up to 97% or more, and after super Acceleration study, stability is preferable, maximum single
Miscellaneous and total impurities incrementss are well below existing Protonix.
Specific implementation mode
In order to further illustrate the present invention, with reference to embodiments to Pantoprazole microplate provided by the invention, its preparation
Method, multiple unit type Pantoprazole enteric sustained-release preparation and preparation method thereof are described in detail.
The preparation of Examples 1 to 3 drug containing label
Composite auxiliary material is prepared according to formula shown in table 1：
The formula of composite auxiliary material in the drug containing label that 1 embodiment of the present invention 1~3 of table provides
Microcrystalline cellulose, ethyl cellulose, crosslinked polyvinylpyrrolidone, the calcium carbonate for weighing aforementioned proportion respectively mix
Uniformly, add water to be configured to the suspension that solid content is 20%, be spray-dried using spray dryer, obtain composite auxiliary material,
The technological parameter of spray drying is：Sample size 20mL/min, spray dryer centrifugal energy nozzle rotating speed 300r/min, inlet air temperature
170 DEG C, 50 DEG C of leaving air temp.
650g composite auxiliary materials are taken respectively, sodium sesquihydrate raw material 250g and the sieve of 40 mesh excessively with the sieve of 40 mesh excessively
Magnesium stearate 100g mixing, obtain drug containing label mixture, mixed drug containing label using 2.5mm circles single punch presses
Object is pressed into the drug containing label of the every about 2mg containing Pantoprazole.
The preparation of 4 drug containing label of embodiment
Prepare composite auxiliary material according to the formula and method of embodiment 1, difference lies in, by microcrystalline cellulose, ethyl cellulose,
Crosslinked polyvinylpyrrolidone, calcium carbonate are uniformly mixed, and water is added to be configured to the suspension that solid content is 30%, the work of spray drying
Skill parameter is：Sample size 10mL/min, spray dryer centrifugal energy nozzle rotating speed 250r/min, 190 DEG C of inlet air temperature, leaving air temp
60℃。
865g composite auxiliary materials are taken, are sieved with the sodium sesquihydrate raw material 125g of the sieve of 40 mesh excessively and 40 mesh excessively hard
Fatty acid magnesium 10g mixing, obtains drug containing label mixture, using 2.5mm circles single punch presses by drug containing label mixture pressure
At the drug containing label of the every about 1mg containing Pantoprazole.
The preparation of 5 drug containing label of embodiment
Prepare composite auxiliary material according to the formula and method of embodiment 1, difference lies in, by microcrystalline cellulose, ethyl cellulose,
Crosslinked polyvinylpyrrolidone, calcium carbonate are uniformly mixed, and water is added to be configured to the suspension that solid content is 10%, the work of spray drying
Skill parameter is：Sample size 30mL/min, spray dryer centrifugal energy nozzle rotating speed 500r/min, 150 DEG C of inlet air temperature, leaving air temp
30℃。
Take 760g be spray-dried after composite auxiliary material, with cross 40 mesh sieve sodium sesquihydrate raw material 200g and
The magnesium stearate 40g mixing for crossing 40 mesh sieve, obtains drug containing label mixture, using 2.5mm circles single punch presses by drug containing
Label mixture is pressed into the drug containing label of the every about 2mg containing Pantoprazole.
