CN105796532A - Rabeprazole sodium sustained-release capsule and preparation method thereof - Google Patents
Rabeprazole sodium sustained-release capsule and preparation method thereof Download PDFInfo
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- CN105796532A CN105796532A CN201610178786.5A CN201610178786A CN105796532A CN 105796532 A CN105796532 A CN 105796532A CN 201610178786 A CN201610178786 A CN 201610178786A CN 105796532 A CN105796532 A CN 105796532A
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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
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Abstract
The invention provides a rabeprazole sodium sustained-release capsule.The capsule comprises an empty capsule, immediate-release enteric-coated pellets and delayed-release enteric-coated pellets, wherein the empty capsule is filled with the immediate-release enteric-coated pellets and the delayed-release enteric-coated pellets.Each immediate-release enteric-coated pellet comprises a first pellet core, a first isolating layer wrapping the surface of the first pellet core and a first enteric-coated layer wrapping the surface of the first isolating layer; each delayed-release enteric-coated pellet comprises a second pellet core, a second isolating layer wrapping the surface of the second pellet core and a second enteric-coated layer wrapping the surface of the second isolating layer.Based on the content of rabeprazole sodium, the mass ratio of the immediate-release enteric-coated pellets to the delayed-release enteric-coated pellets is (1: 2)-(1: 5).The sustained-release capsule comprises the immediate-release rabeprazole sodium enteric-coated pellets and the delayed-release rabeprazole sodium enteric-coated pellets, the sustained-release capsule conducts releasing two times at the different PH environments in the enteric canal, and therefore the problem of nocturnal acid breakthrough and the problem that acid restraining is not complete are solved, and the stability of rabeprazole sodium is improved.The invention further provides a preparation method of the rabeprazole sodium sustained-release capsule.The preparation method is simple.
Description
Technical field
The invention belongs to pharmaceutical preparations technology field, be specifically related to a kind of RABEPRAZOLE SODIUM slow releasing capsule and preparation side thereof
Method.
Background technology
The structural formula of RABEPRAZOLE SODIUM is:
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, mainly use
In gastric ulcer, duodenal ulcer, reflux esophagitis, Zhuo-Emhorn (Zollinger-Ellison) syndrome etc..
Rabeprazole after absorption of human body, its metabolite sulfenamide and H+/K+Cysteine on-ATP enzyme α subunit
Form inactive complex with disulfide-bonded, thus block the common, final of parietal cell gastric acid secretion caused by a variety of causes
Link, has the Acidinhibitor of strength.The rabeprazole product of application is mainly the sodium salt preparation of rabeprazole at present.Lei Beila
Azoles sodium, owing to containing sulfinyl in its structure, degradable under acidity even neutrallty condition, therefore current commercialized product is with intestinal
Solvellae, capsule and injection are main.
RABEPRAZOLE SODIUM nature is unstable, easily decomposes under acidity, high temperature, high humidity and illumination condition, is giving birth to simultaneously
Also degraded variable color is easily there is during producing and storing.Further, can occur during the use of RABEPRAZOLE SODIUM " nocturnal acid dash forward
Broken " phenomenon, i.e. in the case of normal administration, evening 22 when the next day of morning 8 during this period of time in Gastric pH be less than
4.0, and be continued above 1 hour, thus a series of clinical symptoms occurs, hinder the treatment of disease.It is found through experiments, thunder
Shellfish draws azoles sodium unstable in the environment of pH6.8, and indication release under the conditions of higher pH can increase medicine stability.And it is commercially available
And the condition that the rabeprazole sodium enteric-coated preparation of research is almost at pH value more than 5.5 discharges, at low pH even near-neutral pH
Under environment, RABEPRAZOLE SODIUM is unstable, thus the utilization of medicine can produce certain impact.
Summary of the invention
For solving the problems referred to above, the invention provides a kind of RABEPRAZOLE SODIUM slow releasing capsule, this slow releasing capsule includes rapid release
Two kinds of different Rabeprazole sodium enteric-coated micro-pellets of type and slowbreak type so that it is carry out twice releasing under pH environment different in intestinal
Put, thus solve " Control of Nocturnal Gastric Acid Breakthrough " and the halfway problem of acid suppression, also make some drugs in more stable pH condition simultaneously
Lower release, improves the stability of RABEPRAZOLE SODIUM.The present invention also provides for the preparation method of a kind of RABEPRAZOLE SODIUM slow releasing capsule.
First aspect, the invention provides a kind of RABEPRAZOLE SODIUM slow releasing capsule, including Capsules and be filled in institute
Stating the rapid release enteric coated micropill in Capsules and slowbreak enteric coated micropill, described rapid release enteric coated micropill includes the first capsule core, is coated on
First sealing coat on described first capsule core surface and the first enteric layer being coated on described first insulation surface, described slowbreak intestinal
Molten micropill includes the second capsule core, the second sealing coat being coated on described second capsule core surface and is coated on described second sealing coat table
Second enteric layer in face；With RABEPRAZOLE SODIUM content meter, described rapid release enteric coated micropill and the mass ratio of described slowbreak enteric coated micropill
It is 1: 2-1: 5.
Wherein, described first enteric layer dissolves under conditions of higher than pH5.5.
Wherein, described second enteric layer dissolves under conditions of being not less than pH7.0.
Wherein, described first enteric layer includes that the first enteric material, described second enteric layer include the second enteric material, institute
State the first enteric material and described second enteric material includes hydroxypropyl methylcellulose phthalate, cellulose acetate respectively
At least one in phthalic acid ester, methacrylic acid copolymer and polyacrylic acid resin.
Wherein, described first enteric material includes EUDRAGIT L100-55, methacrylic acid-methyl
Acrylic acid methyl ester., hydroxypropyl methylcellulose phthalate or cellulose acetate phthalate.
Wherein, described second enteric material includes EUDRAGIT L100.
Wherein, in described rapid release enteric coated micropill, described first capsule core, described first sealing coat and described first enteric layer
Mass fraction is respectively 45%-80%, 2%-20% and 10%-50%；In described slowbreak enteric coated micropill, described second capsule core,
The mass fraction of described second sealing coat and described second enteric layer is respectively 45%-80%, 2%-20% and 10%-50%.
Wherein, described first capsule core and described second capsule core all include RABEPRAZOLE SODIUM that mass fraction is 5%-30%,
The diluent of 20%-85%, the binding agent of 1%-5%, the pH adjusting agent of 2%-20% and 3%-30% disintegrating agent.
A kind of RABEPRAZOLE SODIUM slow releasing capsule that first aspect present invention provides, this slow releasing capsule includes quick-releasing type and slowbreak
Two kinds of different Rabeprazole sodium enteric-coated micro-pellets of type so that it is carry out twice release under pH environment different in intestinal, thus solve
Certainly " Control of Nocturnal Gastric Acid Breakthrough " and the halfway problem of acid suppression, also makes some drugs discharge under the conditions of more stable pH simultaneously, carries
The stability of high RABEPRAZOLE SODIUM.
Second aspect, the invention provides the preparation method of a kind of RABEPRAZOLE SODIUM slow releasing capsule, comprises the following steps:
Extrusion spheronization method is used to prepare the first capsule core and the second capsule core respectively:
Described first capsule core is placed in fluid bed or seed-coating machine, the first sealing coat coating solution of then spraying, obtains surface
It is coated with the first capsule core of the first sealing coat；Described second capsule core is placed in fluid bed or seed-coating machine, then spraying second every
Absciss layer coating solution, obtaining Surface coating has the second capsule core of the second sealing coat；
The first capsule core that described Surface coating has the first sealing coat is placed in fluid bed or seed-coating machine, the first enteric of spraying
Layer coating solution, is coated with the first enteric layer in described first insulation surface and obtains rapid release enteric coated micropill；Described Surface coating is had
Second capsule core of the second sealing coat is placed in fluid bed or seed-coating machine, the second enteric layer coating solution of spraying, and isolates described second
Layer Surface coating the second enteric layer obtains slowbreak enteric coated micropill；
With RABEPRAZOLE SODIUM content meter, it is 1: 2-1: 5 loadings in mass ratio by rapid release enteric coated micropill and slowbreak enteric coated micropill
In Capsules, prepare RABEPRAZOLE SODIUM slow releasing capsule.
