CN105796532B - A kind of RABEPRAZOLE SODIUM spansule and preparation method thereof - Google Patents
A kind of RABEPRAZOLE SODIUM spansule and preparation method thereof Download PDFInfo
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- CN105796532B CN105796532B CN201610178786.5A CN201610178786A CN105796532B CN 105796532 B CN105796532 B CN 105796532B CN 201610178786 A CN201610178786 A CN 201610178786A CN 105796532 B CN105796532 B CN 105796532B
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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
- A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
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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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
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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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
- A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
Abstract
The present invention provides a kind of RABEPRAZOLE SODIUM spansule, including Capsules and the quick-release enteric-coated micro-pill and slowbreak enteric-coated micro-pill that are filled in Capsules, quick-release enteric-coated micro-pill includes the first capsule core, is coated on first separation layer on the first capsule core surface and is coated on the first enteric layer of the first insulation surface, and slowbreak enteric-coated micro-pill includes the second capsule core, is coated on second separation layer on the second capsule core surface and is coated on the second enteric layer of the second insulation surface；With RABEPRAZOLE SODIUM content meter, the mass ratio of quick-release enteric-coated micro-pill and slowbreak enteric-coated micro-pill is 1: 2-1: 5.The spansule includes quick-releasing type and the two different Rabeprazole sodium enteric-coated micro-pellets of slowbreak type, it is discharged twice under the pH environment for keeping it different in enteron aisle, to solve the problems, such as that " Control of Nocturnal Gastric Acid Breakthrough " and acid suppression are halfway, while improving the stability of RABEPRAZOLE SODIUM.The present invention also provides a kind of RABEPRAZOLE SODIUM spansule preparation method, preparation method is simple.
Description
Technical field
The invention belongs to pharmaceutical preparations technology fields, and in particular to a kind of RABEPRAZOLE SODIUM spansule and its preparation side
Method.
Background technique
The structural formula of RABEPRAZOLE SODIUM are as follows:
Chemical name: 2- [{ 4- (3- methoxy propoxy) -3- picoline -2- base }-methylsulfinyl] -1- hydrogen-benzimidazole sodium
Salt.Rabeprazole and Omeprazole, Lansoprazole, Pantoprazole, esomeprazole etc. belong to proton pump inhibitor, main to use
In gastric ulcer, duodenal ulcer, reflux esophagitis, Zhuo-Emhorn (Zollinger-Ellison) syndrome etc..
Rabeprazole is after absorption of human body, metabolite sulfenamide and H+/K+Cysteine on ATP enzyme α subunit
Inactive compound is formed with disulfide-bonded, to block the common, final of parietal cell gastric acid secretion caused by a variety of causes
Link, the Acidinhibitor with strength.The Rabeprazole product applied at present is mainly the sodium salt preparation of Rabeprazole.Lei Beila
Azoles sodium, it is degradable under acid even neutrallty condition due to containing sulfinyl in its structure, therefore current commercialized product is with intestines
Based on solvellae, capsule and injection.
RABEPRAZOLE SODIUM nature is unstable, easily decomposes under acidity, high temperature, high humidity and illumination condition, while in life
It produces and degradation discoloration also easily occurs in the process for storage.Also, it can occur that " nocturnal acid is prominent in the use process of RABEPRAZOLE SODIUM
It is broken " phenomenon, i.e., in the case where normal administration, the Gastric pH in 22 this period when next day morning 8 is less than at night
4.0, and it is continued above 1 hour, to a series of clinical symptoms occur, hinder the treatment of disease.It is found through experiments that, thunder
Shellfish draws azoles sodium unstable in the environment of pH6.8, and indication release under the conditions of higher pH will increase medicine stability.And it is commercially available
And the rabeprazole sodium enteric-coated preparation of research is almost the condition release in 5.5 or more pH value, in low pH even near-neutral pH
RABEPRAZOLE SODIUM is unstable under environment, to can influence on drug using generation is certain.
Summary of the invention
To solve the above problems, the present invention provides a kind of RABEPRAZOLE SODIUM spansule, which includes quick-release
Type and the two different Rabeprazole sodium enteric-coated micro-pellets of slowbreak type are released twice under the pH environment for keeping it different in enteron aisle
It puts, to solve the problems, such as that " Control of Nocturnal Gastric Acid Breakthrough " and acid suppression are halfway, while also making some drugs in more stable pH condition
Lower release, improves the stability of RABEPRAZOLE SODIUM.The present invention also provides a kind of preparation methods of RABEPRAZOLE SODIUM spansule.
In a first aspect, the present invention provides a kind of RABEPRAZOLE SODIUM spansule, including Capsules and it is filled in institute
The quick-release enteric-coated micro-pill and slowbreak enteric-coated micro-pill in Capsules are stated, the quick-release enteric-coated micro-pill includes the first capsule core, is coated on
First separation layer on first capsule core surface and the first enteric layer for being coated on first insulation surface, the slowbreak intestines
Molten pellet includes the second capsule core, the second separation layer for being coated on second capsule core surface and is coated on the second separation layer table
Second enteric layer in face；With RABEPRAZOLE SODIUM content meter, the mass ratio of the quick-release enteric-coated micro-pill and the slowbreak enteric-coated micro-pill
It is 1: 2-1: 5.
Wherein, first enteric layer dissolves under conditions of being higher than pH5.5.
Wherein, second enteric layer dissolves under conditions of being not less than pH7.0.
Wherein, first enteric layer includes the first enteric material, and second enteric layer includes the second enteric material, institute
It states the first enteric material and second enteric material respectively includes hydroxypropyl methylcellulose phthalate, cellulose acetate
At least one of phthalic acid ester, methacrylic acid copolymer and polyacrylic acid resin.
Wherein, first enteric material includes EUDRAGIT L100-55, methacrylic acid-methyl
Methyl acrylate, hydroxypropyl methylcellulose phthalate or cellulose acetate phthalate.
Wherein, second enteric material includes EUDRAGIT L100.
Wherein, in the quick-release enteric-coated micro-pill, first capsule core, first separation layer and first enteric layer
Mass fraction is respectively 45%-80%, 2%-20% and 10%-50%；In the slowbreak enteric-coated micro-pill, second capsule core,
The mass fraction of second separation layer and second enteric layer is respectively 45%-80%, 2%-20% and 10%-50%.
Wherein, first capsule core and second capsule core include mass fraction be 5%-30% RABEPRAZOLE SODIUM,
The diluent of 20%-85%, the adhesive of 1%-5%, the pH adjusting agent of 2%-20% and 3%-30% disintegrating agent.
A kind of RABEPRAZOLE SODIUM spansule that first aspect present invention provides, which includes quick-releasing type and slowbreak
The two different Rabeprazole sodium enteric-coated micro-pellets of type are discharged under the pH environment for keeping it different in enteron aisle, twice to solve
Certainly " Control of Nocturnal Gastric Acid Breakthrough " and the halfway problem of acid suppression, while discharge some drugs under the conditions of more stable pH, it mentions
The stability of high RABEPRAZOLE SODIUM.
Second aspect, the present invention provides a kind of preparation methods of RABEPRAZOLE SODIUM spansule, comprising the following steps:
First capsule core and the second capsule core are prepared using extrusion spheronization method respectively:
First capsule core is placed in fluidized bed or seed-coating machine, then the first spacer layer coating liquid by spraying, obtains surface
It is coated with the first capsule core of the first separation layer；Second capsule core is placed in fluidized bed or seed-coating machine, then by spraying second every
Absciss layer coating solution obtains to surface and is coated with the second capsule core of the second separation layer；
The first capsule core that the surface is coated with the first separation layer is placed in fluidized bed or seed-coating machine, spraying first enteric
Layer coating solution coats the first enteric layer in first insulation surface and obtains quick-release enteric-coated micro-pill；The surface is coated with
Second capsule core of the second separation layer is placed in fluidized bed or seed-coating machine, spraying second enteric layer coating solution, in second isolation
Layer surface coats the second enteric layer and obtains slowbreak enteric-coated micro-pill；
It is in mass ratio 1: 2-1: 5 loadings by quick-release enteric-coated micro-pill and slowbreak enteric-coated micro-pill with RABEPRAZOLE SODIUM content meter
In Capsules, RABEPRAZOLE SODIUM spansule is made.