The preparation of 6~8 drug containing label of embodiment
According to the method for Examples 1 to 3, drug containing label is prepared according to composite auxiliary material formula shown in table 2：
The formula of composite auxiliary material in the drug containing label that 2 embodiment of the present invention 6~8 of table provides
Embodiment 9~11
According to the method for Examples 1 to 3, drug containing label is prepared according to composite auxiliary material formula shown in table 3：
The formula of composite auxiliary material in the drug containing label that 3 embodiment of the present invention 9~11 of table provides
Embodiment 12~14
According to the method for Examples 1 to 3, drug containing label is prepared according to composite auxiliary material formula shown in table 4：
The formula of composite auxiliary material in the drug containing label that 4 embodiment of the present invention 12~14 of table provides
Embodiment 15~17
According to the method for Examples 1 to 3, drug containing label is prepared according to composite auxiliary material formula shown in table 5：
The formula of composite auxiliary material in the drug containing label that 5 embodiment of the present invention 15~17 of table provides
Embodiment 18~20
According to the method for Examples 1 to 3, drug containing label is prepared according to composite auxiliary material formula shown in table 6：
The formula of composite auxiliary material in the drug containing label that 6 embodiment of the present invention 18~20 of table provides
Embodiment 21~23
According to the method for Examples 1 to 3, drug containing label is prepared according to composite auxiliary material formula shown in table 7：
The formula of composite auxiliary material in the drug containing label that 7 embodiment of the present invention 21~23 of table provides
Embodiment 24~26
According to the method for Examples 1 to 3, drug containing label is prepared according to composite auxiliary material formula shown in table 8：
The formula of composite auxiliary material in the drug containing label that 8 embodiment of the present invention 24~26 of table provides
The investigation of powder property after the spray drying of 27 microplate tableting aid of embodiment
According to the supplementary material ratio and component of Examples 1 to 6, the mode of physical mixed is only carried out, without spray drying
Auxiliary material is handled, other same Examples 1 to 6 of method prepare drug containing label mixture control sample 1-6 respectively.By to powder flow
The powder properties such as dynamic property, compressibility are investigated, and after label auxiliary material is carried out spray drying treatment by research, are mixed to drug containing label
The influence of powder property.
1, powder flowing performance
1.1 angles of repose measure
Using fixed conical bottom method, a certain amount of powder to be measured is taken, so that powder is passed through leakage under certain vibration frequency (about 100Hz)
Bucket flows uniformly on the circular dishware of fixed diameter, until obtaining highest circular cone, the height of cone is surveyed, by tan θ
=h/r seeks angle of repose θ, is repeated 3 times and is averaged.Angle of repose reflection powder ion is shown in that dynamic friction coefficient size, angle of repose are got over
Greatly, friction coefficient is bigger, and the mobility of powder is poorer.Angle of repose evaluation index such as following table：
| Angle of repose (°) | ＜ 30 | 30-35 | 36-40 | ＞ 40 |
| Mobility grade | It is fabulous | It is outstanding | Well | Difference |
1.2 measurement of rate of flow
Using funnel method, diameter 12cm, tubular portion internal diameter 1cm, the funnel of pipe range 15cm is taken to weigh the sample of phase homogenous quantities
Product give the percussion of certain frequency, when all flowing out funnel with stopwatch record sample, calculate flow velocity.
2, powder compressibility energy
2.1 carr's index
Made in the cup that powder uniformly fills a 100mL with some strength vibrations, it is extra above cup to be wiped off with scraping blade
Powder, weigh, with weight divided by 100 up to bulk density.In addition, while powder uniformly flows into 100mL cups, with certain strong
Degree is hit (60 beats/min) to cup, is wiped excessive powder above cup off with scraping blade, is weighed, and weight divided by 100 is up to light
Strike density.
Carr's index=(1- bulk densitys/tap density) * 100%
Carr's index evaluation index see the table below：
| Carr's index | ≤ 15% | 15-25% | 20-25% | >=26% |
| Compressibility grade | It is poor | It can use | Well | It is outstanding |
2.2 river north journeys
By powder funnel at the uniform velocity, be slowly injected into 100mL graduated cylinders, until loose volume is 70-100mL.It will be equipped with powder
Graduated cylinder is freely fallen from horizontal table top 1cm height to desktop, the frequency n fallen and corresponding volume number Vn is recorded, with following
The Cheng Jinhang data processings of the river north：
N/C=N/a+1/ab
In formula, C is that the relative volume of powder reduces score；N is tapping number；Using N/C as ordinate, using N as abscissa,
It is 1/a, intercept 1/ab to obtain straight slope.A reflects the mobility and fillibility of powder with b values.A values are bigger, compressibility
Better；1/b values are smaller, and powder filling is better.
2.3 powdered. elastomer return rates
By powder under a certain pressure direct tablet compressing, measure compression time slice thickness H respectively0And tablet pressure relief is placed for 24 hours
Piece weight H afterwardst, substitute into following formula and calculate elastic recovery rate (ER).
