CN102652734A - Rabeprazole sodium enterosoluble micro-particles and preparation method thereof - Google Patents
Rabeprazole sodium enterosoluble micro-particles and preparation method thereof Download PDFInfo
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Abstract
The invention belongs to the field of pharmaceutical preparations, and particularly relates to novel rabeprazole sodium enterosoluble micro-particles with high stability in an acid medium, and a preparation method thereof. Each rabeprazole sodium enterosoluble micro-particle comprises a blank pill core (1), a medicine-carrying layer (2), an isolation coating layer (3) and an enteric coating layer (4) in sequence from inside to outside. A pH value regulator is used in the medicine-carrying layer, the isolation coating layer is added between the medicine-carrying layer and the enteric coating layer, and particularly, a retarding agent is added into an enteric coating layer combination, so that the acid tolerance of a medicament active ingredient namely rabeprazole sodium which is extremely unstable in acid is well improved. The rabeprazole sodium enterosoluble micro-particles and a preparation thereof can be used for treating diseases such as active duodenal ulcer, benign active gastric ulcer, rodent or ulcerative gastroesophageal reflux accompanied by clinical symptoms and the like.
Description
Technical field
The invention belongs to field of medicine preparations, be specifically related to a kind of novel sodium rabeprazole enteric-coated microgranule that in acid medium, has good stability and preparation method thereof.Said sodium rabeprazole enteric-coated microgranule and preparation thereof can be used for treating active duodenal ulcer, optimum active gastric ulcer, disease such as levy with the aggressivity of clinical symptoms or ulcerative stomach-esophageal reflux.
Background technology
Along with the Chinese society expanding economy, the variation of the change of circumstances and people life style, the increasing of survival pressure, the sickness rate of digestive tract ulcer increases just gradually, becomes a kind of commonly encountered diseases and frequently-occurring disease.Severe complications such as if the ill back of this type of disease is active treatment not, and is can be concurrent hemorrhage, as to bore a hole, block, even about 2%～3% patient Ke Fa canceration.
The main paathogenic factor of digestive tract ulcer morbidity is that acid concentration is too high, the mucosa protective effect weakens with Helicobacter pylori infection etc.Therefore, the treatment of digestive tract ulcer need be used the medicine of gastric acid inhibitory secretion, protection digestive tract mucosa and anti-helicobacter pylori.The final step of gastric acid secretion is that parietal cell secretion film proton pump drives H and the interior K exchange of tubule in the cell, and proton pump is H
+-K
+-ATP enzyme.Proton pump inhibitor has been blocked the last passage of gastric acid secretion, therefore, can suppress the secretion of basic gastric acid and acid that histamine, acetylcholine, gastrin and food stimulus cause secretion.Proton pump inhibitor (PPIS) is the choice drug of present confessed treatment digestive tract ulcer.
RABEPRAZOLE SODIUM is the benzimidazoles compound of new generation behind omeprazole, lansoprazole, and the potent inhibitor for parietal cell most advanced and sophisticated secretion film endoplasm pump (being proton pump) is used for treating the gastroenteropathy that causes because of gastroxia more.The RABEPRAZOLE SODIUM oral absorption is rapid, effectively gastric acid inhibitory secretion, and quick relief of symptoms, clinical effectiveness is definite, and toleration is good.
RABEPRAZOLE SODIUM has higher pKa value as the proton pump inhibitor of a new generation, and it is rapid-action to press down the acid effect, and onset time is all short than omeprazole, lansoprazole; Whole day is kept the higher level that presses down acid, and the time of stomach inner pH value＞3 obviously prolongs; The removing of RABEPRAZOLE SODIUM seldom relies on hepatocyte inner cell pigment P
450(CYP
450) isozyme system (mainly being CYP21C19) metabolism, CYP
450The metabolic power of isozyme does not make significant difference to the rabeprazole clearance rate, in the crowd, can reach effectively to press down the acid effect, and individual variation is little; RABEPRAZOLE SODIUM is mainly by non-enzymatic pathway metabolism, therefore, seldom influences each other between it and the other drug, has very high safety, and clinical efficacy significantly is superior to other proton pump inhibitors.
Patent US2010121068, EP2162449, WO2010006904, WO2010004571, CN101580520 etc. describe the preparation process of sodium rabeprazole compound in detail.
Chinese patent CN101143143 provides the medicine of one type of treatment gastroesophageal reflux disease and functional dyspepsia, comprises the neutral form or the alkaline salt forms of rabeprazole, with and optical voidness stereoisomer or its active metabolite.
RABEPRAZOLE SODIUM is extremely unstable in sour environment, need it be prepared into enteric coated preparation usually clinically, and after this type of preparation oral administration administration, the enteric coating film dissolves in intestinal, and the active component RABEPRAZOLE SODIUM that discharges just begins to be absorbed.At present, the dosage form of RABEPRAZOLE SODIUM is mainly enteric coatel tablets and enteric coated capsule both at home and abroad.Patent US5035899 and WO2008129517 have prepared enteric coated tablet to benzimidazoles compound, and its composition comprises pastille label, contagion gown layer and enteric coating layer.
But above-mentioned common enteric coatel tablets may be owing to the too high initiation GI irritation property of supplementary material local concentration after enteric coating film dissolving, simultaneously in clinical use, and inconvenient fractionated dose; For the patient of gastroenteropathy, particularly for the patient of some dysphagias, can there be certain inconvenience in taking in the process of common tablet.
Oral multiparticulates tablet release technology by in a large number independently microgranule (microgranule, microcapsule, microsphere, coated granule) form the tablet of required dosage; Diameter of particle is at tens of micron to about 1-2 millimeter; Mostly the microgranule outward appearance is spherical or the ellipsoid shape; Can microgranule be processed through art for coating as required have slow release, the functional small unit of rapid release, release characteristics, be pressed into the tablet of suitable hardness at last.U.S. Pat 2008305160 and international monopoly WO03077888, WO2007036671, WO2007109357, WO2007135193 etc. are described multiparticulates medicine-releasing system technology in detail, and these patents are incorporated herein through reference.Multiparticulates tablet release technology has many special advantages: the prominent of single microgranule Chinese medicine released or do not delayed to discharge and can produce appreciable impact to the release of total formulation, guaranteed the performance of the whole curative effect of preparation; After taking, medicine can be dispersed in gastrointestinal tract, thereby alleviates possibly cause because local concentration is too high gastrointestinal is stimulated.
Oral cavity disintegration tablet (orally disintegrating tablets; ODT) when taking, do not need water or only need low amounts of water, tablet is placed lingual surface, need not to chew; Meeting saliva can disintegrate or dissolving; Be that a kind of borrow swallowed the novel troche that power is gone into stomach, taking convenience, rapid-action, bioavailability is high, is particularly useful for dysphagia patients.