Wherein, first capsule core or second capsule core the preparation method comprises the following steps:
RABEPRAZOLE SODIUM, diluent, adhesive, pH adjusting agent and disintegrating agent are mixed and made into softwood, the softwood is thrown
Enter into pill seed-coating machine, the softwood is squeezed out by sieve plate it is in a strip shape, then it is round as a ball be it is spherical, it is dry and after sieving, obtain
To first capsule core or second capsule core.
A kind of preparation method for RABEPRAZOLE SODIUM spansule that second aspect of the present invention provides, preparation method is simple, system
Standby Rabeprazole sodium enteric-coated micro-pellet content is more controllable, can shorten the production cycle, reduces production cost.
To sum up, beneficial effect of the present invention includes the following aspects:
1, first aspect present invention provide a kind of RABEPRAZOLE SODIUM spansule include two kinds of quick-releasing type and slowbreak type not
With Rabeprazole sodium enteric-coated micro-pellet, discharged under the pH environment for keeping it different in enteron aisle twice, to solve " nocturnal acid
Break through " and the halfway problem of acid suppression, while discharge some drugs under the conditions of more stable pH, improve Rabeprazole
The stability of sodium.
2, the preparation method for a kind of RABEPRAZOLE SODIUM spansule that second aspect of the present invention provides, preparation method is simple,
The Rabeprazole sodium enteric-coated micro-pellet content of preparation is more controllable, can shorten the production cycle, reduces production cost.
Detailed description of the invention
Fig. 1 is stability of the RABEPRAZOLE SODIUM bulk pharmaceutical chemicals in pH6.8 phosphate buffer；
Fig. 2 is stability of the RABEPRAZOLE SODIUM bulk pharmaceutical chemicals in pH8.0 phosphate buffer；
Fig. 3 is release of the RABEPRAZOLE SODIUM spansule in pH6.8 phosphate buffer made from the embodiment of the present invention
Degree；
Fig. 4 is that RABEPRAZOLE SODIUM spansule made from the embodiment of the present invention is buffered in pH8.0 trishydroxymethylaminomethane
Release in liquid.
Specific embodiment
The following is a preferred embodiment of the present invention, it is noted that for those skilled in the art
For, various improvements and modifications may be made without departing from the principle of the present invention, these improvements and modifications are also considered as
Protection scope of the present invention.
In a first aspect, the present invention provides a kind of RABEPRAZOLE SODIUM spansule, including Capsules and it is filled in sky
Quick-release enteric-coated micro-pill and slowbreak enteric-coated micro-pill in heart-soothing capsule, quick-release enteric-coated micro-pill include the first capsule core, are coated on the first capsule core
First separation layer on surface and the first enteric layer for being coated on the first insulation surface, slowbreak enteric-coated micro-pill include the second capsule core,
It is coated on second separation layer on the second capsule core surface and is coated on the second enteric layer of the second insulation surface；With RABEPRAZOLE SODIUM
The mass ratio of content meter, quick-release enteric-coated micro-pill and slowbreak enteric-coated micro-pill is 1: 2-1: 5.
In embodiment of the present invention, the mass ratio of quick-release enteric-coated micro-pill and slowbreak enteric-coated micro-pill is 1: 2-1: 5, so that one
Drug dispensing object is first discharged in low pH intestinal environment, to play a role rapidly.Remaining most of drug in higher pH Environment release,
On the one hand on the other hand the stabilization for being conducive to RABEPRAZOLE SODIUM can achieve the purpose of sustained drug release, make drug in blood
Concentration is more stable, avoids the occurrence of " Control of Nocturnal Gastric Acid Breakthrough " and the halfway problem of acid suppression.
In embodiment of the present invention, with RABEPRAZOLE SODIUM content meter, the quality of quick-release enteric-coated micro-pill and slowbreak enteric-coated micro-pill
Than being 1: 3-1: 4.Under the mass ratio, the slow release effect and medicine stability of RABEPRAZOLE SODIUM spansule are preferable.
In embodiment of the present invention, in quick-release enteric-coated micro-pill, the quality of the first capsule core, the first separation layer and the first enteric layer
Score is respectively 45%-80%, 2%-20% and 10%-50%.
In embodiment of the present invention, in slowbreak enteric-coated micro-pill, the quality of the second capsule core, the second separation layer and the second enteric layer
Score is respectively 45%-80%, 2%-20% and 10%-50%.
In embodiment of the present invention, the first capsule core and the second capsule core include the Rabeprazole that mass fraction is 5%-30%
Sodium, the diluent of 20%-85%, the adhesive of 1%-5%, the pH adjusting agent of 2%-20% and 3%-30% disintegrating agent.
In embodiment of the present invention, the first capsule core and the composition of the second capsule core can as and also different, specific root
It is adjusted according to actual needs.
In embodiment of the present invention, diluent is in microcrystalline cellulose, lactose, starch, powdered cellulose and mannitol
At least one.
In a preferred embodiment of the invention, diluent is selected from mannitol and microcrystalline cellulose.
In embodiment of the present invention, it is fine that adhesive is selected from hydroxypropyl methylcellulose, hydroxypropyl cellulose, povidone and carboxymethyl
Tie up at least one of plain sodium.
In a preferred embodiment of the invention, adhesive is selected from hydroxypropyl methylcellulose.
In embodiment of the present invention, pH adjusting agent be selected from calcium carbonate, calcium oxide, calcium hydroxide, sodium carbonate, sodium bicarbonate,
At least one of sodium hydroxide, disodium hydrogen phosphate, sodium phosphate and magnesia.
In a preferred embodiment of the invention, pH adjusting agent is selected from sodium carbonate.
In embodiment of the present invention, disintegrating agent be selected from carboxymethyl starch receive, crospovidone and low substituted hydroxy-propyl fiber
At least one of element.
In a preferred embodiment of the invention, disintegrating agent is selected from low-substituted hydroxypropyl cellulose.
In embodiment of the present invention, by adjust pH adjusting agent in the first capsule core and the second capsule core, the type of disintegrating agent and
Dosage, it can be achieved that release position microenvironment pH value and rate of releasing drug control.
In embodiment of the present invention, the first capsule core and the second capsule core are all made of the preparation of extrusion spheronization method.
In embodiment of the present invention, the first separation layer and the second separation layer include hypromellose, hydroxypropyl fibre
Tie up at least one of element, talcum powder, titanium dioxide, povidone and polyvinylpyrrolidone.
In a preferred embodiment of the invention, the first separation layer and the second separation layer can select Opadry
295K690000。
In an of the invention preferred embodiment, the composition of the first separation layer and the second separation layer can be identical or not
Together, it is adjusted with specific reference to actual needs.
In embodiment of the present invention, the first enteric layer of quick-release enteric-coated micro-pill dissolves under conditions of being higher than pH5.5.
In embodiment of the present invention, the release position of quick-release enteric-coated micro-pill is in duodenum and small intestine leading portion, environment herein
PH is about 5-6.5.
In embodiment of the present invention, the second enteric layer of slowbreak enteric-coated micro-pill dissolves under conditions of being not less than pH7.0.
In embodiment of the present invention, the release position of slowbreak enteric-coated micro-pill is in small intestine posterior segment and colon portion, ring herein
Border pH is about 6.5-8.
General proton pump inhibitor such as Omeprazole, Lansoprazole, Pantoprazole etc. is more stable in 6.8 environment of pH, but
RABEPRAZOLE SODIUM is still unstable with this condition, so the pH of the release environment of RABEPRAZOLE SODIUM is set 2 by the present invention,
Respectively higher than dissolution under conditions of pH5.5 and not less than dissolving under conditions of pH7.0, make some drugs in more stable pH
Under the conditions of discharge, to help to improve the stability of RABEPRAZOLE SODIUM spansule.