Wherein, the preparation method of described first capsule core or described second capsule core is:
RABEPRAZOLE SODIUM, diluent, binding agent, pH adjusting agent and disintegrating agent are mixed and made into soft material, described soft material is thrown
Enter in pill seed-coating machine, described soft material is extruded in strip by sieve plate, the most round as a ball for spherical, after being dried and sieving,
To described first capsule core or described second capsule core.
The preparation method of a kind of RABEPRAZOLE SODIUM slow releasing capsule that second aspect 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, a kind of RABEPRAZOLE SODIUM slow releasing capsule that first aspect present invention provides includes quick-releasing type and two kinds of slowbreak type not
Same Rabeprazole sodium enteric-coated micro-pellet so that it is carry out twice release under pH environment different in intestinal, thus solve " nocturnal acid
Break through " and the halfway problem of acid suppression, also make some drugs discharge under the conditions of more stable pH simultaneously, improve rabeprazole
The stability of sodium.
2, the preparation method of a kind of RABEPRAZOLE SODIUM slow releasing capsule that second aspect 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.
Accompanying drawing explanation
Fig. 1 is RABEPRAZOLE SODIUM crude drug stability in pH6.8 phosphate buffer；
Fig. 2 is RABEPRAZOLE SODIUM crude drug stability in pH8.0 phosphate buffer；
Fig. 3 is the RABEPRAZOLE SODIUM slow releasing capsule release in pH6.8 phosphate buffer that the embodiment of the present invention prepares
Degree；
Fig. 4 is that the RABEPRAZOLE SODIUM slow releasing capsule that the embodiment of the present invention prepares buffers at pH8.0 trishydroxymethylaminomethane
Release in liquid.
Detailed description of the invention
The following stated is the preferred embodiment of the present invention, it is noted that for those skilled in the art
For, under the premise without departing from the principles of the invention, it is also possible to make some improvements and modifications, these improvements and modifications are also considered as
Protection scope of the present invention.
First aspect, the invention provides a kind of RABEPRAZOLE SODIUM slow releasing capsule, including Capsules and be filled in sky
Rapid release enteric coated micropill in heart-soothing capsule and slowbreak enteric coated micropill, rapid release enteric coated micropill includes the first capsule core, is coated on the first capsule core
First sealing coat on surface and be coated on the first enteric layer of the first insulation surface, slowbreak enteric coated micropill include the second capsule core,
It is coated on second sealing coat 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 rapid release enteric coated micropill and slowbreak enteric coated micropill is 1: 2-1: 5.
In embodiment of the present invention, the mass ratio of rapid release enteric coated micropill and slowbreak enteric coated micropill is 1: 2-1: 5 so that one
Medicine is divided first to discharge in low pH intestinal environment, to play a role rapidly.Remaining major part medicine at higher pH Environment release,
On the one hand be conducive to stablizing of RABEPRAZOLE SODIUM, on the other hand can reach the purpose of sustained drug release, make blood Chinese medicine
Concentration is more steady, it is to avoid " Control of Nocturnal Gastric Acid Breakthrough " and the halfway problem of acid suppression occur.
In embodiment of the present invention, with RABEPRAZOLE SODIUM content meter, rapid release enteric coated micropill and the quality of slowbreak enteric coated micropill
Ratio is 1: 3-1: 4.Under this mass ratio, slow release effect and the medicine stability of RABEPRAZOLE SODIUM slow releasing capsule are preferable.
In embodiment of the present invention, in rapid release enteric coated micropill, the first capsule core, the first sealing coat and the quality of the first enteric layer
Mark is respectively 45%-80%, 2%-20% and 10%-50%.
In embodiment of the present invention, in slowbreak enteric coated micropill, the second capsule core, the second sealing coat and the quality of the second enteric layer
Mark is respectively 45%-80%, 2%-20% and 10%-50%.
In embodiment of the present invention, the first capsule core and the second capsule core all include the rabeprazole that mass fraction is 5%-30%
Sodium, the diluent of 20%-85%, the binding agent 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 the same can also be different, concrete root
It is adjusted according to being actually needed.
In embodiment of the present invention, diluent is in microcrystalline Cellulose, lactose, starch, Powderd cellulose and mannitol
At least one.
In the present invention one preferred implementation, diluent is selected from mannitol and microcrystalline Cellulose.
In embodiment of the present invention, binding agent is fine selected from hypromellose, hydroxypropyl cellulose, polyvidone and carboxymethyl
At least one in dimension element sodium.
In the present invention one preferred implementation, binding agent is selected from hypromellose.
In embodiment of the present invention, pH adjusting agent selected from calcium carbonate, calcium oxide, calcium hydroxide, sodium carbonate, sodium bicarbonate,
At least one in sodium hydroxide, disodium hydrogen phosphate, sodium phosphate and magnesium oxide.
In the present invention one preferred implementation, pH adjusting agent is selected from sodium carbonate.
In embodiment of the present invention, disintegrating agent is received selected from carboxymethyl starch, polyvinylpolypyrrolidone and low substituted hydroxy-propyl fiber
At least one in element.
In the present invention one preferred implementation, disintegrating agent is selected from low-substituted hydroxypropyl cellulose.
In embodiment of the present invention, by regulate pH adjusting agent in the first capsule core and the second capsule core, the kind of disintegrating agent and
Consumption, can realize release position microenvironment pH value and the control of rate of releasing drug.
In embodiment of the present invention, the first capsule core and the second capsule core all use extrusion spheronization method to prepare.
In embodiment of the present invention, the first sealing coat and the second sealing coat all include that hydroxypropyl methylcellulose, hydroxypropyl are fine
At least one in dimension element, Pulvis Talci, titanium dioxide, polyvidone and polyvinylpyrrolidone.
In the present invention one preferred implementation, the first sealing coat and the second sealing coat can all select Opadry
295K690000。
In the present invention one preferred implementation, the composition of the first sealing coat and the second sealing coat can identical can not also
With, it is adjusted with specific reference to being actually needed.
In embodiment of the present invention, the first enteric layer of rapid release enteric coated micropill dissolves under conditions of higher than pH5.5.
In embodiment of the present invention, the release position of rapid release enteric coated micropill is at duodenum and small intestinal leading portion, herein environment
PH is about 5-6.5.
In embodiment of the present invention, the second enteric layer of slowbreak enteric coated micropill dissolves under conditions of being not less than pH7.0.
In embodiment of the present invention, the release position of slowbreak enteric coated micropill at small intestinal 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 at pH 6.8 environment, but
RABEPRAZOLE SODIUM is the most unstable with this understanding, so the pH of the release environment of RABEPRAZOLE SODIUM is set to 2 by the present invention,
It is respectively and dissolves higher than under conditions of dissolving under conditions of pH5.5 and being not less than pH7.0, make some drugs at more stable pH
Under the conditions of discharge, thus be favorably improved the stability of RABEPRAZOLE SODIUM slow releasing capsule.
In embodiment of the present invention, the first enteric layer includes that the first enteric material, the first enteric material include hydroxypropyl
In cellulose phthalate, cellulose acetate phthalate, methacrylic acid copolymer and polyacrylic acid resin
At least one.