One Chinese patent application CN200910021345 provides a kind of sodium rabeprazole enteric-coated orally disintegrating tablets and preparation method thereof, and this enteric-coated orally disintegrating tablets mainly is made up of celphere, drug-loaded layer, stabilizing agent, sealing coat, enteric coating, filler and disintegrating agent.But the discovery that we it's a pity, based on the reason of following several respects, also there are some defectives in this invention, for example:
(1) stabilizing agent is selected from one or more in sodium carbonate, sodium bicarbonate, potassium carbonate or the potassium bicarbonate, and they all belong to weak acid and weak base salt.The active component RABEPRAZOLE SODIUM is very easily degraded under acid condition; Need be under the condition of pH＞11; Could keep stable; The described several kinds of weak acid and weak base salt of one Chinese patent application CN200910021345 are as the preparation stabilization agent, and the weak basic condition that provides can't satisfy the requirement of medicine stability, and long-term placement causes active component to be degraded gradually easily and drug effect is reduced.
(2) the sealing coat coating material is selected hydroxypropyl emthylcellulose merely for use.In aqueous environments, moisture gets into the ball core through the enteric coating membrane permeation, and water miscible sealing coat coating material is dissolved, and the medicine on tart enteric coating material and the drug-loaded layer is directly come in contact, and causes active constituents of medicine to be degraded.Therefore, select for use hydroxypropyl emthylcellulose merely, can't play good buffer action to drug-loaded layer and enteric coating layer, thereby cause the acid-resistant strength of tablet relatively poor as the sealing coat coating material.
(3) do not add plasticizer in the enteric coating material, be prone to cause clothing film pliability not enough, prepared microgranule is prone to break in follow-up tabletting process, has a strong impact on the acid-resistant strength and the enteric effect of final preparation.
(4) acid-resistant strength is an extremely important parameter of estimating the enteric coated preparation quality, and one Chinese patent application CN200910021345 fails to provide its acid-resistant strength assay method and result, can't judge the quality of its acid-resistant strength.
Therefore; RABEPRAZOLE SODIUM is extremely strong as a kind of water solublity; And the novel proton pump inhibitor of acid degradation very easily; Particular design be need on prescription screening and preparation technology, carry out,, safety, effectiveness and compliance that patient takes medicine increased so that a kind of sodium rabeprazole enteric-coated microparticle formulation with good stable property to be provided.
Summary of the invention
Technical problem
In order to solve the problems of the technologies described above, particularly in order to improve the water solublity proton pump inhibitor---the stability of RABEPRAZOLE SODIUM in acid medium an object of the present invention is to provide a kind of novel sodium rabeprazole enteric-coated microgranule with good stability.
Another object of the present invention provides a kind of method for preparing above-mentioned sodium rabeprazole enteric-coated microgranule and preparation thereof.
Technical scheme
To achieve these goals, the invention provides a kind of sodium rabeprazole enteric-coated microgranule that in acid medium, has good stability, wherein, said sodium rabeprazole enteric-coated microgranule comprises from the inside to the outside successively:
(1) celphere; It is the innermost layer structure of above-mentioned enteric-coated microsome, the pharmaceutical carrier of following drug-loaded layer compositions, and it is selected from sucrose ball core and the microcrystalline Cellulose ball core; The weight of said celphere is 3～15% of said enteric-coated microsome gross weight, is preferably 5～12%;
(2) drug-loaded layer; It is coated on outside the above-mentioned celphere, is processed by the drug-loaded layer compositions, and said composition comprises active constituents of medicine RABEPRAZOLE SODIUM, binding agent and pH value regulator; The weight of said drug-loaded layer is 10～40% of said enteric-coated microsome gross weight, is preferably 10～30%;
(3) contagion gown layer, it is coated on outside the above-mentioned drug-loaded layer, is processed by the contagion gown layer composition, and said composition comprises binding agent, opacifier and antiplastering aid, and the weight of said contagion gown layer is 5～20% of said enteric-coated microsome gross weight, is preferably 5～15%; With
(4) enteric coating layer; It is coated on outside the above-mentioned contagion gown layer, is processed by the enteric coating layer compositions, and said composition comprises enteric-coating material, plasticizer, antiplastering aid and blocker; The weight of said enteric coating layer is 35～82% of said enteric-coated microsome gross weight, is preferably 40～80%.
The basic design of technical scheme that the present invention adopts is a utilization multiparticulates tablet release technology; Employing fluidized bed coating technology; Bag carries medicated layer compositions, contagion gown compositions, enteric coating compositions on celphere successively, the enteric-coated microsome of preparation RABEPRAZOLE SODIUM.Then,, directly carry out the capsule fill and prepare sodium rabeprazole enteric-coated capsule, sodium rabeprazole enteric-coated microgranule that perhaps will make and acceptable accessories mixing, tabletting, preparation sodium rabeprazole enteric-coated orally disintegrating tablets the sodium rabeprazole enteric-coated microgranule that makes.Wherein, said acceptable accessories comprises filler, disintegrating agent, correctives, lubricant.
The key that technical scheme of the present invention is implemented is to have the preparation of the sodium rabeprazole enteric-coated microgranule of good stability.(the RABEPRAZOLE SODIUM water solublity is fabulous in view of the special physicochemical property of these article active component RABEPRAZOLE SODIUM; Very easily degraded in the acid); The present invention has adopted the combined system of special medicine carrying, isolation, enteric-coating material in the design process of sodium rabeprazole enteric-coated microgranule.In the medicine carrying process, added the pH regulator agent, and, increased the design of contagion gown layer for preventing the influence of enteric coating film itself to active component stability; Especially in the design of enteric coating layer compositions, add special blocker, thereby guaranteed the stability of sodium rabeprazole enteric-coated microgranule.Simultaneously, in the preparation process of the sodium rabeprazole enteric-coated microgranule of inventing, preparation technology optimizes to fluid bed, has guaranteed sodium rabeprazole enteric-coated microgranule of the present invention, can in acid medium, have good acid-resistant strength and stability.
Said sodium rabeprazole enteric-coated microgranule, in acid medium, through acid-resistant strength test in 2 hours, acid-resistant strength was not less than 90%, and more preferably, acid-resistant strength is not less than 95%.