In embodiment of the present invention, the first enteric layer includes the first enteric material, and the first enteric material includes hydroxypropyl
In cellulose phthalate, cellulose acetate phthalate, methacrylic acid copolymer and polyacrylic acid resin
It is at least one.
In a preferred embodiment of the invention, the first enteric material includes EUDRAGIT L100-55, first
Base acrylic acid-methacrylic acid methyl esters, hydroxypropyl methylcellulose phthalate or cellulose acetate phthalate.
In an of the invention preferred embodiment, the first enteric material include EUDRAGIT L100-55 (1:
1), methacrylic acid-methyl methacrylate (1: 1), hydroxypropyl methylcellulose phthalate or cellulose acetate neighbour's benzene
Dicarboxylic acid esters (HPMCP).
It is three models: HP-50 according to the degree of polymerization and phthalandione ester content HPMCP points in a preferred embodiment of the invention,
HP-55 and HP-55s, wherein HP-50 is dissolved in pH >=5.0, and HP-55 and HP-55s are dissolved in pH >=5.5.
In an of the invention preferred embodiment, the first enteric material is Utech L30D-55, Eudragit L100-55, especially
At least one of odd L-100,94 series of Opadry enteric, polyacrylic resin II, HP-50, HP-55 and HP-55s.
In embodiment of the present invention, the first enteric layer further includes antitackiness agent, plasticizer and opacifier.
In embodiment of the present invention, the second enteric layer includes the second enteric material, and the second enteric material includes hydroxypropyl
In cellulose phthalate, cellulose acetate phthalate, methacrylic acid copolymer and polyacrylic acid resin
It is at least one.
In a preferred embodiment of the invention, the second enteric material includes methacrylic acid-methyl methacrylate copolymer
Object.
In a preferred embodiment of the invention, the second enteric material includes methacrylic acid-methyl methacrylate copolymer
Object (1: 2) or EUDRAGIT L100 (35: 65).
In a preferred embodiment of the invention, the second enteric material is Utech S100, Opadry enteric 95 is serial or poly-
Acrylic resin III.
In embodiment of the present invention, the second enteric layer further includes antitackiness agent, plasticizer and opacifier.
In embodiment of the present invention, antitackiness agent is in talcum powder, glycerin monostearate, magnesium stearate and silica
At least one.
In a preferred embodiment of the invention, antitackiness agent is selected from talcum powder.
In embodiment of the present invention, plasticizer is selected from triethyl citrate, polyethylene glycol, castor oil, phthalic acid two
At least one of ethyl ester, triethylglycerides and acetyl triethyl citrate.
In a preferred embodiment of the invention, plasticizer is selected from triethyl citrate.
In embodiment of the present invention, opacifier is selected from least one of titanium dioxide and iron oxide.
In a preferred embodiment of the invention, opacifier is selected from titanium dioxide.
In embodiment of the present invention, the content of each component is recipe quantity in the first enteric layer and the second enteric layer.
A kind of RABEPRAZOLE SODIUM spansule that first aspect of the embodiment of the present invention provides, which includes quick-releasing type
With the two different Rabeprazole sodium enteric-coated micro-pellets of slowbreak type, discharged twice under the pH environment for keeping it different in enteron aisle,
To solve the problems, such as that " Control of Nocturnal Gastric Acid Breakthrough " and acid suppression are halfway, while release that some drugs under the conditions of more stable pH
It puts, improves the stability of RABEPRAZOLE SODIUM.
Second aspect, the present invention provides a kind of preparation methods of RABEPRAZOLE SODIUM spansule, comprising the following steps:
First capsule core and the second capsule core are prepared using extrusion spheronization method respectively:
First capsule core is placed in fluidized bed or seed-coating machine, then the first spacer layer coating liquid by spraying, obtains surface cladding
There is the first capsule core of the first separation layer；Second capsule core is placed in fluidized bed or seed-coating machine, then the second spacer layer coating by spraying
Liquid obtains to surface and is coated with the second capsule core of the second separation layer；
The first capsule core that surface is coated with the first separation layer is placed in fluidized bed or seed-coating machine, spraying first enteric layer packet
Clothing liquid coats the first enteric layer in the first insulation surface and obtains quick-release enteric-coated micro-pill；Surface is coated with the second separation layer
Second capsule core is placed in fluidized bed or seed-coating machine, spraying second enteric layer coating solution, coats the second intestines in the second insulation surface
Soluble layer obtains slowbreak enteric-coated micro-pill；
It is in mass ratio 1: 2-1: 5 loadings by quick-release enteric-coated micro-pill and slowbreak enteric-coated micro-pill with RABEPRAZOLE SODIUM content meter
In Capsules, RABEPRAZOLE SODIUM spansule is made.
In embodiment of the present invention, the first capsule core or the second capsule core the preparation method comprises the following steps:
RABEPRAZOLE SODIUM, diluent, adhesive, pH adjusting agent and disintegrating agent are mixed and made into softwood, softwood is put into
In pill seed-coating machine, softwood is squeezed out by sieve plate it is in a strip shape, then it is round as a ball be it is spherical, it is dry and after sieving, obtain the first ball
Core or the second capsule core.
In embodiment of the present invention, RABEPRAZOLE SODIUM, diluent, adhesive, pH adjusting agent and disintegrating agent quality be normal
Recipe quantity.
In an of the invention preferred embodiment, RABEPRAZOLE SODIUM, diluent, adhesive, pH adjusting agent and disintegrating agent matter
Amount is than being thunder 5-30: 20-85: 1-5: 2-20: 3-30.
In a preferred embodiment of the invention, first in the round as a ball 1min of 1600r/min, then in the round as a ball 3min of 1000r/min.
In embodiment of the present invention, the preparation method of the second capsule core and the first capsule core can be identical.
Traditional blank capsule core medicine-feeding, drugloading rate is not generally high, i.e., enabled to reach very big drugloading rate, but can also have consumption
When, energy consumption the problem of, general coating is all even more long in 2h, and there are liquid wastes and loss.The present invention is by squeezing out rolling
Circule method prepares the first capsule core and the first capsule core, improves the preparation efficiency and drugloading rate of pellet, preparation it is sodium rabeprazole enteric-coated
Pellet content is more controllable, and general 10min of extrusion spheronization or so can be completed, and can be put into baking oven dry, loss later
It is smaller with wasting phenomenon, the production cycle can be shortened, reduce production cost.
In embodiment of the present invention, diluent is in microcrystalline cellulose, lactose, starch, powdered cellulose and mannitol
At least one.
In a preferred embodiment of the invention, diluent is selected from mannitol and microcrystalline cellulose.
In embodiment of the present invention, it is fine that adhesive is selected from hydroxypropyl methylcellulose, hydroxypropyl cellulose, povidone and carboxymethyl
Tie up at least one of plain sodium.
In a preferred embodiment of the invention, adhesive is selected from hydroxypropyl methylcellulose.
In embodiment of the present invention, pH adjusting agent be selected from calcium carbonate, calcium oxide, calcium hydroxide, sodium carbonate, sodium bicarbonate,
At least one of sodium hydroxide, disodium hydrogen phosphate, sodium phosphate and magnesia.
In a preferred embodiment of the invention, pH adjusting agent is selected from sodium carbonate.
In embodiment of the present invention, disintegrating agent be selected from carboxymethyl starch receive, crospovidone and low substituted hydroxy-propyl fiber
At least one of element.
In a preferred embodiment of the invention, disintegrating agent is selected from low-substituted hydroxypropyl cellulose.
In embodiment of the present invention, it is that surface is coated with the first capsule core of the first separation layer the preparation method comprises the following steps: take first every
Layer material is added solvent and is configured to the first spacer layer coating liquid, then the first capsule core is placed in fluidized bed or seed-coating machine, sprays
Mist the first spacer layer coating liquid coats separation layer after dry screening on the first capsule core surface and obtains to surface and be coated with the first isolation
First capsule core of layer.