ER (%)=[(Ht-H0)/H0] * 100%
3, powder property investigates result
The investigation result of 3.1 Examples 1 to 6 and control sample 1~6
The drug containing label mixture for implementing 1~6 preparation the results are shown in Table 9 with the investigation of corresponding control sample 1~6.
After 9 label auxiliary material of table carries out spray drying treatment, the influence to drug containing label mixture powder property
Angle of repose and flow velocity can characterize the mobility of powder.According to angle of repose and measurement of rate of flow, Examples 1 to 6 contains
Tablet core mix powder mobility is fabulous, and the drug containing label mix ingredients of control sample 1-6 is identical, except that
The not spray-dried post-processing of partial supplementary material, and directly mixed by semihydrate raw material with Pantoprazole Sodium, angle of repose detection
As a result it is only good, and flow velocity will be less than the sample of Examples 1 to 6.
Carr's index reflects that the compressibility of powder, the big powder compressibility of carr's index are good；River north Cheng Fanying's is powder
End compressibility and can Packing character, a values are bigger, and compressibility is better；1/b is smaller, and powder filling is better；Elastic recovery rate is piece
Agent in die hole after removing, and the elastic expansion occurred due to the effect of internal stress, elastic return rate height is to sheeting equipment
Caused by damage it is larger, and easily occur sliver phenomena such as.These three indexs are used equally for the compressibility of characterization powder.Test result
It has been shown that, the carr's index of Examples 1 to 6 drug containing label mixture is all higher than control sample 1~6, and elastic recovery rate is small, Chuan Bei
The result of equation also shows, the drug containing label mixture feasibility and fillable of Examples 1 to 6 be superior to control sample 1~
6。
As shown in Table 9, it is compared from five angle of repose, flow velocity, carr's index, river north journey and elastic recovery rate angles
Research.The present invention is first by the excipient of specific proportioning, adhesive, after disintegrant and pH adjusting agent mixing, is configured to solid content 10-
30% suspension, then under certain technological parameter carry out spray drying treatment after obtain composite auxiliary material, the composite auxiliary material again with
Sodium sesquihydrate and lubricant carry out mixed pressuring plate, and the present invention has now surprisingly been found that, using aforesaid way system
The performance of the powder fluidity of the drug containing label mixture of standby gained significantly improves, prepared sodium sesquihydrate
Drug containing label mixture is suitable for carrying out microplate tabletting.
The investigation result of 3.2 embodiments 7~26
The investigation for implementing the drug containing label mixture of 7~26 preparation the results are shown in Table 10.
After 10 label auxiliary material of table carries out spray drying treatment, the influence to drug containing label mixture powder property
As shown in Table 10, the performance that the powder fluidity of the drug containing label mixture of gained is prepared using aforesaid way is notable
It improves, prepared sodium sesquihydrate drug containing label mixture is suitable for carrying out microplate tabletting.
The preparation of 28 Pantoprazole enteric microplate of embodiment
The formula of separation layer is as shown in the table：
Wherein, the substance with * dries and removes in technical process.
By above-mentioned formula, it is weighed into purified water in being filled with liquid, starts electric stirring instrument, is slowly added to the bonding of recipe quantity
Agent is stirred to being completely dissolved, and the antiplastering aid and basic matterial of recipe quantity are then sequentially added into binder solution, and stirring extremely divides
It dissipates uniformly, obtains spacer layer coating liquid.Spacer layer coating is carried out to drug containing label using laboratory is multifunctional fluidized bed, with drug containing
Label weight meter, coating weight gain to 30%.
The formula of enteric layer is as shown in the table：
Wherein, the substance with * dries and removes in technical process.