Adopt the RABEPRAZOLE SODIUM oral cavity disintegration tablet of sodium rabeprazole enteric-coated microgranule preparation of the present invention; Disintegrate rapidly after taking; Discharge RABEPRAZOLE SODIUM medicine carrying enteric-coated microsome wherein; Messenger drug object height degree disperses, and having reduced medicine stimulates gastrointestinal, improves medicine and gastrointestinal contact area.Simultaneously, the medicine carrying granule is carried out special enteric coating, also improved the medicine stability in the transport process in vivo, enteric-coated microsome evenly discharges at the small intestinal position, and drug absorption is stable, and individual variation is little; Reducing irritating drug effect that improved simultaneously.In sodium rabeprazole enteric-coated microgranule of the present invention, the particle diameter of said celphere is 50～400 μ m, is preferably 50～300 μ m, more preferably 100～200 μ m.Can further improve the mouthfeel of pharmaceutical preparation than the celphere of small particle diameter.The weight that said celphere accounts for the drug-loaded layer compositions is preferably 20～70%, and more preferably 25～60%.
In sodium rabeprazole enteric-coated microgranule of the present invention, the drug-loaded layer in the said sodium rabeprazole enteric-coated microgranule is processed by the drug-loaded layer compositions, and described drug-loaded layer compositions comprises active constituents of medicine RABEPRAZOLE SODIUM, binding agent and pH value regulator.
In drug-loaded layer compositions of the present invention, based on the gross weight of drug-loaded layer compositions, the amount of said active constituents of medicine RABEPRAZOLE SODIUM is generally 50～90%, is preferably 60～80%.
In drug-loaded layer compositions of the present invention, the use of binding agent can make the active constituents of medicine RABEPRAZOLE SODIUM in the drug-loaded layer be attached to the surface of celphere better.Binding agent in the said drug-loaded layer compositions can be selected from one or more in hydroxypropyl emthylcellulose, hydroxyethyl-cellulose, hydroxypropyl cellulose, polyvidone and the copolyvidone.Based on the gross weight of drug-loaded layer compositions, said drug-loaded layer adhesive consumption is generally 2～25%, is preferably 3～20%.
In drug-loaded layer compositions of the present invention, the use of pH value regulator mainly is in order to regulate active constituents of medicine pH environment on every side, to prevent its degraded, thereby improve its stability.Said pH value regulator can be selected from one or more in magnesium oxide, magnesium hydroxide, sodium hydroxide, potassium hydroxide and the magnesium carbonate.In addition; The ethanol of also having selected 0.003M sodium hydroxide and 80% is jointly as the solvent of active component RABEPRAZOLE SODIUM; Guarantee that active component is in the strong basicity environment of pH＞11, prevent that pH value from crossing the low active component degraded that causes, guarantee drug effect to greatest extent.Based on the gross weight of drug-loaded layer compositions, the consumption of said pH regulator agent is generally 3～25%, is preferably 5～20%.
Because it is acid that the enteric-coating material (like acrylic resin) that the present invention adopts is self, if on the medicine carrying granule, directly carry out enteric coating, can influence the stability of the active constituents of medicine in the drug-loaded layer.Therefore; The characteristic of sodium rabeprazole enteric-coated microgranule provided by the invention also is; Said sodium rabeprazole enteric-coated microgranule also comprises the contagion gown layer between said drug-loaded layer and enteric coating layer; So that drug-loaded layer and enteric coating layer are isolated, thereby prevent the influence of acrylic resin, and increase the long-time stability of sodium rabeprazole enteric-coated microgranule of the present invention for the active constituents of medicine RABEPRAZOLE SODIUM.
The preparation of contagion gown layer of the present invention can be processed contagion gown layer coating solution through the contagion gown layer composition is dissolved in the The suitable solvent, again with contagion gown layer coating solution, sprays on the medicine carrying granule and forms the contagion gown granule.Said contagion gown layer composition comprises binding agent, opacifier and antiplastering aid.
In contagion gown layer composition of the present invention; Said binding agent can be selected from one or more in hydroxypropyl emthylcellulose, ethyl cellulose, methylcellulose, hydroxyethyl-cellulose, hydroxypropyl cellulose, polyvidone and the copolyvidone, is preferably the mixture of hydroxypropyl emthylcellulose and ethyl cellulose.Can adopt The suitable solvent to disperse the back to use the binding agent dissolving, said The suitable solvent is selected from one or several in ethanol, water, acetone and the isopropyl alcohol.Based on the gross weight of contagion gown layer, said adhesive consumption is generally 70～98%, is preferably 75～95%.
In contagion gown layer composition of the present invention; The use of opacifier can make the contagion gown of drug particles and enteric coating be easy to distinguish; On the other hand, the use of opacifier also can prevent the photodissociation of active constituents of medicine better, thereby increases the stability of pharmaceutical preparation of the present invention.To the selection of the color of opacifier and unrestricted, because of the selection of its color does not influence practical use of the present invention and effect.Said opacifier can be selected from one or more in titanium dioxide, iron oxide red, iron oxide yellow, iron oxide purple and the iron oxide black, is preferably titanium dioxide.Based on the gross weight of contagion gown layer composition, the consumption of said opacifier is generally 1～25%, is preferably 2～15%.
In contagion gown layer composition of the present invention, the use of antiplastering aid can improve the viscosity of isolation coat liquid, thereby guarantees carrying out smoothly of contagion gown layer coating process better.Do not have particular restriction for the antiplastering aid that the present invention adopted, as long as antiplastering aid that is adopted and the active constituents of medicine among the present invention do not interact.Said antiplastering aid can be selected from one or more in Pulvis Talci, glyceryl monostearate and the magnesium stearate.Based on the gross weight of contagion gown layer composition, the consumption of said antiplastering aid is generally 1～20%, is preferably 3～15%.
In sodium rabeprazole enteric-coated microgranule of the present invention; Said enteric coating layer is the important assurance that preparation of the present invention has good acid-resistant strength; Enteric coating layer can be protected sodium rabeprazole enteric-coated microgranule of the present invention; Discharge in small intestinal thereby control it, and avoid discharging under one's belt the degraded of the active constituents of medicine that causes.
In enteric coating layer compositions of the present invention, said enteric-coating material is a kind of functional material, is to have the dependent macromolecular material of pH, and it can control the release of medicine through the dissolving under specific pH value condition.Said enteric-coating material can be selected from one or more in EUDRAGIT S100, methacrylate copolymer (like Eudragit L100-55, Eudragit L30D-55, Eudragit NE30D, EudragitRL30D, Eudragit RS30D etc.), amino methyl acrylic copolymer, Hydroxypropyl Methylcellulose Phathalate, succinic acid acetic acid hydroxy methocel and the succinic acid acetic acid hydroxypropyl methylcellulose.The selection of enteric-coating material is bigger for the preparation influence of preparation of the present invention, and suitable enteric-coating material can be guaranteed the acid-resistant strength and the good stable property of prepared enteric-coated microsome, thereby guarantees the quality of preparation of the present invention.Based on the gross weight of enteric coating layer compositions, the consumption of said enteric-coating material is generally 30～90%, is preferably 40～90%.