In embodiment of the present invention, the first separation layer and the second separation layer include hypromellose, hydroxypropyl fibre
Tie up at least one of element, talcum powder, titanium dioxide, povidone and polyvinylpyrrolidone.
In a preferred embodiment of the invention, the first separation layer and the second separation layer can select Opadry
295K690000。
In embodiment of the present invention, solvent is at least one of dehydrated alcohol and water.
In embodiment of the present invention, surface is coated with the preparation method of the second capsule core of the second separation layer and surface is coated with
The preparation method of first capsule core of the first separation layer can be identical.
In an of the invention preferred embodiment, when coating the first separation layer or the second separation layer, seed-coating machine or fluidized bed
Operating condition are as follows: round as a ball revolving speed is 100-150r/min, and air inlet revolving speed is 1000-1200r/min, and outlet air revolving speed is 1000-
1200r/min, inlet air temperature are 41-43 DEG C, atomizing pressure 0.10-0.14MPa, and coating flow velocity is 3-5g/min.Specifically
Operating condition can as the case may be depending on, be such as adjusted according to the difference of equipment.
In embodiment of the present invention, in the method that the first insulation surface coats the first enteric layer specifically:
First enteric material of recipe quantity, antitackiness agent, plasticizer and opacifier are added in solvent, the first enteric layer is made
Then the first capsule core that surface is coated with the first separation layer is placed in fluidized bed or seed-coating machine by coating solution, spraying first enteric
Layer coating solution coats the first enteric layer after dry screening in the first insulation surface and obtains quick-release enteric-coated micro-pill.
In embodiment of the present invention, the method for the second enteric layer is coated in the second insulation surface and in the first separation layer table
The method that bread covers the first enteric layer can be identical.
In an of the invention preferred embodiment, when coating the first enteric layer or the second enteric layer, seed-coating machine or fluidized bed
Operating condition are as follows: round as a ball revolving speed is 100-150r/min, and air inlet revolving speed is 800-1200r/min, and outlet air revolving speed is 800-
1200r/min, inlet air temperature are 42-45 DEG C, atomizing pressure 0.10-0.14MPa, and coating flow velocity is 2-5g/min.Specifically
Operating condition can as the case may be depending on be such as adjusted according to the difference of equipment.
In embodiment of the present invention, the first enteric layer of quick-release enteric-coated micro-pill dissolves under conditions of being higher than pH5.5.
In embodiment of the present invention, the release position of quick-release enteric-coated micro-pill is in duodenum and small intestine leading portion, environment herein
PH is about 5-6.5.
In embodiment of the present invention, the second enteric layer of slowbreak enteric-coated micro-pill dissolves under conditions of being not less than pH7.0.
In embodiment of the present invention, the release position of slowbreak enteric-coated micro-pill is in small intestine posterior segment and colon portion, ring herein
Border pH is about 6.5-8.
In a preferred embodiment of the invention, the first enteric material includes EUDRAGIT L100-55, first
Base acrylic acid-methacrylic acid methyl esters, hydroxypropyl methylcellulose phthalate or cellulose acetate phthalate.
In an of the invention preferred embodiment, the first enteric material include EUDRAGIT L100-55 (1:
1), methacrylic acid-methyl methacrylate (1: 1), hydroxypropyl methylcellulose phthalate, cellulose acetate neighbour benzene two
Formic acid esters (HPMCP).
It is three models: HP-50 according to the degree of polymerization and phthalandione ester content HPMCP points in a preferred embodiment of the invention,
HP-55 and HP-55s, wherein HP-50 is dissolved in pH >=5.0, and HP-55 and HP-55s are dissolved in pH >=5.5.
In an of the invention preferred embodiment, the first enteric material is Utech L30D-55, Eudragit L100-55, especially
At least one of odd L-100,94 series of Opadry enteric, polyacrylic resin II, HP-50, HP-55 and HP-55s.
In embodiment of the present invention, the first enteric layer further includes antitackiness agent, plasticizer and opacifier.
In embodiment of the present invention, the second enteric layer includes the second enteric material, and the second enteric material includes hydroxypropyl
In cellulose phthalate, cellulose acetate phthalate, methacrylic acid copolymer and polyacrylic acid resin
It is at least one.
In a preferred embodiment of the invention, the second enteric material includes methacrylic acid-methyl methacrylate copolymer
Object.
In a preferred embodiment of the invention, the second enteric material includes methacrylic acid-methyl methacrylate copolymer
Object (1: 2) or EUDRAGIT L100 (35: 65).
In a preferred embodiment of the invention, the second enteric material is Utech S100, Opadry enteric 95 is serial or poly-
Acrylic resin III.
In embodiment of the present invention, the second enteric layer further includes antitackiness agent, plasticizer and opacifier.
In embodiment of the present invention, antitackiness agent is in talcum powder, glycerin monostearate, magnesium stearate and silica
At least one.
In a preferred embodiment of the invention, antitackiness agent is selected from talcum powder.
In embodiment of the present invention, plasticizer is selected from triethyl citrate, polyethylene glycol, castor oil, phthalic acid two
At least one of ethyl ester, triethylglycerides and acetyl triethyl citrate.
In a preferred embodiment of the invention, plasticizer is selected from triethyl citrate.
In embodiment of the present invention, opacifier is selected from least one of titanium dioxide and iron oxide.
In a preferred embodiment of the invention, opacifier is selected from titanium dioxide.
In a preferred embodiment of the invention, solvent is at least one of water and dehydrated alcohol.
In embodiment of the present invention, the content of each component is recipe quantity in the first enteric layer and the second enteric layer.
In embodiment of the present invention, with RABEPRAZOLE SODIUM content meter, the quality of quick-release enteric-coated micro-pill and slowbreak enteric-coated micro-pill
Than being 1: 3-1: 4.Under the mass ratio, the slow release effect of RABEPRAZOLE SODIUM spansule is preferable.
A kind of preparation method for RABEPRAZOLE SODIUM spansule that second aspect of the embodiment of the present invention provides, preparation method letter
Single, the Rabeprazole sodium enteric-coated micro-pellet content of preparation is more controllable, can shorten the production cycle, reduces production cost.
Embodiment 1
A kind of RABEPRAZOLE SODIUM spansule, including Capsules and the quick-release enteric-coated micro-pill being filled in Capsules
With slowbreak enteric-coated micro-pill, quick-release enteric-coated micro-pill includes the first capsule core, the first separation layer and cladding for being coated on the first capsule core surface
In the first enteric layer of the first insulation surface, slowbreak enteric-coated micro-pill includes the second capsule core, is coated on the of the second capsule core surface
Two separation layers and the second enteric layer for being coated on the second insulation surface；Shown in the composition of quick-release enteric-coated micro-pill table 1 specific as follows,
The composition of slowbreak enteric-coated micro-pill is specifically as shown in the following table 2；Wherein the water in table, dehydrated alcohol equal solvent amount refer to preparing
The amount of preceding addition, during the preparation process or after preparation, solvent can be volatilized or be evaporated, and it is interior that this is that this field skill personnel are understood that
Hold, details are not described herein.
Table 1
Table 2
A kind of preparation method of RABEPRAZOLE SODIUM spansule, comprising the following steps:
1, quick-release enteric-coated micro-pill is prepared
(1) every supplementary material is weighed respectively by the recipe quantity of table 1, under conditions of relative humidity (RH) is less than 70% indoors
Mixing sieving, (adhesive is the second for the hydroxypropyl methylcellulose (HPMC E5) that mass fraction is 5% to the adhesive of addition 70g later
Alcohol-water (35: 65, w/w) solution, wherein the quality of hydroxypropyl methylcellulose is 3.5g), multi-functional pill packet is put into after softwood is made
In clothing machine, 30r/min squeezes out (aperture 1.0mm) under cooling water cycling condition, 1600r/min round as a ball 1min, 1000r/min rolling
Circle 3min, dry 2h under the conditions of 40 DEG C, enters the wind revolving speed 600r/min, outlet air revolving speed 600r/min, screens -24 mesh of 20 mesh later
Pellet is to get the first capsule core containing RABEPRAZOLE SODIUM.