In the present invention one preferred implementation, the first enteric material includes EUDRAGIT L100-55, first
Base acrylic acid-methacrylic acid methyl ester, hydroxypropyl methylcellulose phthalate or cellulose acetate phthalate.
In the present invention one preferred implementation, 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).
In the present invention one preferred implementation, it is divided into three model: HP-50 according to the degree of polymerization and phthalate ester content HPMCP,
HP-55 and HP-55s, wherein HP-50 dissolves in pH >=5.0, HP-55 and HP-55s dissolves in pH >=5.5.
In the present invention one preferred implementation, the first enteric material is especially strange L30D-55, Eudragit L100-55, especially
At least one in strange L-100, Opadry enteric 94 series, polyacrylic resin II, HP-50, HP-55 and HP-55s.
In embodiment of the present invention, the first enteric layer also includes antitackiness agent, plasticizer and opacifier.
In embodiment of the present invention, the second enteric layer includes that the second enteric material, the second enteric material include hydroxypropyl
In cellulose phthalate, cellulose acetate phthalate, methacrylic acid copolymer and polyacrylic acid resin
At least one.
In the present invention one preferred implementation, the second enteric material includes methacrylic acid-methyl methacrylate copolymer
Thing.
In the present invention one preferred implementation, the second enteric material includes methacrylic acid-methyl methacrylate copolymer
Thing (1: 2) or EUDRAGIT L100 (35: 65).
In the present invention one preferred implementation, the second enteric material is especially strange S100, Opadry enteric 95 series or poly-
Acrylic resin III.
In embodiment of the present invention, the second enteric layer also includes antitackiness agent, plasticizer and opacifier.
In embodiment of the present invention, antitackiness agent is in Pulvis Talci, glyceryl monostearate, magnesium stearate and silicon dioxide
At least one.
In the present invention one preferred implementation, antitackiness agent is selected from Pulvis Talci.
In embodiment of the present invention, plasticizer is selected from triethyl citrate, Polyethylene Glycol, Oleum Ricini, phthalic acid two
At least one in ethyl ester, triethylglycerides and acetyl triethyl citrate.
In the present invention one preferred implementation, plasticizer is selected from triethyl citrate.
In embodiment of the present invention, at least one in titanium dioxide and ferrum oxide of opacifier.
In the present invention one preferred implementation, opacifier is selected from titanium dioxide.
In embodiment of the present invention, in the first enteric layer and the second enteric layer, the content of each component is recipe quantity.
A kind of RABEPRAZOLE SODIUM slow releasing capsule that embodiment of the present invention first aspect provides, this slow releasing capsule includes quick-releasing type
With two kinds of different Rabeprazole sodium enteric-coated micro-pellets of slowbreak type so that it is carry out twice release under pH environment different in intestinal,
Thus solve " Control of Nocturnal Gastric Acid Breakthrough " and the halfway problem of acid suppression, also make some drugs release under the conditions of more stable pH simultaneously
Put, improve the stability of RABEPRAZOLE SODIUM.
Second aspect, the invention provides the preparation method of a kind of RABEPRAZOLE SODIUM slow releasing capsule, comprises the following steps:
Extrusion spheronization method is used to prepare the first capsule core and the second capsule core respectively:
First capsule core is placed in fluid bed or seed-coating machine, the first sealing coat coating solution of then spraying, obtains Surface coating
There is the first capsule core of the first sealing coat；Second capsule core is placed in fluid bed or seed-coating machine, the second sealing coat coating of then spraying
Liquid, obtaining Surface coating has the second capsule core of the second sealing coat；
The first capsule core that Surface coating has the first sealing coat is placed in fluid bed or seed-coating machine, the first enteric layer bag of spraying
Clothing liquid, is coated with the first enteric layer in the first insulation surface and obtains rapid release enteric coated micropill；Surface coating is had the second sealing coat
Second capsule core is placed in fluid bed or seed-coating machine, the second enteric layer coating solution of spraying, and is coated with the second intestinal in the second insulation surface
Soluble layer obtains slowbreak enteric coated micropill；
With RABEPRAZOLE SODIUM content meter, it is 1: 2-1: 5 loadings in mass ratio by rapid release enteric coated micropill and slowbreak enteric coated micropill
In Capsules, prepare RABEPRAZOLE SODIUM slow releasing capsule.
In embodiment of the present invention, the preparation method of the first capsule core or the second capsule core is:
RABEPRAZOLE SODIUM, diluent, binding agent, pH adjusting agent and disintegrating agent are mixed and made into soft material, soft material is put into
In pill seed-coating machine, soft material is extruded in strip by sieve plate, the most round as a ball for spherical, after being dried and sieving, obtain the first ball
Core or the second capsule core.
In embodiment of the present invention, the quality of RABEPRAZOLE SODIUM, diluent, binding agent, pH adjusting agent and disintegrating agent is normal
Recipe quantity.
In the present invention one preferred implementation, the matter of RABEPRAZOLE SODIUM, diluent, binding agent, pH adjusting agent and disintegrating agent
Amount ratio is thunder 5-30: 20-85: 1-5: 2-20: 3-30.
In the present invention one preferred implementation, first at the round as a ball 1min of 1600r/min, then at the round as a ball 3min of 1000r/min.
In embodiment of the present invention, the second capsule core can be identical with the preparation method of the first capsule core.
Traditional celphere medicine-feeding, drug loading is the highest, i.e. enables the drug loading reaching the biggest, but also can there is consumption
Time, the problem of power consumption, general coating is all even more long at 2h, and there is liquid waste and loss.The present invention is rolled by extrusion
Circule method prepares the first capsule core and the first capsule core, improves preparation efficiency and the drug loading of micropill, preparation sodium rabeprazole enteric-coated
Micropill content is more controllable, and general about the 10min of extrusion spheronization can complete, and the most just can be put in baking oven and be dried, loss
Less 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, Powderd cellulose and mannitol
At least one.
In the present invention one preferred implementation, diluent is selected from mannitol and microcrystalline Cellulose.
In embodiment of the present invention, binding agent is fine selected from hypromellose, hydroxypropyl cellulose, polyvidone and carboxymethyl
At least one in dimension element sodium.
In the present invention one preferred implementation, binding agent is selected from hypromellose.
In embodiment of the present invention, pH adjusting agent selected from calcium carbonate, calcium oxide, calcium hydroxide, sodium carbonate, sodium bicarbonate,
At least one in sodium hydroxide, disodium hydrogen phosphate, sodium phosphate and magnesium oxide.
In the present invention one preferred implementation, pH adjusting agent is selected from sodium carbonate.
In embodiment of the present invention, disintegrating agent is received selected from carboxymethyl starch, polyvinylpolypyrrolidone and low substituted hydroxy-propyl fiber
At least one in element.
In the present invention one preferred implementation, disintegrating agent is selected from low-substituted hydroxypropyl cellulose.
In embodiment of the present invention, Surface coating has the preparation method of the first capsule core of the first sealing coat to be: take first every
Layer material, adds solvent and is configured to the first sealing coat coating solution, then the first capsule core be placed in fluid bed or seed-coating machine, spray
Mist the first sealing coat coating solution, at the first capsule core Surface coating sealing coat, after being dried screening, obtaining Surface coating has the first isolation
First capsule core of layer.
In embodiment of the present invention, the first sealing coat and the second sealing coat all include that hydroxypropyl methylcellulose, hydroxypropyl are fine
At least one in dimension element, Pulvis Talci, titanium dioxide, polyvidone and polyvinylpyrrolidone.