By above-mentioned formula, it is weighed into the purified water of recipe quantity 50% in being filled with liquid, is heated to 70~80 DEG C, weighs recipe quantity
Plasticizer, in antiplastering aid and emulsifier to hot water, sheared and disperseed with high speed shear dispersant, the purifying of remaining recipe quantity is added
Water, stirring are cooled to room temperature, and it is spare to obtain emulsion.The Eudragit L 30D aqueous dispersions containing recipe quantity separately are weighed, are being stirred
Under state, emulsion is added thereto, is dispersed with stirring uniformly, obtains enteric coating liquid.It is multifunctional fluidized bed right using laboratory
Separation layer label carries out enteric layer coating, in terms of separation layer label weight, coating weight gain to 45%.
The formula of exterior coating is as shown in the table：
Wherein, the substance with * dries and removes in technical process.
By above-mentioned formula, it is weighed into the purified water of recipe quantity in being filled with liquid, starts electric stirring instrument, the viscous of recipe quantity is added
Then mixture, stirring are added the antiplastering aid of recipe quantity, obtain exterior coating coating solution to dissolving.Using the multi-functional stream in laboratory
Change bed and outer coatings, in terms of enteric layer label weight, coating weight gain to 3% are carried out to enteric layer label.
The preparation of 29 Pantoprazole enteric microplate of embodiment
The formula of separation layer is as shown in the table：
Wherein, the substance with * dries and removes in technical process.
By above-mentioned formula, it is weighed into purified water in being filled with liquid, starts electric stirring instrument, is slowly added to the bonding of recipe quantity
Agent is stirred to being completely dissolved, and the antiplastering aid and basic matterial of recipe quantity are then sequentially added into binder solution, and stirring extremely divides
It dissipates uniformly, obtains spacer layer coating liquid.Spacer layer coating is carried out to drug containing label using laboratory is multifunctional fluidized bed, with drug containing
Label weight meter, coating weight gain to 40%.
The formula of enteric layer is as shown in the table：
Wherein, the substance with * dries and removes in technical process.
By above-mentioned formula, it is weighed into the purified water of recipe quantity 50% in being filled with liquid, is heated to 70-80 DEG C, weighs recipe quantity
Plasticizer, in antiplastering aid and emulsifier to hot water, sheared and disperseed with high speed shear dispersant, the purifying of remaining recipe quantity is added
Water, stirring are cooled to room temperature, and it is spare to obtain emulsion.The Eudragit L 30D aqueous dispersions containing recipe quantity separately are weighed, are being stirred
Under state, emulsion is added thereto, is dispersed with stirring uniformly, obtains enteric coating liquid.It is multifunctional fluidized bed right using laboratory
Separation layer label carries out enteric layer coating, in terms of separation layer label weight, coating weight gain to 35%.
The formula of exterior coating is as shown in the table：
Wherein, the substance with * dries and removes in technical process.
By above-mentioned formula, it is weighed into the purified water of recipe quantity in being filled with liquid, starts electric stirring instrument, the viscous of recipe quantity is added
Then mixture, stirring are added the antiplastering aid of recipe quantity, obtain exterior coating coating solution to dissolving.Using the multi-functional stream in laboratory
Change bed and outer coatings, in terms of enteric layer label weight, coating weight gain to 5% are carried out to enteric layer label.
The preparation of 30 Pantoprazole enteric microplate of embodiment
The formula of separation layer is as shown in the table：
Wherein, the substance with * dries and removes in technical process.
By above-mentioned formula, it is weighed into purified water in being filled with liquid, starts electric stirring instrument, is slowly added to the bonding of recipe quantity
Agent is stirred to being completely dissolved, and the antiplastering aid and basic matterial of recipe quantity are then sequentially added into binder solution, and stirring extremely divides
It dissipates uniformly, obtains spacer layer coating liquid.Spacer layer coating is carried out to drug containing label using laboratory is multifunctional fluidized bed, with drug containing
Label weight meter, coating weight gain to 20%.
The formula of enteric layer is as shown in the table：
Wherein, the substance with * dries and removes in technical process.