(2) dissolution of recipe quantity Opadry stomach dissolution type coating material is dispersed in dehydrated alcohol, water is added later, mixing is equal
It is even to be sieved up to the first spacer layer coating liquid.
First capsule core obtained above is put into multi-functional pill seed-coating machine, round as a ball revolving speed 150r/min, air inlet turns
Fast 1200r/min, outlet air revolving speed 1200r/min, adjusts wriggling revolution speed by 41-43 DEG C of inlet air temperature, atomizing pressure 0.14MPa,
First spacer layer coating flow velocity is about 3g/min, side spray packet under conditions of the first spacer layer coating liquid is persistently slowly stirred
Clothing, the dry 10min of 40 DEG C of air inlets, screens -24 mesh pellet of 20 mesh, obtains to surface and be coated with the first ball of the first separation layer later
Core.
(3) the Utech L30D-55 of recipe quantity is added in the water of part, the suspension of Utech L 30D-55 is made,
Separately the triethyl citrate of recipe quantity and talcum powder is taken to be added in remaining water, Utech L is added to after high speed shear 10min
In the suspension of 30D-55, sieving is after stirring 30min to get the first enteric layer coating solution.
(4) the first capsule core that surface obtained above is coated with the first separation layer is put into multi-functional pill seed-coating machine
In, round as a ball revolving speed 150r/min enters the wind revolving speed 800r/min, and outlet air revolving speed 800r/min, 42-45 DEG C of inlet air temperature, atomization is pressed
Power 0.12MPa adjusts wriggling revolution speed, and it is about 2.6g/min that the first enteric layer, which is coated flow velocity, continues slowly to stir in coating solution
Side spray is coated under conditions of mixing, and coats the first enteric layer in the first insulation surface, later the dry 10min of 40 DEG C of air inlets, screening
- 24 mesh pellet of 20 mesh, obtains RABEPRAZOLE SODIUM quick-releasing type enteric-coated micro-pill.
2, slowbreak enteric-coated micro-pill is prepared
(1) every supplementary material is weighed respectively by the recipe quantity of above-mentioned table 2, indoors the item of relative humidity (RH) less than 70%
Sieving is mixed under part, (mass fraction is that the alcohol-water (35: 65, w/w) of 5%HPMC E5 is molten to the adhesive of addition 70g later
Liquid), it is put into multi-functional pill seed-coating machine after softwood is made, (aperture is 30r/min extrusion under cooling water cycling condition
1.0mm), the round as a ball 3min of the round as a ball 1min of 1600r/min, 1000r/min, dry 2h under the conditions of 40 DEG C, enters the wind revolving speed later
600r/min, outlet air revolving speed 600r/min screen -24 mesh pellet of 20 mesh to get the second capsule core containing RABEPRAZOLE SODIUM.
(2) dissolution of recipe quantity Opadry stomach dissolution type coating material is dispersed in dehydrated alcohol, water is added later, mixing is equal
It is even to be sieved up to the second spacer layer coating liquid.
The second capsule core of drug containing obtained above is put into multi-functional pill seed-coating machine, round as a ball revolving speed 150r/min, into
Wind revolving speed 1200r/min, outlet air revolving speed 1200r/min, adjusts peristaltic pump by 41-43 DEG C of inlet air temperature, atomizing pressure 0.14MPa
Revolving speed, the second spacer layer coating flow velocity is about 3g/min, side under conditions of the second spacer layer coating liquid is persistently slowly stirred
Spray coating, the dry 10min of 40 DEG C of air inlets, screens -24 mesh pellet of 20 mesh, obtains to surface and be coated with the second of the second separation layer later
Capsule core.
(3) the Utech S100 of recipe quantity is added in the water of part, triethyl citrate is added later, stirs evenly,
The suspension of Utech S100 is made, separately takes the talcum powder of recipe quantity and titanium dioxide to be added in remaining water, high speed shear
It is added to after 10min in the suspension of Utech S100, sieving is after stirring 45min to get the second enteric layer coating solution.
(4) the second capsule core that surface obtained above is coated with the second separation layer is put into multi-functional pill seed-coating machine
In, round as a ball revolving speed 150r/min enters the wind revolving speed 800r/min, outlet air revolving speed 800r/min, and 42~45 DEG C of inlet air temperature, atomization is pressed
Power 0.12MPa adjusts wriggling revolution speed, and it is about 2.6g/min that the second enteric layer, which is coated flow velocity, in the second enteric layer coating solution
Side spray is coated under conditions of being persistently slowly stirred, and the dry 10min of 40 DEG C of air inlets, screens -24 mesh pellet of 20 mesh, obtain thunder shellfish later
Draw azoles sodium slowbreak type enteric-coated micro-pill.
3, RABEPRAZOLE SODIUM spansule is prepared
Quick-releasing type and slowbreak type Rabeprazole sodium enteric-coated micro-pellet are packed into the ratio of 1: 3 (with RABEPRAZOLE SODIUM content meter)
To get RABEPRAZOLE SODIUM spansule in Capsules.
Embodiment 2
A kind of RABEPRAZOLE SODIUM spansule, including Capsules and the quick-release enteric-coated micro-pill being filled in Capsules
With slowbreak enteric-coated micro-pill, quick-release enteric-coated micro-pill includes the first capsule core, the first separation layer and cladding for being coated on the first capsule core surface
In the first enteric layer of the first insulation surface, slowbreak enteric-coated micro-pill includes the second capsule core, is coated on the of the second capsule core surface
Two separation layers and the second enteric layer for being coated on the second insulation surface；The composition of quick-release enteric-coated micro-pill is as shown in table 3 below, slowbreak
The composition of enteric-coated micro-pill is as shown in the following table 4；
Table 3
Table 4
A kind of preparation method of RABEPRAZOLE SODIUM spansule, comprising the following steps:
1, quick-release enteric-coated micro-pill is prepared
(1) every supplementary material is weighed respectively by the recipe quantity of above-mentioned table 3, indoors the item of relative humidity (RH) less than 70%
Sieving is mixed under part, (mass fraction is that the alcohol-water (35: 65, w/w) of 5%HPMC E5 is molten to the adhesive of addition 70g later
Liquid), it is put into multi-functional pill seed-coating machine after softwood is made, (aperture is 30r/min extrusion under cooling water cycling condition
1.0mm), the round as a ball 3min of the round as a ball 1min of 1600r/min, 1000r/min, dry 2h under the conditions of 40 DEG C, enters the wind revolving speed later
600r/min, outlet air revolving speed 600r/min screen -24 mesh pellet of 20 mesh to get the first capsule core containing RABEPRAZOLE SODIUM.
(2) dissolution of recipe quantity Opadry stomach dissolution type coating material is dispersed in dehydrated alcohol, water is added later, mixing is equal
It is even to be sieved up to the first spacer layer coating liquid.
The first capsule core of drug containing obtained above is put into multi-functional pill seed-coating machine, round as a ball revolving speed 150r/min, into
Wind revolving speed 1200r/min, outlet air revolving speed 1200r/min, adjusts peristaltic pump by 41-43 DEG C of inlet air temperature, atomizing pressure 0.14MPa
Revolving speed, the first spacer layer coating flow velocity is about 3g/min, side under conditions of the first spacer layer coating liquid is persistently slowly stirred
Spray coating, the dry 10min of 40 DEG C of air inlets, screens -24 mesh pellet of 20 mesh, obtains to surface and be coated with the first of the first separation layer later
Capsule core.