In the present invention one preferred implementation, the first sealing coat and the second sealing coat can all select Opadry
295K690000。
In embodiment of the present invention, solvent is at least one in dehydrated alcohol and water.
In embodiment of the present invention, Surface coating has the preparation method of the second capsule core of the second sealing coat and Surface coating to have
The preparation method of the first capsule core of the first sealing coat can be identical.
In the present invention one preferred implementation, when being coated with the first sealing coat or the second sealing coat, seed-coating machine or fluid bed
Operating condition is: round as a ball rotating speed is 100-150r/min, and air intake rotating speed is 1000-1200r/min, and air-out rotating speed is 1000-
1200r/min, inlet temperature is 41-43 DEG C, and atomizing pressure is 0.10-0.14MPa, and coating solution flow velocity is 3-5g/min.Specifically
Operating condition can as the case may be depending on, as the difference according to equipment is adjusted.
In embodiment of the present invention, the first insulation surface be coated with the first enteric layer method particularly as follows:
First enteric material of recipe quantity, antitackiness agent, plasticizer and opacifier are added in solvent and makes the first enteric layer
Coating solution, then has the first capsule core of the first sealing coat to be placed in fluid bed or seed-coating machine, the first enteric of spraying by Surface coating
Layer coating solution, is coated with the first enteric layer in the first insulation surface, after being dried screening, obtains rapid release enteric coated micropill.
In embodiment of the present invention, it is coated with the method for the second enteric layer and at the first sealing coat table in the second insulation surface
Bread covers the method for the first enteric layer can be identical.
In the present invention one preferred implementation, when being coated with the first enteric layer or the second enteric layer, seed-coating machine or fluid bed
Operating condition is: round as a ball rotating speed is 100-150r/min, and air intake rotating speed is 800-1200r/min, and air-out rotating speed is 800-
1200r/min, inlet temperature is 42-45 DEG C, and atomizing pressure is 0.10-0.14MPa, and coating solution flow velocity is 2-5g/min.Specifically
Operating condition can as the case may be depending on as being adjusted according to the difference of equipment.
In embodiment of the present invention, the first enteric layer of rapid release enteric coated micropill dissolves under conditions of higher than pH5.5.
In embodiment of the present invention, the release position of rapid release enteric coated micropill is at duodenum and small intestinal leading portion, herein environment
PH is about 5-6.5.
In embodiment of the present invention, the second enteric layer of slowbreak enteric coated micropill dissolves under conditions of being not less than pH7.0.
In embodiment of the present invention, the release position of slowbreak enteric coated micropill at small intestinal posterior segment and colon portion, ring herein
Border pH is about 6.5-8.
In the present invention one preferred implementation, the first enteric material includes EUDRAGIT L100-55, first
Base acrylic acid-methacrylic acid methyl ester, hydroxypropyl methylcellulose phthalate or cellulose acetate phthalate.
In the present invention one preferred implementation, the first enteric material include EUDRAGIT L100-55 (1:
1), methacrylic acid-methyl methacrylate (1: 1), hydroxypropyl methylcellulose phthalate, cellulose acetate neighbour's benzene two
Formic acid esters (HPMCP).
In the present invention one preferred implementation, it is divided into three model: HP-50 according to the degree of polymerization and phthalate ester content HPMCP,
HP-55 and HP-55s, wherein HP-50 dissolves in pH >=5.0, HP-55 and HP-55s dissolves in pH >=5.5.
In the present invention one preferred implementation, the first enteric material is especially strange L30D-55, Eudragit L100-55, especially
At least one in strange L-100, Opadry enteric 94 series, polyacrylic resin II, HP-50, HP-55 and HP-55s..
In embodiment of the present invention, the first enteric layer also includes antitackiness agent, plasticizer and opacifier.
In embodiment of the present invention, the second enteric layer includes that the second enteric material, the second enteric material include hydroxypropyl
In cellulose phthalate, cellulose acetate phthalate, methacrylic acid copolymer and polyacrylic acid resin
At least one.
In the present invention one preferred implementation, the second enteric material includes methacrylic acid-methyl methacrylate copolymer
Thing.
In the present invention one preferred implementation, the second enteric material includes methacrylic acid-methyl methacrylate copolymer
Thing (1: 2) or EUDRAGIT L100 (35: 65).
In the present invention one preferred implementation, the second enteric material is especially strange S100, Opadry enteric 95 series or poly-
Acrylic resin III.
In embodiment of the present invention, the second enteric layer also includes antitackiness agent, plasticizer and opacifier.
In embodiment of the present invention, antitackiness agent is in Pulvis Talci, glyceryl monostearate, magnesium stearate and silicon dioxide
At least one.
In the present invention one preferred implementation, antitackiness agent is selected from Pulvis Talci.
In embodiment of the present invention, plasticizer is selected from triethyl citrate, Polyethylene Glycol, Oleum Ricini, phthalic acid two
At least one in ethyl ester, triethylglycerides and acetyl triethyl citrate.
In the present invention one preferred implementation, plasticizer is selected from triethyl citrate.
In embodiment of the present invention, at least one in titanium dioxide and ferrum oxide of opacifier.
In the present invention one preferred implementation, opacifier is selected from titanium dioxide.
In the present invention one preferred implementation, solvent is at least one in water and dehydrated alcohol.
In embodiment of the present invention, in the first enteric layer and the second enteric layer, the content of each component is recipe quantity.
In embodiment of the present invention, with RABEPRAZOLE SODIUM content meter, rapid release enteric coated micropill and the quality of slowbreak enteric coated micropill
Ratio is 1: 3-1: 4.Under this mass ratio, the slow release effect of RABEPRAZOLE SODIUM slow releasing capsule is preferable.
The preparation method of a kind of RABEPRAZOLE SODIUM slow releasing capsule that embodiment of the present invention second aspect 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 slow releasing capsule, including Capsules and the rapid release enteric coated micropill that is filled in Capsules
With slowbreak enteric coated micropill, rapid release enteric coated micropill includes the first capsule core, the first sealing coat being coated on the first capsule core surface and cladding
In the first enteric layer of the first insulation surface, slowbreak enteric coated micropill includes the second capsule core, is coated on the of the second capsule core surface
Two sealing coats and the second enteric layer being coated on the second insulation surface；Shown in the composition table specific as follows 1 of rapid release enteric coated micropill,
The composition of slowbreak enteric coated micropill is specifically by shown in table 2 below；Wherein the water in form, the amount of dehydrated alcohol equal solvent refer to preparation
The amount of front addition, in preparation process or after preparation, solvent can volatilize or evaporate, it is interior that this is that this area skill personnel may be appreciated
Hold, do not repeat them here.
Table 1
Table 2
The preparation method of a kind of RABEPRAZOLE SODIUM slow releasing capsule, comprises the following steps:
1, rapid release enteric coated micropill is prepared
(1) every supplementary material is weighed respectively by the recipe quantity of table 1, under conditions of indoor relative humidity (RH) is less than 70%
Mixing is sieved, add afterwards 70g binding agent (binding agent be mass fraction be the second of the hypromellose (HPMC E5) of 5%
Alcohol-water (35: 65, w/w) solution, wherein the quality of hypromellose is 3.5g), put into multi-functional pill bag after making soft material
In clothing machine, cooling water circulation under the conditions of 30r/min extrusion (aperture is 1.0mm), the round as a ball 1min of 1600r/min, 1000r/min roll
Circle 3min, is dried 2h, air intake rotating speed 600r/min, air-out rotating speed 600r/min afterwards under the conditions of 40 DEG C, screens 20 mesh-24 mesh
Micropill, obtains the first capsule core containing RABEPRAZOLE SODIUM.