By above-mentioned formula, it is weighed into the purified water of recipe quantity 50% in being filled with liquid, is heated to 70-80 DEG C, weighs recipe quantity
Plasticizer, in antiplastering aid and emulsifier to hot water, sheared and disperseed with high speed shear dispersant, the purifying of remaining recipe quantity is added
Water, stirring are cooled to room temperature, and it is spare to obtain emulsion.The Eudragit L 30D aqueous dispersions containing recipe quantity separately are weighed, are being stirred
Under state, emulsion is added thereto, is dispersed with stirring uniformly, obtains enteric coating liquid.It is multifunctional fluidized bed right using laboratory
Separation layer label carries out enteric layer coating, in terms of separation layer label weight, coating weight gain to 50%.
The formula of exterior coating is as shown in the table：
Wherein, the substance with * dries and removes in technical process.
By above-mentioned formula, it is weighed into the purified water of recipe quantity in being filled with liquid, starts electric stirring instrument, the viscous of recipe quantity is added
Then mixture, stirring are added the antiplastering aid of recipe quantity, obtain exterior coating coating solution to dissolving.Using the multi-functional stream in laboratory
Change bed and outer coatings, in terms of enteric layer label weight, coating weight gain to 1% are carried out to enteric layer label.
The preparation of 31~33 multiple unit type Pantoprazole enteric sustained and controlled release capsule of embodiment
The content of Pantoprazole in embodiment 8,10 Pantoprazole enteric microplate of embodiment 9 and embodiment, root are measured respectively
Microplate filling amount in every capsule is determined according to content.By the amount of every capsule specification of Pantoprazole Sodium containing 20mg, by embodiment 8,
The Pantoprazole enteric microplate enteric microplate of embodiment 9 and embodiment 10 is poured into respectively in ordinary rigid capsule shells, obtains multiple-unit
Type Pantoprazole enteric sustained and controlled release capsule.
The preparation of 34 multiple unit type Pantoprazole enteric slow-release tablet of embodiment
Multiple unit type Pantoprazole enteric slow-release tablet (20mg) (microplate：Auxiliary material=1:7) it is formulated as follows：
By the pellet that exterior coating is coated by recipe quantity, microcrystalline cellulose Vivapur200, microcrystalline cellulose Avicel
PH102, magnesium stearate, crosslinked polyvinylpyrrolidone are uniformly mixed, and suppress multiple unit type Pantoprazole enteric slow-release tablet.
The preparation of 35 multiple unit type Pantoprazole enteric slow-release tablet of embodiment
Multiple unit type Pantoprazole enteric slow-release tablet (20mg) (microplate：Auxiliary material=1:3) it is formulated as follows：
By the pellet that exterior coating is coated by recipe quantity, microcrystalline cellulose vivapur200, microcrystalline cellulose Avicel
PH102, low-substituted hydroxypropyl cellulose, colloidal silicon dioxide are uniformly mixed by recipe quantity, suppress Pantoprazole multiple unit type intestines
Molten microplate piece (every containing about Pantoprazole 20mg).
The preparation of 36 multiple unit type Pantoprazole enteric slow-release tablet of embodiment
Multiple unit type Pantoprazole enteric slow-release tablet (20mg) (microplate：Auxiliary material=1:4) formula is as follows：
By the pellet that exterior coating is coated by recipe quantity, microcrystalline cellulose vivapur200, microcrystalline cellulose Avicel
PH102, pregelatinized starch, sodium stearyl fumarate are uniformly mixed, and suppress Pantoprazole multiple unit type enteric microplate piece.
Embodiment 37 prepares sample leading indicator testing result
Respectively to Pantoprazole enteric microplate acid-resistant strength obtained, content in embodiment 28, embodiment 29 and embodiment 30
The uniformity is investigated, and the result is shown in table 11 and table 12, table 11 is the acid-resistant strength of sample prepared by the embodiment of the present invention 28~30
It investigates as a result, the uniformity of dosage units that table 12 is sample prepared by the embodiment of the present invention 28~30 investigates result.