The compressibility of enteric-coated microsome and clothing film pliability can directly influence the acid-resistant strength of final preparation.This is because good clothing film pliability can guarantee that the clothing film does not produce slight crack in the tabletting process, thereby prevents that the acid solution in the sour environment from seeing through the crack entering ball in-core portion on clothing film surface, degrades active constituents of medicine.The use of plasticizer can make the enteric coating film have better pliability and extensibility, has guaranteed that prepared enteric coating film does not break in follow-up tabletting process.In enteric coating layer compositions of the present invention, said plasticizer can be selected from one or more in triethyl citrate, ATBC, dimethyl phthalate, diethyl phthalate, dibutyl phthalate, dibutyl sebacate, citroflex A-4, glycerol acetate and the Oleum Ricini.Based on the gross weight of enteric coating layer compositions, plasticizer dosage is generally 1～30%, is preferably 5～25%.
In enteric coating layer of the present invention, the effect of said antiplastering aid with can select material and above-mentioned contagion gown layer for use in identical.Based on the gross weight of enteric coating layer compositions, the consumption of said antiplastering aid is generally 3～40%, is preferably 5～30%.
Active constituents of medicine in the preparation of the present invention---RABEPRAZOLE SODIUM has fabulous water solublity; But it is extremely unstable in acid; So need in the enteric coating film, add special blocker, with the stability of the active constituents of medicine that guarantees enteric-coated microsome and ball core better.Common enteric coating film soaks in acid medium owing to there is certain moisture permeability for a long time, and moisture is prone to see through the enteric coating film and gets in the microgranule, and active constituents of medicine is degraded.Therefore, common enteric coating is difficult to guarantee the required acid-resistant strength of preparation of the present invention.Blocker is another important component in the enteric coating layer compositions of preparation of the present invention; Usually the character that has waxiness and waterproof; Can play the enteric coating film and prevent that moisture penetration from going into the effect of enteric-coated microsome, thereby reduce the probability that active constituents of medicine that the infiltration because of moisture causes contacts with acid enteric-coating material greatly.Therefore, the adding of blocker can further improve the acid-resistant strength of final preparation.
In enteric coating compositions of the present invention, said blocker can be selected from one or more in stearic acid, mono stearate glyceryl ester and the liquid paraffin.Based on the gross weight of enteric coating layer compositions, the consumption of said blocker is generally 1～20%, is preferably 3～15%.
Usually; In order to guarantee the use of blocker; Use in enteric coat layer of the present invention under the condition of aqueous coatings material; Enteric coating layer compositions of the present invention can also comprise an amount of emulsifying agent, said emulsifying agent can be selected from the fatty acid Pyrusussuriensis smooth, gather that Pyrusussuriensis is smooth, in polyoxyethylene fatty acid ester (like polysorbate60, Tween 80 etc.) and the polyoxyethylene aliphatic alcohol ether one or more.
After sodium rabeprazole enteric-coated microgranule preparation of the present invention is accomplished; Can be used for preparing enteric coated preparation; Can directly said sodium rabeprazole enteric-coated microgranule be carried out the capsule fill; Perhaps, prepare sodium rabeprazole enteric-coated orally disintegrating tablets with said sodium rabeprazole enteric-coated microgranule and mixing acceptable accessories tabletting.In technique scheme, the preferred for preparation sodium rabeprazole enteric-coated orally disintegrating tablets, said acceptable accessories comprises disintegrating agent, filler, correctives and lubricant etc.
In sodium rabeprazole enteric-coated orally disintegrating tablets according to the present invention, based on the gross weight of enteric-coated orally disintegrating tablets, the percentage by weight of enteric-coated microsome and acceptable accessories is following: enteric-coated microsome accounts for 5～59%, and preferred 15～55%; Disintegrating agent accounts for 5～25%, and preferred 5～20%; Filler accounts for 35～65%, and preferred 40～60%; Correctives accounts for 0.01～2%, and preferred 0.1～2%; Lubricant accounts for 0.1～3%, and preferred 0.3%～2%.
In acceptable accessories of the present invention, disintegrating agent is wherein indispensable a kind of, and ideal disintegrating agent not only can make the tablet molding, particulate dispersion after can also quickening disintegrate and increasing disintegrate, thereby the disintegration of assurance oral cavity disintegration tablet.Said disintegrating agent can be selected from one or more in polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, carboxymethyl starch sodium, pregelatinized Starch, microcrystalline Cellulose, alginic acid and the sodium carboxymethyl cellulose.Based on the gross weight of enteric-coated orally disintegrating tablets, the consumption of said disintegrating agent is generally disintegrating agent and accounts for 5～25%, and preferred 5～20%.
In acceptable accessories of the present invention, the adding of filler can be beneficial to the molding and the divided dose of tablet in order to increase the quality and the volume of oral cavity disintegration tablet.Filler can be divided into water-soluble filler according to dissolubility, like lactose, sucrose, mannitol, sorbitol, glucose etc., and the water-insoluble filler, like starch, microcrystalline Cellulose etc., the filler that the present invention adopted is selected from one or more in them.Based on the gross weight of enteric-coated orally disintegrating tablets, the consumption of said filler is generally 35～65%, and preferred 40～60%.
In acceptable accessories of the present invention, in order to improve and shield the bitterness of medicine, increase the compliance that the patient takes medicine, need in adjuvant, add correctives usually.Especially for than bitterness or the strong medicine of zest, the selection of correctives is the emphasis of prescription screening.Said correctives can be selected from one or more in various essence, sweeting agent, sucrose, cyclamate, citric acid and the aspartame.Based on the gross weight of enteric-coated orally disintegrating tablets, the consumption of said correctives is generally 0.01～2%, and preferred 0.1～2%.
In acceptable accessories of the present invention, the adding of lubricant can improve the flowability of preparation of the present invention in high speed tabletting process, thereby improves the uniformity of the content of said preparation.Do not have particular restriction for the lubricant that the present invention adopted, as long as lubricant that is adopted and the active constituents of medicine in the preparation of the present invention do not interact.Said lubricant can be selected from one or more of magnesium stearate, calcium stearate, zinc stearate, Pulvis Talci, micropowder silica gel, glyceryl monostearate and sodium stearyl fumarate.Based on the gross weight of enteric-coated orally disintegrating tablets, the consumption of said lubricant is generally 0.1～3%, and preferred 0.3%～2%.