(2) dissolving of recipe quantity Opadry stomach dissolution type coating material being dispersed in dehydrated alcohol, add water afterwards, mixing is all
Even sieving i.e. obtains the first sealing coat coating solution.
First capsule core obtained above being put in multi-functional pill seed-coating machine, round as a ball rotating speed 150r/min, air intake turns
Speed 1200r/min, air-out rotating speed 1200r/min, inlet temperature 41-43 DEG C, atomizing pressure 0.14MPa, regulate peristaltic pump rotating speed,
First sealing coat coating solution flow velocity is about 3g/min, side spray bag under conditions of the first sealing coat coating solution is persistently slowly stirred
Clothing, 40 DEG C of air intakes are dried 10min afterwards, screen 20 mesh-24 mesh micropills, and obtaining Surface coating has the first ball of the first sealing coat
Core.
(3) the especially strange L30D-55 of recipe quantity is joined in part water, prepares the suspension of especially strange L 30D-55,
The triethyl citrate and the Pulvis Talci that separately take recipe quantity join in residue water, join especially strange L after high speed shear 10min
In the suspension of 30D-55, sieve after stirring 30min, obtain the first enteric layer coating solution.
(4) Surface coating obtained above have the first capsule core of the first sealing coat put into multi-functional pill seed-coating machine
In, round as a ball rotating speed 150r/min, air intake rotating speed 800r/min, air-out rotating speed 800r/min, inlet temperature 42-45 DEG C, atomization pressure
Power 0.12MPa, regulates peristaltic pump rotating speed, and the first enteric layer coating solution flow velocity is about 2.6g/min, the most slowly stirs at coating solution
Side spray coating under conditions of mixing, is coated with the first enteric layer in the first insulation surface, and 40 DEG C of air intakes are dried 10min afterwards, screening
20 mesh-24 mesh micropills, obtain RABEPRAZOLE SODIUM quick-releasing type enteric coated micropill.
2, slowbreak enteric coated micropill is prepared
(1) every supplementary material is weighed respectively by the recipe quantity of above-mentioned table 2, at the indoor relative humidity (RH) bar less than 70%
Under part, mixing is sieved, and (mass fraction is that the alcohol-water (35: 65, w/w) of 5%HPMC E5 is molten to add the binding agent of 70g afterwards
Liquid), put in multi-functional pill seed-coating machine after making soft material, cooling water circulation under the conditions of 30r/min extrusion (aperture is
1.0mm), the round as a ball 3min of the round as a ball 1min of 1600r/min, 1000r/min, under the conditions of 40 DEG C, it is dried 2h, air intake rotating speed afterwards
600r/min, air-out rotating speed 600r/min, screen 20 mesh-24 mesh micropills, obtain the second capsule core containing RABEPRAZOLE SODIUM.
(2) dissolving of recipe quantity Opadry stomach dissolution type coating material being dispersed in dehydrated alcohol, add water afterwards, mixing is all
Even sieving i.e. obtains the second sealing coat coating solution.
Pastille the second capsule core obtained above is put in multi-functional pill seed-coating machine, round as a ball rotating speed 150r/min, enters
Wind rotating speed 1200r/min, air-out rotating speed 1200r/min, inlet temperature 41-43 DEG C, atomizing pressure 0.14MPa, regulate peristaltic pump
Rotating speed, the second sealing coat coating solution flow velocity is about 3g/min, side under conditions of the second sealing coat coating solution is persistently slowly stirred
Spray coating, 40 DEG C of air intakes are dried 10min afterwards, screen 20 mesh-24 mesh micropills, and obtaining Surface coating has the second of the second sealing coat
Capsule core.
(3) the especially strange S100 of recipe quantity is joined in part water, adds triethyl citrate afterwards, stir,
Preparing the suspension of especially strange S100, the Pulvis Talci and the titanium dioxide that separately take recipe quantity join in residue water, high speed shear
Join in the suspension of especially strange S100 after 10min, sieve after stirring 45min, obtain the second enteric layer coating solution.
(4) Surface coating obtained above have the second capsule core of the second sealing coat put into multi-functional pill seed-coating machine
In, round as a ball rotating speed 150r/min, air intake rotating speed 800r/min, air-out rotating speed 800r/min, inlet temperature 42～45 DEG C, atomization pressure
Power 0.12MPa, regulates peristaltic pump rotating speed, and the second enteric layer coating solution flow velocity is about 2.6g/min, at the second enteric layer coating solution
Side spray coating under conditions of being persistently slowly stirred, 40 DEG C of air intakes are dried 10min afterwards, screen 20 mesh-24 mesh micropills, obtain thunder shellfish
Draw azoles sodium slowbreak type enteric coated micropill.
3, preparation RABEPRAZOLE SODIUM slow releasing capsule
Quick-releasing type and slowbreak type Rabeprazole sodium enteric-coated micro-pellet are loaded in the ratio of 1: 3 (with RABEPRAZOLE SODIUM content meter)
In Capsules, obtain RABEPRAZOLE SODIUM slow releasing capsule.
Embodiment 2
A kind of RABEPRAZOLE SODIUM slow releasing capsule, including Capsules and the rapid release enteric coated micropill that is filled in Capsules
With slowbreak enteric coated micropill, rapid release enteric coated micropill includes the first capsule core, the first sealing coat being coated on the first capsule core surface and cladding
In the first enteric layer of the first insulation surface, slowbreak enteric coated micropill includes the second capsule core, is coated on the of the second capsule core surface
Two sealing coats and the second enteric layer being coated on the second insulation surface；The composition of rapid release enteric coated micropill is as shown in table 3 below, slowbreak
The composition of enteric coated micropill is by shown in table 4 below；
Table 3
Table 4
The preparation method of a kind of RABEPRAZOLE SODIUM slow releasing capsule, comprises the following steps:
1, rapid release enteric coated micropill is prepared
(1) every supplementary material is weighed respectively by the recipe quantity of above-mentioned table 3, at the indoor relative humidity (RH) bar less than 70%
Under part, mixing is sieved, and (mass fraction is that the alcohol-water (35: 65, w/w) of 5%HPMC E5 is molten to add the binding agent of 70g afterwards
Liquid), put in multi-functional pill seed-coating machine after making soft material, cooling water circulation under the conditions of 30r/min extrusion (aperture is
1.0mm), the round as a ball 3min of the round as a ball 1min of 1600r/min, 1000r/min, under the conditions of 40 DEG C, it is dried 2h, air intake rotating speed afterwards
600r/min, air-out rotating speed 600r/min, screen 20 mesh-24 mesh micropills, obtain the first capsule core containing RABEPRAZOLE SODIUM.
(2) dissolving of recipe quantity Opadry stomach dissolution type coating material being dispersed in dehydrated alcohol, add water afterwards, mixing is all
Even sieving i.e. obtains the first sealing coat coating solution.
Pastille the first capsule core obtained above is put in multi-functional pill seed-coating machine, round as a ball rotating speed 150r/min, enters
Wind rotating speed 1200r/min, air-out rotating speed 1200r/min, inlet temperature 41-43 DEG C, atomizing pressure 0.14MPa, regulate peristaltic pump
Rotating speed, the first sealing coat coating solution flow velocity is about 3g/min, side under conditions of the first sealing coat coating solution is persistently slowly stirred
Spray coating, 40 DEG C of air intakes are dried 10min afterwards, screen 20 mesh-24 mesh micropills, and obtaining Surface coating has the first of the first sealing coat
Capsule core.
(3) the especially strange L 30D-55 of recipe quantity is joined in part water, prepares the suspension of especially strange L 30D-55,
The triethyl citrate and the Pulvis Talci that separately take recipe quantity join in residue water, join especially strange L after high speed shear 10min
In the suspension of 30D-55, sieve after stirring 30min, obtain the first enteric layer coating solution.