The acid-resistant strength of sample prepared by 11 embodiment of the present invention 28~30 of table investigates result (n=6)
| Embodiment 28 | Embodiment 29 | Embodiment 30 | |
| Acid-resistant strength result | 98.7% ± 1.2% | 98.2% ± 0.8% | 97.5% ± 1.1% |
The uniformity of dosage units of sample prepared by 12 embodiment of the present invention 28~30 of table investigates result (n=10)
By table 11 and table 12 it is found that method using the present invention, the coating material and weightening ratio of selection, prepared dissolves
Support draws azoles enteric microplate acid-resistant strength to be all higher than 90%, meets Chinese Pharmacopoeia (version in 2015) requirement；And press Chinese Pharmacopoeia (2015
Version) uniformity of dosage units method measures, and the uniformity of dosage units of the sample of embodiment 28~30 meets Chinese Pharmacopoeia requirement, and tablet is equal
One property is good.
Respectively to multiple unit type Pantoprazole enteric slow-release tablet made from embodiment 34~36 from appearance, content, acidproof
Power, release, uniformity of dosage units project carry out quality testing.Testing result shows, multiple unit type prepared by embodiment 34~36
Pantoprazole enteric slow-release tablet smooth in appearance, piece shape rule, while Chinese Pharmacopoeia (version in 2015) the uniformity of dosage units method of pressing
It measures, uniformity of dosage units meets pharmacopoeial requirements.
Using listing multiple unit type Pantoprazole natrium capsule (trade name：) compared, it measures implement respectively
Multiple unit type Pantoprazole enteric sustained and controlled release capsule made from example 31~33, multiple unit type made from embodiment 34~36 dissolve Tuo La
The acid-resistant strength and uniformity of dosage units of azoles enteric slow-release tablet, the result is shown in table 13 and table 14, table 13 be the embodiment of the present invention 31~
36 provide multiple unit type Pantoprazole enteric sustained-release preparations acid-resistant strength investigate as a result, table 14 be the embodiment of the present invention 31~
The uniformity of dosage units of the 36 multiple unit type Pantoprazole enteric sustained-release preparations provided investigates result.
13 multiple unit type Pantoprazole enteric sustained-release preparation acid-resistant strength of table investigates result (n=6)
14 multiple unit type Pantoprazole enteric sustained-release preparation uniformity of dosage units of table investigates result (n=10)
By table 13 and table 14 it is found that multiple unit type pantoprazole acid-resistant strength provided by the invention is all higher than 90%,
Meet Chinese Pharmacopoeia (version in 2015) requirement.The result shows that microplate, during tabletted, coating membrane is uninfluenced,
And measured by Chinese Pharmacopoeia (version in 2015) uniformity of dosage units method, uniformity of dosage units meets pharmacopoeial requirements.
Under the conditions of super acceleration (60 ± 2 DEG C, RH 75% ± 5%), multiple unit type made from embodiment 34~36 is dissolved into support
Draw azoles enteric slow-release tablet and listing multiple unit type Pantoprazole Sodium micro pill capsuleAfter unlap, it is all made of double aluminium
Packaging, parallel study simultaneously check character, detection level and the variation in relation to substance, and the result is shown in table 15, table 15 is that the present invention is real
The super accelerated stability of multiple unit type Pantoprazole enteric slow-release tablet for applying the offer of example 34~36 investigates result.
Table 15 surpasses accelerated stability and investigates result (n=2)
The above results are shown, under super acceleration environment, multiple unit type Pantoprazole enteric made from embodiment 34~36 is slow
The increase of controlled release tablet impurity is small compared with listing preparation, and preparation is more stablized.
The above is only a preferred embodiment of the present invention, it is noted that for the ordinary skill people of the art
For member, various improvements and modifications may be made without departing from the principle of the present invention, these improvements and modifications are also answered
It is considered as protection scope of the present invention.