Another technical scheme of the present invention also provides a kind of method for preparing of sodium rabeprazole enteric-coated microgranule, and this method for preparing may further comprise the steps:
1. the drug-loaded layer compositions is coated on the celphere, and preparation medicine carrying granule;
2. with said medicine carrying granule with contagion gown layer composition coating, and preparation contagion gown granule;
3. with said contagion gown granule with enteric coating layer compositions coating, and the preparation enteric-coated microsome.
Above-mentioned method for preparing further may further comprise the steps: with said enteric-coated microsome and mixing acceptable accessories and prepare sodium rabeprazole enteric-coated orally disintegrating tablets.
The present invention is particle drug-loaded for carrying out, bag contagion gown, enteric coated mode do not have special limitation; But select because fluidized bed coating technology be a kind of conventional of those skilled in the art, the present invention step 1.-3. in the mode of preferred employing fluidized bed coating carry out particle drug-loaded, wrap contagion gown, enteric coated.For example, step 1. in, celphere is added fluid bed, regulate operating parameters such as air quantity, temperature, spray into the medicine carrying solution for preparing, carry out medicine carrying, and preparation medicine carrying granule.Step 2. in, above-mentioned medicine carrying granule is added fluid bed, regulate operating parameters such as air quantity, temperature, spray into the isolation coat liquid for preparing, preparation contagion gown granule.Step 3. in, the contagion gown granule is added fluid bed, regulate operating parameters such as air quantity, temperature, spray into the enteric coating liquid for preparing, and the preparation full of enteric coated granules.After preparing full of enteric coated granules, be preferable over and solidify dry 3h under 45 ℃ of conditions, subsequent use.
In the method for preparing of sodium rabeprazole enteric-coated microgranule of the present invention, bigger for the subsequent preparation process influence of preparation of the present invention to the control of sodium rabeprazole enteric-coated grain diameter.When enteric coated particles particle diameter during greater than 500 μ m, prepared preparation (especially oral cavity disintegration tablet) mouthfeel is relatively poor.Therefore, the present invention preferably adopts the less enteric-coated microsome of particle diameter.Sodium rabeprazole enteric-coated granule of the present invention, its particle diameter are 80～450 μ m, are preferably 100～400 μ m, more preferably 100～350 μ m.
The sodium rabeprazole enteric-coated granule that makes through method for preparing of the present invention, can with mixing acceptable accessories and tabletting, perhaps directly carry out the capsule fill.Method for preparing of the present invention preferably is prepared into sodium rabeprazole enteric-coated orally disintegrating tablets with sodium rabeprazole enteric-coated microgranule.
The concrete grammar of preparation tablets is that those skilled in the art's routine is selected; For example; Directly carry out tabletting behind the enteric coated particles mix homogeneously that can acceptable accessories and said method be made; After also can acceptable accessories that the present invention adopted being granulated, the enteric coated particles mix homogeneously and the tabletting that make with said method again.
The active constituents of medicine RABEPRAZOLE SODIUM that the present invention adopts is prone to degrade in sour environment, and is comparatively stable under alkali condition.Therefore; In optimal technical scheme of the present invention; Use is by the solvent of the common system of forming of the ethanol of 0.003M sodium hydroxide and 80% as active constituents of medicine; Having guaranteed that active constituents of medicine is in the strong basicity environment of pH＞11, thereby prevent that pH value from crossing the low active constituents of medicine degraded that causes, and guaranteed drug effect to greatest extent.
In the preparation process of contagion gown layer, can earlier said contagion gown layer composition be dissolved in and process isolation coat liquid in the The suitable solvent, again isolation coat liquid is sprayed on the above-mentioned medicine carrying granule, form the contagion gown granule.Can adopt The suitable solvent with after the binding agent in the said contagion gown layer composition dissolving, add opacifier and antiplastering aid again and process isolation coat liquid.Said The suitable solvent can be selected from one or more in ethanol, water, acetone and the isopropyl alcohol.
In the preparation process of enteric coating layer, can be earlier with said enteric coat layer composition dissolves in The suitable solvent and process enteric coating liquid, again enteric coating liquid is sprayed on the above-mentioned contagion gown granule, after the dry enteric coated particles that forms.Be used to prepare the The suitable solvent of enteric coating liquid of the present invention, need be according to the present invention the kind of selected enteric-coating material select, said solvent can be selected from one or more in water, ethanol, acetone, isopropyl alcohol and the dichloromethane.
Beneficial effect
Advantage based on multiparticulates medicine-releasing system and Orally disintegrating drug-supplying system; For further improving digestive tract disease patient's compliance; Reduce untoward reaction; Increase the curative effect of medicine, the present invention will improve existing preparation formulation, and a kind of sodium rabeprazole enteric-coated microgranule with good stability is provided.In the hope of making medicine reach maximum utility in vivo, reduce the purpose of medicine irritation and untoward reaction, have crucial meaning.
In order to improve the stability of water solublity proton pump inhibitor RABEPRAZOLE SODIUM in acid medium, the present invention designs through special prescription: the use of pH value regulator in the drug-loaded layer; In order to prevent the influence of enteric coating layer itself, increased the design of contagion gown layer to active constituents of medicine stability; Especially in the design of enteric coating layer compositions, added special blocker.The above-mentioned technological means that the present invention takes has all been improved the acid-resistant strength of extremely unsettled active constituents of medicine RABEPRAZOLE SODIUM in acid well.
The present invention has adopted fluidized bed coating preparation technology to prepare sodium rabeprazole enteric-coated microgranule, to guarantee sodium rabeprazole enteric-coated microgranule of the present invention, can in acid medium, have good acid-resistant strength and stability.
The basic design of technical scheme that the present invention adopts is a utilization multiparticulates tablet release technology; Employing fluidized bed coating technology; On celphere, wrap drug-loaded layer compositions, contagion gown layer composition, enteric coating layer compositions successively, the enteric-coated microsome of preparation RABEPRAZOLE SODIUM.Then; With the sodium rabeprazole enteric-coated microgranule that makes; Directly carry out the capsule fill and prepare sodium rabeprazole enteric-coated capsule; Sodium rabeprazole enteric-coated microgranule that perhaps will make and acceptable accessories mixing, tabletting, the preparation sodium rabeprazole enteric-coated orally disintegrating tablets is preferably the preparation sodium rabeprazole enteric-coated orally disintegrating tablets.
Adopt the sodium rabeprazole enteric-coated orally disintegrating tablets of sodium rabeprazole enteric-coated microgranule preparation provided by the invention; According to the method in Chinese Pharmacopoeia 2010 version (two appendix XC); Said enteric-coated microsome has good acid-resistant strength in acid medium, acid-resistant strength was no less than 90% in 2 hours; More preferably, 2 hours acid-resistant strengths are no less than 95%.Adopt the method in Chinese Pharmacopoeia 2010 version (two appendix XC), said enteric-coated microsome in TRIS buffer the release degree greater than 80%; More preferably, said enteric-coated microsome in TRIS buffer the release degree greater than 85%.Through 6 months accelerated tests, significant change did not all take place in the parameters of sodium rabeprazole enteric-coated microgranule provided by the invention (comprising stability and long-time stability in the acid).