The first capsule core that Surface coating obtained above has the first sealing coat is put in multi-functional pill seed-coating machine, rolling
Circle rotating speed 150r/min, air intake rotating speed 800r/min, air-out rotating speed 800r/min, inlet temperature 42～45 DEG C, atomizing pressure
0.12MPa, regulates peristaltic pump rotating speed, and the first enteric layer coating solution flow velocity is about 2.6g/min, holds at the first enteric layer coating solution
Continuing side spray coating under conditions of being slowly stirred, be coated with the first enteric layer in the first insulation surface, 40 DEG C of air intakes are dried afterwards
10min, screens 20 mesh-24 mesh micropills, obtains RABEPRAZOLE SODIUM quick-releasing type enteric coated micropill.
2, slowbreak enteric coated micropill is prepared
(1) every supplementary material is weighed respectively by above-mentioned table 4 recipe quantity, in the indoor relative humidity (RH) condition less than 70%
Lower mixing is sieved, and adds binding agent alcohol-water (35: 65, the w/w) solution of 5%HPMC E5 (mass fraction be) of 70g afterwards,
Put in multi-functional pill seed-coating machine after making soft material, cooling water circulation under the conditions of 30r/min extrusion (aperture is 1.0mm),
The round as a ball 3min of the round as a ball 1min of 1600r/min, 1000r/min, is dried 2h, air intake rotating speed 600r/min afterwards under the conditions of 40 DEG C,
Air-out rotating speed 600r/min, screens 20 mesh-24 mesh micropills, obtains the second capsule core containing RABEPRAZOLE SODIUM.
(2) dissolving of recipe quantity Opadry stomach dissolution type coating material being dispersed in dehydrated alcohol, add water afterwards, mixing is all
Even sieving i.e. obtains the second sealing coat coating solution.
Second capsule core obtained above being put in multi-functional pill seed-coating machine, round as a ball rotating speed 150r/min, air intake turns
Speed 1200r/min, air-out rotating speed 1200r/min, inlet temperature 41-43 DEG C, atomizing pressure 0.14MPa, regulate peristaltic pump rotating speed,
Coating solution flow velocity is about 3g/min, side spray coating under conditions of the second sealing coat coating solution is persistently slowly stirred, 40 DEG C afterwards
Air intake is dried 10min, screens 20 mesh-24 mesh micropills, and obtaining Surface coating has the second capsule core of the second sealing coat.
(3) the especially strange S100 of recipe quantity is joined in part water, adds triethyl citrate afterwards, stir,
Preparing the suspension of especially strange S100, the Pulvis Talci and the titanium dioxide that separately take recipe quantity join in residue water, high speed shear
Join in the suspension of especially strange S100 after 10min, sieve after stirring 45min, obtain the second enteric layer coating solution.
The second capsule core that Surface coating obtained above has the second sealing coat is put in multi-functional pill seed-coating machine, rolling
Circle rotating speed 150r/min, air intake rotating speed 800r/min, air-out rotating speed 800r/min, inlet temperature 42-45 DEG C, atomizing pressure
0.12MPa, regulates peristaltic pump rotating speed, and coating solution flow velocity is about 2.6g/min, side under conditions of coating solution is persistently slowly stirred
Spray coating, is coated with the first enteric layer in the first insulation surface, and 40 DEG C of air intakes are dried 10min afterwards, screen 20 mesh-24 mesh micro-
Ball, obtains RABEPRAZOLE SODIUM slowbreak type enteric coated micropill.
3, preparation RABEPRAZOLE SODIUM slow releasing capsule
Quick-releasing type and slowbreak type Rabeprazole sodium enteric-coated micro-pellet are loaded in the ratio of 1: 3 (with RABEPRAZOLE SODIUM content meter)
In Capsules, obtain RABEPRAZOLE SODIUM slow releasing capsule.
Embodiment 3
The preparation method of a kind of RABEPRAZOLE SODIUM slow releasing capsule, comprises the following steps:
Step 1 is identical with embodiment 1 with step 2；
3, preparation RABEPRAZOLE SODIUM slow releasing capsule
Quick-releasing type and slowbreak type Rabeprazole sodium enteric-coated micro-pellet are loaded in the ratio of 1: 4 (with RABEPRAZOLE SODIUM content meter)
In Capsules, obtain RABEPRAZOLE SODIUM slow releasing capsule.
Embodiment 4
The preparation method of a kind of RABEPRAZOLE SODIUM slow releasing capsule, comprises the following steps:
Step 1 is identical with embodiment 2 with step 2；
3, preparation RABEPRAZOLE SODIUM slow releasing capsule
Quick-releasing type and slowbreak type Rabeprazole sodium enteric-coated micro-pellet are loaded in the ratio of 1: 2 (with RABEPRAZOLE SODIUM content meter)
In Capsules, obtain RABEPRAZOLE SODIUM slow releasing capsule.
Embodiment 5
The preparation method of a kind of RABEPRAZOLE SODIUM slow releasing capsule, comprises the following steps:
Step 1 is identical with embodiment 2 with step 2；
3, preparation RABEPRAZOLE SODIUM slow releasing capsule
Quick-releasing type and slowbreak type Rabeprazole sodium enteric-coated micro-pellet are loaded in the ratio of 1: 5 (with RABEPRAZOLE SODIUM content meter)
In Capsules, obtain RABEPRAZOLE SODIUM slow releasing capsule.
Embodiment 6
The preparation method of a kind of RABEPRAZOLE SODIUM slow releasing capsule, comprises the following steps:
In addition to the composition and embodiment 1 difference of the first enteric layer, other are all identical with embodiment 1.
The composition of the present embodiment the first enteric layer is as shown in table 5 below, and the preparation method of the first enteric layer coating solution is:
The especially strange L100 of recipe quantity is joined in part dehydrated alcohol, prepares the solution of especially strange L100, separately take place
Triethyl citrate and the Pulvis Talci of side's amount join in residue water and dehydrated alcohol, join especially after high speed shear 10min
In the solution of strange L 100, sieve after stirring 30min, obtain the first enteric layer coating solution.
Table 5
Embodiment 7
The preparation method of a kind of RABEPRAZOLE SODIUM slow releasing capsule, comprises the following steps:
In addition to the composition and embodiment 1 difference of the first enteric layer, other are all identical with embodiment 1.
The composition of the present embodiment the first enteric layer is as shown in table 6 below, and the preparation method of the first enteric layer coating solution is:
The polyacrylic acid resin II of recipe quantity is joined in part dehydrated alcohol, prepares polyacrylic acid resin II
Solution, the triethyl citrate and the Pulvis Talci that separately take recipe quantity join in residue water and dehydrated alcohol, after high speed shear 10min
Join in the solution of polyacrylic acid resin II, sieve after stirring 30min, obtain the first enteric layer coating solution.
Table 6
Embodiment 8
The preparation method of a kind of RABEPRAZOLE SODIUM slow releasing capsule, comprises the following steps:
In addition to the composition and embodiment 1 difference of the first enteric layer, other are all identical with embodiment 1.
The composition of the present embodiment the first enteric layer is as shown in table 7 below, and the preparation method of the first enteric layer coating solution is:
The Hydroxypropyl methyl cellulose phtalate of recipe quantity is joined in part dehydrated alcohol, prepare hypromellose
Element phthalic acid ester solution, separately take the triethyl citrate of recipe quantity, Pulvis Talci and titanium dioxide join residue water and
In dehydrated alcohol, join in the solution of Hydroxypropyl methyl cellulose phtalate after high speed shear 10min, after stirring 30min
Sieve, obtain the first enteric layer coating solution.