Claims (15)
1. a kind of Pantoprazole microplate, including drug containing label, the drug containing label by 12.5wt%~25wt% Pantoprazole
Or the lubricant of its salt, 1wt%~10wt% and the composite auxiliary material of 65wt%~86.5wt% are made through dry method vertical compression, it is described multiple
Close auxiliary material by the filler of 45wt%~95wt%, the adhesive of 2wt%~25wt%, 2wt%~25wt% disintegrant and
The pH adjusting agent of 1wt%~5wt% is spray-dried to be made；
The filler is selected from microcrystalline cellulose, lactose, starch, modified starch, pregelatinized starch, mannitol, dextrin and sucrose
In it is one or more；
Described adhesive is selected from polyvinylpyrrolidone, chitosan, starch, converted starch, dextrin, ethyl cellulose and hydroxypropyl
It is one or more in methylcellulose；
The disintegrant is selected from crosslinked polyvinylpyrrolidone, low-substituted hydroxypropyl cellulose, hydroxyethyl cellulose, carboxymethyl and forms sediment
It is one or more in powder sodium, croscarmellose sodium, microcrystalline cellulose, alginic acid and pregelatinized starch；
The pH adjusting agent is selected from aluminium hydroxide, potassium hydroxide, sodium hydroxide, magnesium hydroxide, sodium citrate, potassium citrate, carbon
It is one or more in sour sodium, sodium bicarbonate, saleratus and calcium carbonate.
2. Pantoprazole microplate according to claim 1, which is characterized in that further include the isolation for wrapping up the drug containing label
Layer, the enteric for wrapping up the separation layer delay controlled release layer and wrap up the coatings that the enteric delays controlled release layer.
3. Pantoprazole microplate according to claim 1 or 2, which is characterized in that the filler is selected from microcrystalline cellulose
One or both of with lactose；
Described adhesive is selected from one or both of starch and ethyl cellulose；
The disintegrant is selected from one or both of crosslinked polyvinylpyrrolidone and low-substituted hydroxypropyl cellulose；
The pH adjusting agent is selected from one or both of sodium carbonate and calcium carbonate.
4. Pantoprazole microplate according to claim 1 or 2, which is characterized in that the lubricant is selected from magnesium stearate, hard
One kind or more in resin acid calcium, stearic acid, sodium stearyl fumarate, talcum powder, sodium stearyl fumarate, colloidal silicon dioxide
Kind.
5. Pantoprazole microplate according to claim 1 or 2, which is characterized in that the grain of the Pantoprazole and lubricant
Diameter is independently less than 450 μm.
6. Pantoprazole microplate according to claim 2, which is characterized in that the separation layer includes：Adhesive, antiplastering aid
And basic matterial；In the separation layer, described adhesive is selected from hydroxypropyl methyl cellulose, hydroxypropyl cellulose, Methyl cellulose
It is one or more in element, ethyl cellulose, sodium carboxymethylcellulose, povidone；In the separation layer, the antiplastering aid is selected from
Talcum powder, magnesium stearate, glycerin monostearate it is one or more；In the separation layer, the basic matterial is selected from hydrogen-oxygen
Change aluminium, potassium hydroxide, sodium hydroxide, magnesium hydroxide, calcium carbonate, magnesium carbonate, sodium carbonate, magnesia, one kind in aluminium oxide or
It is a variety of；
The enteric delays controlled release layer：Enteric slow release material, plasticizer, antiplastering aid and emulsifier；The enteric delays controlled release layer
In, the enteric delays controlled-release material and is selected from methacrylic acid copolymer, Cellacefate, phthalic acid hydroxypropyl
It is one or more in ylmethyl cellulose, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose；The intestines
In molten slow controlled release layer, the plasticizer is selected from triethyl citrate, triacetyl glycerine, phthalic acid ester, two fourth of sebacic acid
It is one or more in ester, cetanol, polyethylene glycol；The enteric delays in controlled release layer, and the antiplastering aid is selected from talcum powder, tristearin
Sour magnesium, glycerin monostearate it is one or more；The enteric delay controlled release layer in, the emulsifier be selected from PLURONICS F87,
One or both of Tween-80；
The coatings include：Adhesive and antiplastering aid；In the coatings, described adhesive is selected from hydroxypropyl methyl fiber
It is one or more in element, hydroxypropyl cellulose, methylcellulose, ethyl cellulose, sodium carboxymethylcellulose；The coatings
In, the antiplastering aid be selected from talcum powder, magnesium stearate, glycerin monostearate it is one or more.