Adopt the sodium rabeprazole enteric-coated enteric-coated orally disintegrating tablets of sodium rabeprazole enteric-coated microgranule preparation provided by the invention; Disintegrate rapidly after taking; Discharge medicine carrying enteric-coated microsome wherein; Messenger drug object height degree disperses, and having reduced active constituents of medicine stimulates gastrointestinal, and has improved medicine and gastrointestinal contact area.Simultaneously, medicine carrying granule of the present invention is carried out special enteric coating, also improved the medicine stability in the transport process in vivo.Said enteric coated particles evenly discharges at the small intestinal position, and drug absorption is stable, and individual variation is little, is promptly reducing irritating drug effect that also improved simultaneously.
Adopt the sodium rabeprazole enteric-coated enteric-coated orally disintegrating tablets of sodium rabeprazole enteric-coated microgranule preparation provided by the invention; Also have take medicine conveniently, disintegrate rapidly, discharge and receive advantages such as gastrointestinal effects is little, zest is little, increased the safety that patient takes medicine, effectiveness and compliance.Said sodium rabeprazole enteric-coated microgranule and preparation thereof can be used for the treatment of digestive tract disease such as duodenal ulcer and gastric ulcer.
In sum, the sodium rabeprazole enteric-coated enteric-coated orally disintegrating tablets of sodium rabeprazole enteric-coated microgranule preparation provided by the invention has the following advantages:
(1) RABEPRAZOLE SODIUM is extremely unstable in acid medium; The present invention has adopted special prescription design and preparation means; A kind of sodium rabeprazole enteric-coated microgranule (acid-resistant strength is greater than 95%) with good stable property is provided, for the stability that solves the water solublity proton pump inhibitor provides a kind of good approach and scheme;
(2) adopted the multiparticulates drug-supplying system, after taking, enteric-coated microsome can be dispersed in the gastrointestinal tract; Transport process receives gastrointestinal tract environment (like gastrointestinal tract dynamia; Rate of evacuation, food) influence is less, and the prominent of single microgranule Chinese medicine released or do not delay to discharge and can produce appreciable impact to the release of total formulation in the system; Absorb and stablize, individual variation is little;
(3) can avoid common enteric coated tablet disintegrate after, the zest that supplementary material local concentration too high (mainly being alkaline stabiliser) possibly cause, the medicine after the disintegrate is dispersed in gastrointestinal tract, has alleviated the GI irritation property of medicine;
(4) in the clinical use, be easy to fractionated dose, make things convenient for the patient to use;
(5) can under anhydrous condition, take, good mouthfeel, easy-to-swallow, for the patient provides a kind of new dosage form that makes things convenient for, safety, compliance are good.
Description of drawings
Fig. 1 is the generalized section of the sodium rabeprazole enteric-coated orally disintegrating tablets of the present invention's preparation;
Fig. 2 is the microscopical appearance photo of the sodium rabeprazole enteric-coated microgranule of the present invention's preparation;
Fig. 3 is the release in vitro curve of the sodium rabeprazole enteric-coated orally disintegrating tablets that makes among the embodiment of the invention 1～embodiment 8;
The stable bar diagram that Fig. 4 measures under 40 ℃ of 75%RH conditions for the sodium rabeprazole enteric-coated orally disintegrating tablets that makes among embodiments of the invention 5 and the reference embodiment;
The stable bar diagram that Fig. 5 measures under 50 ℃ of 75%RH conditions for the sodium rabeprazole enteric-coated orally disintegrating tablets that makes among the embodiment of the invention 5 and the reference embodiment.
The specific embodiment
To combine embodiment further to illustrate the present invention below, the object of the invention, characteristic and advantage will become obvious to those skilled in the art through following description.Following listed examples can be used for helping to understand the present invention, limits the scope of the present invention and should not be considered as.
Unless otherwise, all percentage ratios all are weight percentage.
One. prescription
Table 1 prescription is formed
Two. method for preparing
1. the particulate preparation of medicine carrying
1. the preparation of medicine carrying solution: take by weighing each component of drug-loaded layer compositions according to the prescription in the last table 1, disperse and ethanol-sodium hydroxide solution of 80% of being dissolved in, stir, subsequent use.
2. medicine carrying: the prescription according in the last table 1 takes by weighing celphere, adds fluid bed (Mini-Glatt, Gera, Germany is special); Regulate operating parameter (30 ℃ of temperature, air quantity 1.5bar, atomizing pressure 1.0bar such as air quantity, temperature, atomizing pressure; Down together, no longer repeat), spray into the above-mentioned medicine carrying solution for preparing; Carry out medicine carrying, thereby make the medicine carrying granule.
2. the particulate preparation of contagion gown
1. the preparation of isolation coat liquid: take by weighing each component of contagion gown compositions according to the prescription in the last table 1, disperse and be dissolved in 80% the alcoholic solution, mix homogeneously, subsequent use.
2. wrap contagion gown: with the above-mentioned medicine carrying granule that makes, add fluid bed, regulate operating parameters such as air quantity, temperature, spray into the isolation coat liquid for preparing, the bag contagion gown, thus make the contagion gown granule.
3. the preparation of full of enteric coated granules
1. the preparation of enteric coating liquid: take by weighing each component of enteric coating compositions according to the prescription in the last table 1, be scattered in the medium solution of recipe quantity, fully mixing is subsequent use;
2. enteric coated: with the above-mentioned contagion gown granule that makes, add fluid bed, regulate operating parameters such as air quantity, temperature, spray into the above-mentioned enteric coating liquid for preparing, enteric coated.
3. solidify: the granule with the intact enteric coating of above-mentioned bag, place 45 ℃ of baking ovens, dry 3h, thus make full of enteric coated granules.
4. the preparation of sodium rabeprazole enteric-coated orally disintegrating tablets
Take by weighing acceptable accessories and prepare the sodium rabeprazole enteric-coated microgranule of accomplishing according to the prescription in the last table 1, fully behind the mix homogeneously, tabletting promptly gets sodium rabeprazole enteric-coated orally disintegrating tablets.
Three. the mensuration of release degree
Chromatographic condition and system suitability test: use octadecylsilane chemically bonded silica to be filler; Methanol-water-triethylamine-glacial acetic acid (55: 45: 0.01: 0.002) be mobile phase; The detection wavelength is 286nm.Number of theoretical plate calculates by the RABEPRAZOLE SODIUM peak should be not less than 2000.