Table 7
Embodiment 9
The preparation method of a kind of RABEPRAZOLE SODIUM slow releasing capsule, comprises the following steps:
In addition to the composition and embodiment 1 difference of the second enteric layer, other are all identical with embodiment 1.
The composition of the present embodiment the second enteric layer is as shown in table 8 below, and the preparation method of the second enteric layer coating solution is:
The polyacrylic acid resin III of recipe quantity is joined in part dehydrated alcohol, prepares polyacrylic acid resin III
Solution, separately take the triethyl citrate of recipe quantity and Pulvis Talci join in residue water and dehydrated alcohol, high speed shear 10min
After join in the solution of polyacrylic acid resin III, sieve after stirring 30min, obtain the second enteric layer coating solution.
Table 8
Embodiment 10
RABEPRAZOLE SODIUM slow releasing capsule 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) measure, the RABEPRAZOLE SODIUM slow releasing capsule weighing Example 1 and Example 2 of the present invention respectively prepared (contains altogether
Have RABEPRAZOLE SODIUM about 100mg), with 0.1mol/L hydrochloric acid solution 750ml as dissolution medium, temperature is 37 DEG C, and rotating speed is 100r/
After min, 120min, in process container, add the 0.2mol/L sodium radio-phosphate,P-32 solution 250ml of 37 DEG C immediately, molten with 2mol/L hydrochloric acid
Liquid or 2mol/L sodium hydroxide solution regulation pH value are to 6.8, and temperature rotating speed is constant, respectively 5,10,15,30,45,60,90,
120,150,180,210,240, after 270min, take solution and filter through 0.45 μm filter membrane, precision measures filtrate 3ml, joins and contains
Have in the cillin bottle of 0.5mol/L sodium hydroxide solution of 1ml, shake up, as need testing solution after filtration；Another accurate title thunder shellfish
Drawing azoles sodium raw materials medicine 25mg, put in 25ml volumetric flask, be diluted to scale with 0.5mol/L sodium hydroxide solution, precision measures afterwards
3mL puts in 10mL volumetric flask, and 0.5mol/L sodium hydroxide solution is diluted to scale, and precision measures 1ml, adds phosphate buffer
(0.1mol/L hydrochloric acid solution 750ml adds 0.2mol/L sodium radio-phosphate,P-32 solution 250ml, with 2mol/L hydrochloric acid solution or 2mol/L hydrogen
Sodium hydroxide solution regulation pH value is to 6.8) 3ml, filter after shaking up, as reference substance solution.
Test sample and reference substance solution are measured rabeprazole sodium content by external standard method by efficient liquid phase, chromatographic condition:
Chromatographic column Diamonsil C18Chromatographic column (4.6mm × 200mm, 5 μm)；Flowing phase 0.015mol/L disodium hydrogen phosphate (adjust by phosphoric acid
Joint pH to 6.0)-acetonitrile (65: 35)；Detection wavelength 290nm；Column temperature 30 DEG C；Sample size 10 μ L, auto injection.Then calculate not
Release with 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) measure, the RABEPRAZOLE SODIUM slow releasing capsule weighing Example 1 and Example 2 of the present invention respectively prepared (contains altogether
Have RABEPRAZOLE SODIUM about 100mg), with 0.1mol/L hydrochloric acid solution 700ml as dissolution medium, temperature is 37 DEG C, and rotating speed is 100r/
After min, 120min, in process container, add the 0.6mol/L tris solution 300ml of 37 DEG C immediately, use
2mol/L hydrochloric acid solution or 2mol/L sodium hydroxide solution regulation pH value are to 8.0, and temperature rotating speed is constant, respectively 5,10,15,
30,45,60,90, after 120min, take solution and filter through 0.45 μm filter membrane, precision measures filtrate 3ml, joins containing 1ml's
In the cillin bottle of 0.5mol/L sodium hydroxide solution, shake up, as need testing solution after filtration；Another accurate title RABEPRAZOLE SODIUM is former
Material medicine 25mg, puts in 25ml volumetric flask, is diluted to scale with 0.5mol/L sodium hydroxide solution, and precision measures 3mL and puts afterwards
In 10mL volumetric flask, 0.5mol/L sodium hydroxide solution is diluted to scale, and precision measures 1ml, adds trishydroxymethylaminomethane
Buffer (adds 0.6mol/L tris solution 300ml, uses 2mol/L salt in 0.1mol/L hydrochloric acid solution 700ml
Acid solution or 2mol/L sodium hydroxide solution regulation pH value are to 8.0) 3ml, filter after shaking up, as reference substance solution.
Test sample and reference substance solution are measured rabeprazole sodium content by external standard method by efficient liquid phase, chromatographic condition:
Chromatographic column Diamonsil C18Chromatographic column (4.6mm × 200mm, 5 μm)；Flowing phase 0.015mol/L disodium hydrogen phosphate (adjust by phosphoric acid
Joint pH to 6.0)-acetonitrile (65: 35)；Detection wavelength 290nm；Column temperature 30 DEG C；Sample size 10 μ L, auto injection.Then calculate not
Release with time RABEPRAZOLE SODIUM.Test result is as shown in Figure 3 and Figure 4.
RABEPRAZOLE SODIUM crude drug is crossed 100 mesh sieves, respectively weighs 100mg, put into the pH6.8 phosphoric acid being preheated to 37 DEG C 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, regulates pH to 6.8 with 2mol/L hydrochloric acid or 2mol/L sodium hydroxide) and pH8.0 phosphate buffer in (take phosphoric acid hydrogen
Dipotassium 5.59g and potassium dihydrogen phosphate 0.41g, adds water and makes to be dissolved into 1000ml, adjusts with 2mol/L hydrochloric acid or 2mol/L sodium hydroxide
Joint pH to 8.0), respectively 5,10,20,30,45,60min, take solution and filter through 0.45 μm filter membrane, precision measures filtrate 3ml,
Join in the cillin bottle of the 0.5mol/L sodium hydroxide solution containing 1ml, shake up, as need testing solution after filtration；Another essence
Close title RABEPRAZOLE SODIUM crude drug 25mg, puts in 25ml volumetric flask, is diluted to scale with 0.5mol/L sodium hydroxide solution, afterwards
Precision measures 3mL and puts in 10mL volumetric flask, and 0.5mol/L sodium hydroxide solution is diluted to scale, and precision measures 1ml, adds
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), as reference substance, measures RABEPRAZOLE SODIUM in different solute
Content.Test result is as depicted in figs. 1 and 2.
Fig. 1 is RABEPRAZOLE SODIUM crude drug stability in pH6.8 phosphate buffer；Fig. 2 is that RABEPRAZOLE SODIUM is former
Material medicine stability in pH8.0 phosphate buffer；Fig. 3 is that the RABEPRAZOLE SODIUM slow releasing capsule that the embodiment of the present invention prepares exists
Release in pH6.8 phosphate buffer；Fig. 4 be the embodiment of the present invention prepare RABEPRAZOLE SODIUM slow releasing capsule at pH8.0
Release in TRIS buffer.
It can be seen that RABEPRAZOLE SODIUM crude drug is the most unstable in pH6.8 phosphate buffer from Fig. 1 and Fig. 2
Fixed, and relatively stable in pH8.0 phosphate buffer.