7. Pantoprazole microplate according to claim 6, which is characterized in that in the separation layer, described adhesive is hydroxyl
Two kinds of propyl methocel and hydroxypropyl cellulose；The antiplastering aid is talcum powder；The basic matterial is calcium carbonate；
The enteric delays in controlled release layer, and it is methacrylic acid copolymer that the enteric, which delays controlled-release material,；The plasticizer is lemon
The one or two of triethylenetetraminehexaacetic acid ester, triacetyl glycerine；The antiplastering aid is glycerin monostearate；The emulsifier is to spit
Temperature -80；
During the coatings include, described adhesive is the one or two of hydroxypropyl methyl cellulose, hydroxypropyl cellulose；Institute
It is magnesium stearate to state antiplastering aid.
8. the preparation method of Pantoprazole microplate described in claim 1, including：
It is spray-dried after filler, adhesive, disintegrant, pH adjusting agent are mixed with water, obtains composite auxiliary material；
By direct tablet compressing after the composite auxiliary material, Pantoprazole or its salt and mix lubricant.
9. preparation method according to claim 8, which is characterized in that further include：
Package separation layer, enteric delay controlled release layer and coatings on the drug containing label that direct tablet compressing obtains successively.
10. preparation method according to claim 8 or claim 9, which is characterized in that the technological parameter of the spray drying is：Into
Sample amount is 10mL/min~30mL/min；Spray dryer centrifugal energy nozzle rotating speed is 250r/min~500r/min；Inlet air temperature
It is 150 DEG C~190 DEG C；Leaving air temp is 30 DEG C~60 DEG C.
11. a kind of multiple unit type Pantoprazole enteric sustained-release preparation, including described in multiple claim 1~7 any one
Pantoprazole microplate.
12. multiple unit type Pantoprazole enteric sustained-release preparation according to claim 11, which is characterized in that its dosage form is
Tablet or capsule.
13. multiple unit type Pantoprazole enteric sustained-release preparation according to claim 12, which is characterized in that its dosage form is
Tablet further includes additional auxiliary material；The mass ratio of the Pantoprazole microplate and additional auxiliary material is 1：3~7.
14. multiple unit type Pantoprazole enteric sustained-release preparation according to claim 13, which is characterized in that described additional
Auxiliary material includes the filler of 75wt%~90wt%, the disintegrant of 8wt%~21wt% and the lubricant of 2wt%~5wt%；
In the additional auxiliary material, the filler is selected from microcrystalline cellulose Vivapur200 and microcrystalline cellulose Avicel PH102
Mixture；
In the additional auxiliary material, the lubricant is selected from magnesium stearate, calcium stearate, stearic acid, sodium stearyl fumarate, talcum
It is one or more in powder, sodium stearyl fumarate, colloidal silicon dioxide；
In the additional auxiliary material, the disintegrant is selected from crosslinked polyvinylpyrrolidone, low-substituted hydroxypropyl cellulose, ethoxy
One kind or more of cellulose, sodium carboxymethyl starch, croscarmellose sodium, microcrystalline cellulose, alginic acid, pregelatinized starch
Kind.
15. multiple unit type Pantoprazole enteric sustained-release preparation according to claim 14, which is characterized in that described additional
In auxiliary material, in the filler, microcrystalline cellulose Vivapur200 and the mass ratio of microcrystalline cellulose Avicel PH102 are preferred
It is 1:1；
In the additional auxiliary material, the lubricant is selected from magnesium stearate, sodium stearyl fumarate, one kind in colloidal silicon dioxide or
It is a variety of；
In the additional auxiliary material, the disintegrant is selected from crosslinked polyvinylpyrrolidone, low-substituted hydroxypropyl cellulose and crystallite
It is one or more in cellulose.
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| CN107789326A (en) * | 2016-08-29 | 2018-03-13 | 北京科信必成医药科技发展有限公司 | A kind of Hydrochioro microplate and preparation method thereof |
| CN111973567A (en) * | 2020-08-21 | 2020-11-24 | 北京诺康达医药科技股份有限公司 | Auxiliary material composition and preparation method and application thereof |
| CN114159397B (en) * | 2021-11-02 | 2023-03-24 | 北京微智瑞医药科技有限公司 | Oseltamivir phosphate micro-tablet and preparation method and preparation thereof |
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