Get the preparation that makes among the embodiment 1～8 respectively,, adopt dissolution determination second method (two appendix XC of Chinese Pharmacopoeia version in 2010) device according to drug release determination method (two appendix XD of Chinese Pharmacopoeia version in 2010, the second method method 1); With 0.1mol/L hydrochloric acid solution 700mL is dissolution medium, and rotating speed is that per minute 100 changes, operation in accordance with the law; After 2 hours, add 37 ± 0.5 ℃ 0.6mol/L tris solution 300mL, mixing; Regulate pH value to 8.0 with 2mol/L hydrochloric acid solution or 2mol/L sodium hydroxide solution, remained in operation 15 minutes, it is an amount of to get solution; Precision is measured 3.0mL, adds 0.3mol/L sodium hydroxide solution 1.0mL immediately, mixing; Supernatant is got as need testing solution in centrifugal (8000rpm, 15 minutes).
Other gets the about 0.05g of RABEPRAZOLE SODIUM reference substance, and accurate the title decides, and puts in the 50mL measuring bottle, adds the 0.3mol/L sodium hydroxide solution and makes dissolving, and be diluted to scale; Shake up, precision is measured 3.0mL, puts in the 100mL measuring bottle, adds the 0.3mol/L sodium hydroxide solution to scale; Shake up, precision is measured 1.0mL, adds TRIS buffer 3.0mL, mixing; Supernatant is got, as reference substance solution in centrifugal (8000rpm, 15 minutes).
Get each 10 μ L of above-mentioned need testing solution and reference substance solution, injecting chromatograph, the record chromatogram goes out every burst size by external standard method with calculated by peak area, and the release degree is 80% just up to specification greater than labelled amount.Test result is shown in the following table 2.
Four. the mensuration of acid-resistant strength
Get the rabeprazole preparation of sodium that makes among the embodiment 1～8 respectively; According to drug release determination method (two appendix XD of Chinese Pharmacopoeia version in 2010, the second method method 1); Adopting dissolution determination second method (two appendix XC of Chinese Pharmacopoeia version in 2010) device, is dissolution medium with 0.1mol/L hydrochloric acid solution 700mL, and rotating speed is that per minute 100 changes; Operation in accordance with the law is after 2 hours; The leaching enteric-coated microsome is put in the mortar, adds 0.1M NaOH solution 20mL, fully grinds; Add the gradation of 0.001M NaOH solution again and be transferred in the 100mL measuring bottle, ultrasonic 5 minutes, make dissolving, put be chilled to room temperature after, standardize solution shakes up, centrifugal (8000rpm, 15 minutes) are got supernatant and are filtered through 0.45 μ m microporous filter membrane, as need testing solution.
It is an amount of that other gets the RABEPRAZOLE SODIUM reference substance, and precision is claimed fixed, adds the also quantitative dilution of 0.001MNaOH solution dissolving and process the solution that contains 100 μ g among every 1mL approximately.Precision is measured need testing solution 10 μ L, injects chromatograph of liquid, the record chromatogram; With calculated by peak area, acid-resistant strength is 90% just up to specification greater than labelled amount by external standard method.Test result is shown in the following table 2.
The test result of table 2 release degree and acid-resistant strength
Five. stability study
(embodiment 5 comprises contagion gown layer prepared preparation according to the invention to get the rabeprazole preparation of sodium that makes among embodiment 5 and the reference embodiment respectively; Reference embodiment is an ordinary preparation), each 5, put in the mortar; Add 0.2M NaOH solution 20mL, fully grind; Add 0.001M NaOH solution 20mL again, gradation is transferred in the 50mL measuring bottle, ultrasonic 5 minutes, make dissolving, put be chilled to room temperature after, standardize solution shakes up, centrifugal (8000rpm, 10 minutes), supernatant filters through 0.45 μ m microporous filter membrane, as need testing solution; Precision is measured need testing solution 1mL, puts in the 100mL measuring bottle, adds the 0.001MNaOH solution dilution to scale, processes contrast solution (1%).Get contrast solution 10 μ L and inject chromatograph of liquid, regulate instrumental sensitivity, make the peak height of main constituent chromatographic peak be about 20% of monitor full scale;
Precision is measured above-mentioned contrast solution and each 10 μ L of need testing solution, according to the liquid-phase condition under the release degree item, and injection chromatograph of liquid, 2 times of writing down chromatogram to main constituent peak retention time.If any impurity peaks, measure each impurity peak area sum in the chromatogram of need testing solution, must not be greater than 3.5 times (3.5%) of contrast solution main constituent peak-to-peak area.
Test result is shown in the following table 3, and the result relatively sees Fig. 4 and Fig. 5.
The test result of table 3 stability
Claims (16)
1. sodium rabeprazole enteric-coated microgranule, said sodium rabeprazole enteric-coated microgranule comprises from the inside to the outside successively:
(1) celphere, it is the innermost layer structure of above-mentioned enteric-coated microsome;
(2) drug-loaded layer, it is coated on outside the above-mentioned celphere, is processed by the drug-loaded layer compositions, and said composition comprises active constituents of medicine RABEPRAZOLE SODIUM, binding agent and pH value regulator;
(3) contagion gown layer, it is coated on outside the above-mentioned drug-loaded layer, is processed by the contagion gown layer composition, and said composition comprises binding agent, opacifier and antiplastering aid; With
(4) enteric coating layer, it is coated on outside the above-mentioned contagion gown layer, is processed by the enteric coating layer compositions, and said composition comprises enteric-coating material, plasticizer, antiplastering aid and blocker.
2. sodium rabeprazole enteric-coated microgranule according to claim 1; Wherein, Directly said sodium rabeprazole enteric-coated microgranule is carried out the capsule fill; Perhaps with said sodium rabeprazole enteric-coated microgranule and mixing acceptable accessories tabletting and be prepared into sodium rabeprazole enteric-coated orally disintegrating tablets, preferably said sodium rabeprazole enteric-coated microgranule is prepared into enteric-coated orally disintegrating tablets.
3. sodium rabeprazole enteric-coated microgranule according to claim 1 and 2, wherein, based on the gross weight of sodium rabeprazole enteric-coated microgranule, said sodium rabeprazole enteric-coated microgranule comprises:
(1) 3～15%, preferred 5～12% celphere;
(2) 10～40%, preferred 10～30% drug-loaded layer;
(3) 5～20%, preferred 5～15% contagion gown layer; With
(4) 35～82%, preferred 40～80% enteric coating layer.
4. sodium rabeprazole enteric-coated microgranule according to claim 1 and 2; Wherein, said celphere is selected from sucrose ball core and the microcrystalline Cellulose ball core, and the particle diameter of said celphere is 50～400 μ m; Be preferably 50～300 μ m, more preferably 100～200 μ m.