(3) the Utech L 30D-55 of recipe quantity is added in the water of part, the suspension of Utech L 30D-55 is made,
Separately the triethyl citrate of recipe quantity and talcum powder is taken to be added in remaining water, Utech L is added to after high speed shear 10min
In the suspension of 30D-55, sieving is after stirring 30min to get the first enteric layer coating solution.
The first capsule core that surface obtained above is coated with the first separation layer is put into multi-functional pill seed-coating machine, is rolled
Circle revolving speed 150r/min, enter the wind revolving speed 800r/min, outlet air revolving speed 800r/min, 42~45 DEG C of inlet air temperature, atomizing pressure
0.12MPa adjusts wriggling revolution speed, and it is about 2.6g/min that the first enteric layer, which is coated flow velocity, is held in the first enteric layer coating solution
Continue side spray under conditions of being slowly stirred to be coated, coats the first enteric layer, later 40 DEG C of air inlet dryings in the first insulation surface
10min screens -24 mesh pellet of 20 mesh, obtains RABEPRAZOLE SODIUM quick-releasing type enteric-coated micro-pill.
2, slowbreak enteric-coated micro-pill is prepared
(1) every supplementary material is weighed respectively by above-mentioned 4 recipe quantity of table, indoors the condition of relative humidity (RH) less than 70%
The adhesive (alcohol-water (35: 65, w/w) solution that mass fraction is 5%HPMC E5) of 70g is added in lower mixing sieving later,
It being put into multi-functional pill seed-coating machine after softwood is made, 30r/min squeezes out (aperture 1.0mm) under cooling water cycling condition,
The 1600r/min round as a ball 3min of round as a ball 1min, 1000r/min, dry 2h under the conditions of 40 DEG C, enters the wind revolving speed 600r/min later,
Outlet air revolving speed 600r/min screens -24 mesh pellet of 20 mesh to get the second capsule core containing RABEPRAZOLE SODIUM.
(2) dissolution of recipe quantity Opadry stomach dissolution type coating material is dispersed in dehydrated alcohol, water is added later, mixing is equal
It is even to be sieved up to the second spacer layer coating liquid.
Second capsule core obtained above is put into multi-functional pill seed-coating machine, round as a ball revolving speed 150r/min, air inlet turns
Fast 1200r/min, outlet air revolving speed 1200r/min, adjusts wriggling revolution speed by 41-43 DEG C of inlet air temperature, atomizing pressure 0.14MPa,
Being coated flow velocity is about 3g/min, and side spray is coated under conditions of the second spacer layer coating liquid is persistently slowly stirred, and 40 DEG C later
Dry 10min is entered the wind, -24 mesh pellet of 20 mesh is screened, obtains to surface and be coated with the second capsule core of the second separation layer.
(3) the Utech S100 of recipe quantity is added in the water of part, triethyl citrate is added later, stirs evenly,
The suspension of Utech S100 is made, separately takes the talcum powder of recipe quantity and titanium dioxide to be added in remaining water, high speed shear
It is added to after 10min in the suspension of Utech S100, sieving is after stirring 45min to get the second enteric layer coating solution.
The second capsule core that surface obtained above is coated with the second separation layer is put into multi-functional pill seed-coating machine, is rolled
Circle revolving speed 150r/min, enters the wind revolving speed 800r/min, outlet air revolving speed 800r/min, and 42-45 DEG C of inlet air temperature, atomizing pressure
0.12MPa adjusts wriggling revolution speed, and coating flow velocity is about 2.6g/min, side under conditions of coating solution is persistently slowly stirred
Spray coating coats the first enteric layer in the first insulation surface, and the dry 10min of 40 DEG C of air inlets, screening -24 mesh of 20 mesh are micro- later
Ball obtains RABEPRAZOLE SODIUM slowbreak type enteric-coated micro-pill.
3, RABEPRAZOLE SODIUM spansule is prepared
Quick-releasing type and slowbreak type Rabeprazole sodium enteric-coated micro-pellet are packed into the ratio of 1: 3 (with RABEPRAZOLE SODIUM content meter)
To get RABEPRAZOLE SODIUM spansule in Capsules.
Embodiment 3
A kind of preparation method of RABEPRAZOLE SODIUM spansule, comprising the following steps:
Step 1 and step 2 and embodiment 1 it is identical；
3, RABEPRAZOLE SODIUM spansule is prepared
Quick-releasing type and slowbreak type Rabeprazole sodium enteric-coated micro-pellet are packed into the ratio of 1: 4 (with RABEPRAZOLE SODIUM content meter)
To get RABEPRAZOLE SODIUM spansule in Capsules.
Embodiment 4
A kind of preparation method of RABEPRAZOLE SODIUM spansule, comprising the following steps:
Step 1 and step 2 and embodiment 2 it is identical；
3, RABEPRAZOLE SODIUM spansule is prepared
Quick-releasing type and slowbreak type Rabeprazole sodium enteric-coated micro-pellet are packed into the ratio of 1: 2 (with RABEPRAZOLE SODIUM content meter)
To get RABEPRAZOLE SODIUM spansule in Capsules.
Embodiment 5
A kind of preparation method of RABEPRAZOLE SODIUM spansule, comprising the following steps:
Step 1 and step 2 and embodiment 2 it is identical；
3, RABEPRAZOLE SODIUM spansule is prepared
Quick-releasing type and slowbreak type Rabeprazole sodium enteric-coated micro-pellet are packed into the ratio of 1: 5 (with RABEPRAZOLE SODIUM content meter)
To get RABEPRAZOLE SODIUM spansule in Capsules.
Embodiment 6
A kind of preparation method of RABEPRAZOLE SODIUM spansule, comprising the following steps:
In addition to the composition of the first enteric layer and embodiment 1 are different, other are all identical with embodiment 1.
The composition of the first enteric layer of the present embodiment is as shown in table 5 below, the first enteric layer coating solution the preparation method comprises the following steps:
The Utech L100 of recipe quantity is added in the dehydrated alcohol of part, the solution of Utech L100 is made, separately takes place
The triethyl citrate and talcum powder just measured are added in remaining water and dehydrated alcohol, are added to especially after high speed shear 10min
In the solution of odd L 100, sieving is after stirring 30min to get the first enteric layer coating solution.
Table 5
Embodiment 7
A kind of preparation method of RABEPRAZOLE SODIUM spansule, comprising the following steps:
In addition to the composition of the first enteric layer and embodiment 1 are different, other are all identical with embodiment 1.
The composition of the first enteric layer of the present embodiment is as shown in table 6 below, the first enteric layer coating solution the preparation method comprises the following steps:
Polyacrylic acid resin II of recipe quantity is added in the dehydrated alcohol of part, polyacrylic acid resin II is made
Solution separately takes the triethyl citrate of recipe quantity and talcum powder to be added in remaining water and dehydrated alcohol, after high speed shear 10min
It is added in polyacrylic acid resin II solution, sieving is after stirring 30min to get the first enteric layer coating solution.
Table 6
Embodiment 8
A kind of preparation method of RABEPRAZOLE SODIUM spansule, comprising the following steps:
In addition to the composition of the first enteric layer and embodiment 1 are different, other are all identical with embodiment 1.
The composition of the first enteric layer of the present embodiment is as shown in table 7 below, the first enteric layer coating solution the preparation method comprises the following steps:
The hypromellose phthalate of recipe quantity is added in the dehydrated alcohol of part, hypromellose is made
The solution of plain phthalic acid ester, separately take the triethyl citrate, talcum powder and titanium dioxide of recipe quantity be added to remaining water and
It in dehydrated alcohol, is added in the solution of hypromellose phthalate after high speed shear 10min, after stirring 30min
Sieving is to get the first enteric layer coating solution.
Table 7
Embodiment 9
A kind of preparation method of RABEPRAZOLE SODIUM spansule, comprising the following steps:
In addition to the composition of the second enteric layer and embodiment 1 are different, other are all identical with embodiment 1.