From the release data of Fig. 3 and Fig. 4, the RABEPRAZOLE SODIUM slow releasing capsule of the embodiment of the present invention 1 preparation exists
In the medium of pH6.8, the release of 60min is about 18%, the most mainly the release of rapid release enteric coated micropill, and 180min releases
Degree of putting is about 60%, and the release of the RABEPRAZOLE SODIUM slow releasing capsule 60min in the ph 6.8 media of embodiment 2 preparation is
About 20%, the most mainly release of rapid release enteric coated micropill, the release of 180min is about 70%.Due to RABEPRAZOLE SODIUM
In the environment of pH is 6.8, stability is the highest, and the RABEPRAZOLE SODIUM of fraction is decomposed, and therefore release is not up to 100%.
RABEPRAZOLE SODIUM slow releasing capsule release of 30min in the medium of pH8.0 of embodiment 1 preparation is about 27%, 120min
Release be 90%, embodiment 2 preparation RABEPRAZOLE SODIUM slow releasing capsule release of 30min in the medium of pH8.0 be
The release of about 30%, 120min is about 88%, and the RABEPRAZOLE SODIUM slow releasing capsule of embodiment 1 and embodiment 2 preparation exists
The release of about 120min reaches about 90%, and RABEPRAZOLE SODIUM slow releasing capsule is described, and in the medium of pH8.0, stability is relatively
Good.It addition, the release of embodiment 2 is the highest, reason may be the replacement hydroxyl added in embodiment 2
The consumption of propyl cellulose and sodium carbonate is the most, and therefore dissolution discharges faster.
Therefore, the present invention is dissolved under different pH value by controlling enteric material, can be under different pH value condition
Release quick-releasing type and slowbreak type enteric coated micropill, serve the effect of slow release well, can solve in therapeutic process " night respectively
Acid breaks through " problem and improve RABEPRAZOLE SODIUM in the stability of absorption site.
Embodiment 11
RABEPRAZOLE SODIUM slow releasing capsule influence factor tests
The RABEPRAZOLE SODIUM slow releasing capsule prepared with embodiment 1 and embodiment 2, reference Chinese Pharmacopoeia 2015 editions four 9001
Carry out influence factor's test.
Influence factor tests: hot test (40 DEG C ± 2 DEG C), high wet test (75% ± 5%), exposure experiments to light (4000Lx
± 500Lx), it was measured in the 0th, 5,10 days, the results are shown in Table 9,10 and 11.
Table 9 hot test result
Table 10 high humidity result of the test
Table 11 exposure experiments to light result
Shown in table 9 to table 11, embodiments of the invention 1 and the made RABEPRAZOLE SODIUM slow releasing capsule of embodiment 2 are at height
Under temperature, high humidity, illumination condition, the 5th day and the character of 10 days, content and release have no significant change, and illustrate that the present invention implements
The made RABEPRAZOLE SODIUM slow releasing capsule of example is relatively stable.
Embodiment described above only have expressed the several embodiments of the present invention, and it describes more concrete and detailed, but also
Therefore the restriction to the scope of the claims of the present invention can not 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, it is also possible to make some deformation and improvement, these broadly fall into the guarantor of the present invention
Protect scope.Therefore, the protection domain of patent of the present invention should be as the criterion with claims.
Claims (10)
1. a RABEPRAZOLE SODIUM slow releasing capsule, it is characterised in that include Capsules and be filled in described Capsules
Rapid release enteric coated micropill and slowbreak enteric coated micropill, described rapid release enteric coated micropill includes the first capsule core, is coated on described first capsule core
First sealing coat on surface and be coated on the first enteric layer of described first insulation surface, described slowbreak enteric coated micropill includes the
Two capsule core, it is coated on second sealing coat on described second capsule core surface and is coated on the second enteric of described second insulation surface
Layer；With RABEPRAZOLE SODIUM content meter, the mass ratio of described rapid release enteric coated micropill and described slowbreak enteric coated micropill is 1: 2-1: 5.
2. RABEPRAZOLE SODIUM slow releasing capsule as claimed in claim 1, it is characterised in that described first enteric layer is being higher than
Dissolve under conditions of pH5.5.
3. RABEPRAZOLE SODIUM slow releasing capsule as claimed in claim 1, it is characterised in that described second enteric layer is being not less than
Dissolve under conditions of pH7.0.
4. RABEPRAZOLE SODIUM slow releasing capsule as claimed in claim 1, it is characterised in that described first enteric layer includes the first intestinal
Molten material, described second enteric layer includes the second enteric material, described first enteric material and described second enteric material respectively
Including hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, methacrylic acid copolymer and poly-third
At least one in olefin(e) acid resin.
5. RABEPRAZOLE SODIUM slow releasing capsule as claimed in claim 4, it is characterised in that described 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 slow releasing capsule as claimed in claim 4, it is characterised in that described second enteric material includes methyl
Acryl acid-methyl methacrylate copolymer.
7. RABEPRAZOLE SODIUM slow releasing capsule as claimed in claim 1, it is characterised in that in described rapid release enteric coated micropill, described
The mass fraction of the first capsule core, described first sealing coat and described first enteric layer be respectively 45%-80%, 2%-20% and
10%-50%；In described slowbreak enteric coated micropill, described second capsule core, described second sealing coat and the matter of described second enteric layer
Amount mark is respectively 45%-80%, 2%-20% and 10%-50%.
8. RABEPRAZOLE SODIUM slow releasing capsule as claimed in claim 1, it is characterised in that described first capsule core and described second ball
Core all includes that mass fraction is the RABEPRAZOLE SODIUM of 5%-30%, the diluent of 20%-85%, the binding agent of 1%-5%, 2%-
The pH adjusting agent of 20% and the disintegrating agent of 3%-30%.
9. the preparation method of a RABEPRAZOLE SODIUM slow releasing capsule, it is characterised in that comprise the following steps:
Extrusion spheronization method is used to prepare the first capsule core and the second capsule core respectively:
Described first capsule core is placed in fluid bed or seed-coating machine, the first sealing coat coating solution of then spraying, obtains Surface coating
There is the first capsule core of the first sealing coat；Described second capsule core is placed in fluid bed or seed-coating machine, the second sealing coat of then spraying
Coating solution, obtaining Surface coating has the second capsule core of the second sealing coat；
The first capsule core that described Surface coating has the first sealing coat is placed in fluid bed or seed-coating machine, the first enteric layer bag of spraying
Clothing liquid, is coated with the first enteric layer in described first insulation surface and obtains rapid release enteric coated micropill；Described Surface coating is had second
Second capsule core of sealing coat is placed in fluid bed or seed-coating machine, the second enteric layer coating solution of spraying, at described second sealing coat table
Bread covers the second enteric layer and obtains slowbreak enteric coated micropill；
With RABEPRAZOLE SODIUM content meter, it is that 1: 2-1: 5 loadings are hollow in mass ratio by rapid release enteric coated micropill and slowbreak enteric coated micropill
In capsule, prepare RABEPRAZOLE SODIUM slow releasing capsule.
10. the preparation method of RABEPRAZOLE SODIUM slow releasing capsule as claimed in claim 9, it is characterised in that described first capsule core
Or the preparation method of described second capsule core is:
RABEPRAZOLE SODIUM, diluent, binding agent, pH adjusting agent and disintegrating agent are mixed and made into soft material, described soft material is put into
In pill seed-coating machine, described soft material is extruded in strip by sieve plate, the most round as a ball for spherical, after being dried and sieving, obtain institute
State the first capsule core or described second capsule core.
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Cited By (1)
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| CN110946845A (en) * | 2018-09-26 | 2020-04-03 | 河南天晟泰丰医药科技有限公司 | Dextrobeprazole sodium sustained-release capsule and preparation method thereof |
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| CN110946845A (en) * | 2018-09-26 | 2020-04-03 | 河南天晟泰丰医药科技有限公司 | Dextrobeprazole sodium sustained-release capsule and preparation method thereof |
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| CN105796532B (en) | 2018-12-21 |
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