5. sodium rabeprazole enteric-coated microgranule according to claim 1 and 2, wherein, the binding agent in the said drug-loaded layer compositions is selected from one or more in hydroxypropyl emthylcellulose, hydroxyethyl-cellulose, hydroxypropyl cellulose, polyvidone and the copolyvidone.
6. sodium rabeprazole enteric-coated microgranule according to claim 1 and 2, wherein, said pH value regulator is selected from one or more in magnesium oxide, magnesium hydroxide, sodium hydroxide, potassium hydroxide and the magnesium carbonate.
7. sodium rabeprazole enteric-coated microgranule according to claim 1 and 2; Wherein, the binding agent in the said contagion gown layer composition is selected from one or more in hydroxypropyl emthylcellulose, ethyl cellulose, methylcellulose, hydroxyethyl-cellulose, hydroxypropyl cellulose, polyvidone and the copolyvidone.
8. sodium rabeprazole enteric-coated microgranule according to claim 1 and 2, wherein, said opacifier is selected from one or more in titanium dioxide, iron oxide red, iron oxide yellow, iron oxide purple and the iron oxide black.
9. sodium rabeprazole enteric-coated microgranule according to claim 1 and 2, wherein, the antiplastering aid in said contagion gown layer composition and the enteric coating layer compositions is selected from one or more in Pulvis Talci, glyceryl monostearate and the magnesium stearate.
10. sodium rabeprazole enteric-coated microgranule according to claim 1 and 2; Wherein, said enteric-coating material is selected from one or more in EUDRAGIT S100, methacrylate copolymer, amino methyl acrylic copolymer, Hydroxypropyl Methylcellulose Phathalate, succinic acid acetic acid hydroxy methocel and the succinic acid acetic acid hydroxypropyl methylcellulose.
11. sodium rabeprazole enteric-coated microgranule according to claim 1 and 2; Wherein, said plasticizer is selected from one or more in triethyl citrate, ATBC, dimethyl phthalate, diethyl phthalate, dibutyl phthalate, dibutyl sebacate, citroflex A-4, glycerol acetate and the Oleum Ricini.
12. sodium rabeprazole enteric-coated microgranule according to claim 1 and 2, wherein, said blocker is selected from one or more in stearic acid, mono stearate glyceryl ester and the liquid paraffin.
13. sodium rabeprazole enteric-coated microgranule according to claim 2, wherein, said acceptable accessories comprises disintegrating agent, filler, correctives and lubricant.
14. the method for preparing of the described sodium rabeprazole enteric-coated microgranule of claim 1, this method for preparing may further comprise the steps:
1. the drug-loaded layer compositions is coated on the celphere, and preparation medicine carrying granule;
2. with said medicine carrying granule with contagion gown layer composition coating, and preparation contagion gown granule;
3. with said contagion gown granule with enteric coating layer compositions coating, and the preparation enteric-coated microsome.
15. method for preparing according to claim 14, wherein, step 1.-3. in, adopt the mode of fluidized bed coating to carry out particle drug-loaded, bag contagion gown and enteric coated.
16. method for preparing according to claim 14, wherein, said method for preparing further may further comprise the steps: with said enteric-coated microsome and mixing acceptable accessories and prepare sodium rabeprazole enteric-coated orally disintegrating tablets.
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| CN104274423A (en) * | 2013-07-02 | 2015-01-14 | 杭州赛利药物研究所有限公司 | Rabeprazole enteric capsule and preparation method thereof |
| CN104398494A (en) * | 2014-11-21 | 2015-03-11 | 广东东阳光药业有限公司 | Meleumycin enteric capsule and preparation method thereof |
| CN104922086A (en) * | 2015-06-21 | 2015-09-23 | 珠海润都制药股份有限公司 | Preparation method of proton pump inhibitor enteric-coated tablet |
| CN105434400A (en) * | 2015-12-24 | 2016-03-30 | 寿光富康制药有限公司 | Preparation method of tiny proton pump inhibitor enteric-coated pellet |
| CN107375226A (en) * | 2017-06-22 | 2017-11-24 | 江苏豪森药业集团有限公司 | Sodium rabeprazole enteric-coated tablet and preparation method thereof |
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| CN112168800A (en) * | 2020-09-28 | 2021-01-05 | 南京长澳医药科技有限公司 | Rabeprazole sodium enteric-coated orally disintegrating tablet and preparation method thereof |
| CN112641749A (en) * | 2020-12-31 | 2021-04-13 | 海南华益泰康药业有限公司 | Rabeprazole sodium enteric-coated tablet and preparation method thereof |
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| CN104274423A (en) * | 2013-07-02 | 2015-01-14 | 杭州赛利药物研究所有限公司 | Rabeprazole enteric capsule and preparation method thereof |
| CN104274423B (en) * | 2013-07-02 | 2018-08-17 | 杭州赛利药物研究所有限公司 | Rabeprazole capsulae enterosolubilis and preparation method thereof |
| CN104398494A (en) * | 2014-11-21 | 2015-03-11 | 广东东阳光药业有限公司 | Meleumycin enteric capsule and preparation method thereof |
| CN104398494B (en) * | 2014-11-21 | 2018-01-23 | 广东东阳光药业有限公司 | A kind of meleumycin capsulae enterosolubilis and preparation method |
| CN104922086A (en) * | 2015-06-21 | 2015-09-23 | 珠海润都制药股份有限公司 | Preparation method of proton pump inhibitor enteric-coated tablet |
| CN104922086B (en) * | 2015-06-21 | 2018-01-16 | 珠海润都制药股份有限公司 | A kind of preparation method of proton pump inhibitor enteric coatel tablets |
| CN105434400A (en) * | 2015-12-24 | 2016-03-30 | 寿光富康制药有限公司 | Preparation method of tiny proton pump inhibitor enteric-coated pellet |
| CN105434400B (en) * | 2015-12-24 | 2018-09-21 | 寿光富康制药有限公司 | A kind of preparation method of the minimum enteric-coated micro-pill of proton pump inhibitor |
| CN107375226A (en) * | 2017-06-22 | 2017-11-24 | 江苏豪森药业集团有限公司 | Sodium rabeprazole enteric-coated tablet and preparation method thereof |
| 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 |
| CN112168800A (en) * | 2020-09-28 | 2021-01-05 | 南京长澳医药科技有限公司 | Rabeprazole sodium enteric-coated orally disintegrating tablet and preparation method thereof |
| CN112641749A (en) * | 2020-12-31 | 2021-04-13 | 海南华益泰康药业有限公司 | Rabeprazole sodium enteric-coated tablet and preparation method thereof |
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