The composition of the second enteric layer of the present embodiment is as shown in table 8 below, the second enteric layer coating solution the preparation method comprises the following steps:
Polyacrylic acid resin III of recipe quantity is added in the dehydrated alcohol of part, polyacrylic acid resin III is made
Solution, separately take the triethyl citrate of recipe quantity and talcum powder to be added in remaining water and dehydrated alcohol, high speed shear 10min
It is added in polyacrylic acid resin III solution afterwards, sieving is after stirring 30min to get the second enteric layer coating solution.
Table 8
Embodiment 10
RABEPRAZOLE SODIUM spansule dissolution test
(1) release in pH6.8 phosphate buffer
Dissolution determination method (the general rule 0931 of sodium rabeprazole enteric-coated capsule in reference " Chinese Pharmacopoeia " 2015 editions two
Second method method 1) measurement, RABEPRAZOLE SODIUM spansule made from Example 1 and Example 2 of the present invention is weighed respectively (to be contained altogether
Have RABEPRAZOLE SODIUM about 100mg), using 0.1mol/L hydrochloric acid solution 750ml as dissolution medium, temperature is 37 DEG C, revolving speed 100r/
After min, 120min, 37 DEG C of 0.2mol/L sodium radio-phosphate,P-32 solution 250ml is added in process container immediately, it is molten with 2mol/L hydrochloric acid
Liquid or 2mol/L sodium hydroxide solution adjust pH value to 6.8, and temperature revolving speed is constant, respectively 5,10,15,30,45,60,90,
120,150,180,210,240, after 270min, solution is taken to filter through 0.45 μm of filter membrane, precision measures filtrate 3ml, is added to and contains
Have in the cillin bottle of 0.5mol/L sodium hydroxide solution of 1ml, shake up, test solution is used as after filtering；Another accurate title thunder shellfish
Azoles sodium raw materials medicine 25mg is drawn, sets in 25ml volumetric flask, is diluted to scale with 0.5mol/L sodium hydroxide solution, it is accurate later to measure
3mL is set in 10mL volumetric flask, and 0.5mol/L sodium hydroxide solution is diluted to scale, and precision measures 1ml, and phosphate buffer is added
(add 0.2mol/L sodium radio-phosphate,P-32 solution 250ml in 0.1mol/L hydrochloric acid solution 750ml, with 2mol/L hydrochloric acid solution or 2mol/L hydrogen
Sodium hydroxide solution adjusts pH value to 6.8) 3ml, filters after shaking up, as reference substance solution.
Test sample and reference substance solution are measured into Rabeprazole sodium content by efficient liquid phase by external standard method, chromatographic condition:
Chromatographic column Diamonsil C18Chromatographic column (4.6mm × 200mm, 5 μm)；Mobile phase 0.015mol/L disodium hydrogen phosphate (phosphoric acid tune
PH is saved to 6.0)-acetonitrile (65: 35)；Detection wavelength 290nm；30 DEG C of column temperature；10 μ L of sample volume, automatic sampling.Then it calculates not
With the release of time RABEPRAZOLE SODIUM.
(2) release in the TRIS buffer of pH8.0
Dissolution determination method (the general rule 0931 of sodium rabeprazole enteric-coated capsule in reference " Chinese Pharmacopoeia " 2015 editions two
Second method method 1) measurement, RABEPRAZOLE SODIUM spansule made from Example 1 and Example 2 of the present invention is weighed respectively (to be contained altogether
Have RABEPRAZOLE SODIUM about 100mg), using 0.1mol/L hydrochloric acid solution 700ml as dissolution medium, temperature is 37 DEG C, revolving speed 100r/
After min, 120min, 37 DEG C of 0.6mol/L tris solution 300ml is added in process container immediately, uses
2mol/L hydrochloric acid solution or 2mol/L sodium hydroxide solution adjust pH value to 8.0, and temperature revolving speed is constant, respectively 5,10,15,
30,45,60,90, after 120min, solution is taken to filter through 0.45 μm of filter membrane, precision measures filtrate 3ml, is added to containing 1ml's
It in the cillin bottle of 0.5mol/L sodium hydroxide solution, shakes up, test solution is used as after filtering；Another accurate title RABEPRAZOLE SODIUM is former
Expect medicine 25mg, set in 25ml volumetric flask, be diluted to scale with 0.5mol/L sodium hydroxide solution, the accurate 3mL that measures is set later
In 10mL volumetric flask, 0.5mol/L sodium hydroxide solution is diluted to scale, and precision measures 1ml, and trishydroxymethylaminomethane is added
Buffer (adds 0.6mol/L tris solution 300ml, with 2mol/L salt in 0.1mol/L hydrochloric acid solution 700ml
Acid solution or 2mol/L sodium hydroxide solution adjust pH value to 8.0) 3ml, filter after shaking up, as reference substance solution.
Test sample and reference substance solution are measured into Rabeprazole sodium content by efficient liquid phase by external standard method, chromatographic condition:
Chromatographic column Diamonsil C18Chromatographic column (4.6mm × 200mm, 5 μm)；Mobile phase 0.015mol/L disodium hydrogen phosphate (phosphoric acid tune
PH is saved to 6.0)-acetonitrile (65: 35)；Detection wavelength 290nm；30 DEG C of column temperature；10 μ L of sample volume, automatic sampling.Then it calculates not
With the release of time RABEPRAZOLE SODIUM.Test result is as shown in Figure 3 and Figure 4.
RABEPRAZOLE SODIUM bulk pharmaceutical chemicals are sieved with 100 mesh sieve, 100mg is respectively weighed, investment is preheated to 37 DEG C of pH6.8 phosphoric acid respectively
Salt buffer (takes 0.2mol/L potassium dihydrogen phosphate 250ml, adds 0.2mol/L sodium hydroxide solution 118ml, be diluted with water to
1000ml adjusts pH to 6.8) and (taking phosphoric acid hydrogen in pH8.0 phosphate buffer with 2mol/L hydrochloric acid or 2mol/L sodium hydroxide
Dipotassium 5.59g and potassium dihydrogen phosphate 0.41g, adds water to make to be dissolved into 1000ml, with 2mol/L hydrochloric acid or 2mol/L sodium hydroxide tune
PH is saved to 8.0), respectively in 5,10,20,30,45,60min, solution is taken to filter through 0.45 μm of filter membrane, precision measures filtrate 3ml,
It is added in the cillin bottle of the 0.5mol/L sodium hydroxide solution containing 1ml, shakes up, test solution is used as after filtering；Another essence
Close title RABEPRAZOLE SODIUM bulk pharmaceutical chemicals 25mg, sets in 25ml volumetric flask, is diluted to scale with 0.5mol/L sodium hydroxide solution, later
Precision measures 3mL and sets in 10mL volumetric flask, and 0.5mol/L sodium hydroxide solution is diluted to scale, and precision measures 1ml, is added
PH6.8 phosphate buffer (test sample of corresponding pH6.8 phosphate buffer) or pH8.0 TRIS buffer
(test sample of corresponding pH8.0 TRIS buffer) is used as reference substance, measures RABEPRAZOLE SODIUM in different solutes
Content.Test result is as depicted in figs. 1 and 2.
Fig. 1 is stability of the RABEPRAZOLE SODIUM bulk pharmaceutical chemicals in pH6.8 phosphate buffer；Fig. 2 is that RABEPRAZOLE SODIUM is former
Expect stability of the medicine in pH8.0 phosphate buffer；Fig. 3 is that RABEPRAZOLE SODIUM spansule made from the embodiment of the present invention exists
Release in pH6.8 phosphate buffer；Fig. 4 is RABEPRAZOLE SODIUM spansule made from the embodiment of the present invention in pH8.0
Release in TRIS buffer.
It is very unstable in pH6.8 phosphate buffer from can be seen that RABEPRAZOLE SODIUM bulk pharmaceutical chemicals in Fig. 1 and Fig. 2
Fixed, and it is relatively stable in pH8.0 phosphate buffer.
By the release data of Fig. 3 and Fig. 4 it is found that RABEPRAZOLE SODIUM spansule prepared by the embodiment of the present invention 1 exists
The release of 60min is 18% or so in the medium of pH6.8, and the mainly release of quick-release enteric-coated micro-pill at this time, 180min's releases
Degree of putting is 60% or so, and the release of RABEPRAZOLE SODIUM spansule 60min in the ph 6.8 media prepared by embodiment 2 is
20% or so, the mainly release of quick-release enteric-coated micro-pill at this time, the release of 180min is 70% or so.Due to RABEPRAZOLE SODIUM
Stability is not high in the environment of pH is 6.8, and the RABEPRAZOLE SODIUM of fraction is decomposed, therefore release is not up to 100%.
The release of RABEPRAZOLE SODIUM spansule 30min in the medium of pH8.0 prepared by embodiment 1 is 27% or so, 120min
Release be 90%, embodiment 2 prepare RABEPRAZOLE SODIUM spansule in the medium of pH8.0 the release of 30min be
The release of 30% or so, 120min are 88% or so, and RABEPRAZOLE SODIUM spansule prepared by embodiment 1 and embodiment 2 exists
The release of 120min or so reaches 90% or so, illustrate RABEPRAZOLE SODIUM spansule in the medium of pH8.0 stability compared with
It is good.In addition, the release of embodiment 2 is higher compared with Example 1, reason may be the substitution hydroxyl being added in embodiment 2
The dosage of propyl cellulose and sodium carbonate is slightly more, therefore dissolves out release faster.
Therefore, the present invention is dissolved under different pH value by controlling enteric material, can be under different pH value conditions
Quick-releasing type and slowbreak type enteric-coated micro-pill are discharged respectively, are played the role of being sustained well, be can solve in therapeutic process " night
Acid break through " problem and improve RABEPRAZOLE SODIUM absorption site stability.
Embodiment 11
The test of RABEPRAZOLE SODIUM spansule influence factor
With RABEPRAZOLE SODIUM spansule made from embodiment 1 and embodiment 2, referring to Chinese Pharmacopoeia 2015 editions four 9001
Carry out influence factor test.
Influence factor test: hot test (40 DEG C ± 2 DEG C), high humidity test (75% ± 5%), exposure experiments to light (4000Lx
± 500Lx), it was measured in the 0th, 5,10 day, the results are shown in Table 9,10 and 11.
9 high temperature test result of table
10 high humidity test result of table
11 exposure experiments to light result of table
As shown in table 9 to table 11, the embodiment of the present invention 1 and the made RABEPRAZOLE SODIUM spansule of embodiment 2 are in height
Under temperature, high humidity, illumination condition, the 5th day and 10 days character, content and release has no significant change, and illustrates implementation of the present invention
The made RABEPRAZOLE SODIUM spansule of example is relatively stable.
The embodiments described above only express several embodiments of the present invention, and the description thereof is more specific and detailed, but simultaneously
Limitations on the scope of the patent of the present invention therefore cannot be interpreted as.It should be pointed out that for those of ordinary skill in the art
For, without departing from the inventive concept of the premise, various modifications and improvements can be made, these belong to guarantor of the invention
Protect range.Therefore, the scope of protection of the patent of the invention shall be subject to the appended claims.
Claims (8)
1. a kind of RABEPRAZOLE SODIUM spansule, which is characterized in that including Capsules and be filled in the Capsules
Quick-release enteric-coated micro-pill and slowbreak enteric-coated micro-pill, the quick-release enteric-coated micro-pill include the first capsule core, be coated on first capsule core
First separation layer on surface and the first enteric layer for being coated on first insulation surface, the slowbreak enteric-coated micro-pill include the
Two capsule cores, the second separation layer for being coated on second capsule core surface and the second enteric for being coated on second insulation surface
Layer；In the quick-release enteric-coated micro-pill, the mass fraction point of first capsule core, first separation layer and first enteric layer
It Wei not 45%-80%, 2%-20% and 10%-50%；In the slowbreak enteric-coated micro-pill, second capsule core, described second every
The mass fraction of absciss layer and second enteric layer is respectively 45%-80%, 2%-20% and 10%-50%；With Rabeprazole
The mass ratio of sodium content meter, the quick-release enteric-coated micro-pill and the slowbreak enteric-coated micro-pill is 1:2-1:5, first capsule core and institute
State the second capsule core and include mass fraction be the RABEPRAZOLE SODIUM of 5%-30%, the diluent of 20%-85%, 1%-5% it is viscous
The disintegrating agent of mixture, the pH adjusting agent of 2%-20% and 3%-30%；The quick-release enteric-coated micro-pill is in the environment that pH is 5.0-6.5
Lower release.
2. RABEPRAZOLE SODIUM spansule as described in claim 1, which is characterized in that first enteric layer is being higher than
It is dissolved under conditions of pH5.5.
3. RABEPRAZOLE SODIUM spansule as described in claim 1, which is characterized in that second enteric layer is being not less than
It is dissolved under conditions of pH7.0.
4. RABEPRAZOLE SODIUM spansule as described in claim 1, which is characterized in that first enteric layer includes the first intestines
Molten material, second enteric layer include the second enteric material, first enteric material and second enteric material difference
Including hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, methacrylic acid copolymer and poly- third
At least one of olefin(e) acid resin.
5. RABEPRAZOLE SODIUM spansule as claimed in claim 4, which is characterized in that first enteric material includes methyl
Acrylic acid-acrylic acetoacetic ester copolymer, methacrylic acid-methyl methacrylate, hydroxypropyl methylcellulose phthalate
Or cellulose acetate phthalate.
6. RABEPRAZOLE SODIUM spansule as claimed in claim 4, which is characterized in that second enteric material includes methyl
Acryl acid-methyl methacrylate copolymer.
7. a kind of preparation method of RABEPRAZOLE SODIUM spansule as claimed in any one of claims 1 to 6, which is characterized in that packet
Include following steps:
First capsule core and the second capsule core are prepared using extrusion spheronization method respectively:
First capsule core is placed in fluidized bed or seed-coating machine, then the first spacer layer coating liquid by spraying, obtains surface cladding
There is the first capsule core of the first separation layer；Second capsule core is placed in fluidized bed or seed-coating machine, then the second separation layer by spraying
Coating solution obtains to surface and is coated with the second capsule core of the second separation layer；
The first capsule core that the surface is coated with the first separation layer is placed in fluidized bed or seed-coating machine, spraying first enteric layer packet
Clothing liquid coats the first enteric layer in first insulation surface and obtains quick-release enteric-coated micro-pill；The surface is coated with second
Second capsule core of separation layer is placed in fluidized bed or seed-coating machine, spraying second enteric layer coating solution, in the second separation layer table
Bread covers the second enteric layer and obtains slowbreak enteric-coated micro-pill；
It is in mass ratio that 1:2-1:5 loading is hollow by quick-release enteric-coated micro-pill and slowbreak enteric-coated micro-pill with RABEPRAZOLE SODIUM content meter
In capsule, RABEPRAZOLE SODIUM spansule is made.
8. the preparation method of RABEPRAZOLE SODIUM spansule as claimed in claim 7, which is characterized in that first capsule core or
Second capsule core the preparation method comprises the following steps:
RABEPRAZOLE SODIUM, diluent, adhesive, pH adjusting agent and disintegrating agent are mixed and made into softwood, the softwood is put into
In pill seed-coating machine, the softwood is squeezed out by sieve plate it is in a strip shape, then it is round as a ball be it is spherical, it is dry and after sieving, obtain institute
State the first capsule core or second capsule core.
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| CN102552159B (en) * | 2010-12-22 | 2013-07-17 | 南京长澳医药科技有限公司 | Rabeprazole sodium enteric-coated micro-pellet and preparation method thereof |
| CN102600109B (en) * | 2012-04-13 | 2014-09-17 | 乐普药业股份有限公司 | Dexlansoprazole sustained release capsule and preparation method thereof |
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