CN104414978A - Enteric-coated micropellet containing esomeprazole magnesium - Google Patents
Enteric-coated micropellet containing esomeprazole magnesium Download PDFInfo
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Abstract
The invention relates to an enteric-coated micropellet containing esomeprazole magnesium. The enteric-coated micropellet comprises an inert pellet core, a medicament-loaded layer, an isolation layer and an enteric-coated layer, wherein the enteric-coated layer contains a methacrylic acid/ethyl acrylate 1: 1 copolymer, glyceryl monostearate, Tween 80 and talcum powder, wherein the methacrylic acid/ethyl acrylate 1: 1 copolymer is preferably Eudragit L30D-55. The enteric-coated micropellet containing esomeprazole magnesium, provided by the invention, can give consideration to acid resistance, release rate and stability of a product for a long time in the placement process, can meet or exceed existing preparation quality standards; and furthermore, the enteric-coated micropellet is prepared by simple process steps, is suitable for a relatively large pellet core (0.3mm-1mm), has the characteristic of low production cost, and is more suitable for large-scale industrialized production.
Description
Technical field
The present invention relates to pharmaceutical preparation, be specifically related to a kind of enteric coated micropill containing esomeprazole magnesium.
Background technology
Esomeprazole (Esomeprazole; 5-methoxyl group-2-((S)-((4-methoxyl group-3; 5-dimethyl-2-pyridine radicals) methyl) sulfinyl-1 H-benzimidazole) be proton pump inhibitor of new generation (PPI), by suppressing the H of parietal cell
+/ K
+-ATP enzyme reduces gastric acid secretion, prevents the formation of gastric acid.Esomeprazole is the laevoisomer of first generation PPI omeprazole, compare with the dextroisomer of omeprazole with omeprazole raceme, there is onset faster, acid suppression better effects if, without obvious investigation into nocturnal acid breakthrough, lasting acid suppression in 24 hours, individual variation is few, interacting the advantage such as few with other drug, is that current therapic acid is diseases related, as the drug of first choice of peptic ulcer, Gastroesophageal reflux disease, Zollinger-Ellison Syndrome etc.
The Yuan Yan producer of Esomeprazole magnesium salt is Britain's AstraZeneca (AstraZeneca) company.February calendar year 2001, U.S. food Drug Administration ratified the listing of its enteric coated capsule, and commodity are called the resistance to letter of Nexium(), in August, 2003, Chinese food Drug Administration ratifies its prefabricated enteric coated micropill import of esomeprazole magnesium of producing.
Due to the existence of sulfoxide group in esomeprazole magnesium structure, medicine is extremely unstable in acid condition, and easily in gastric acid, degraded destroys.In order to ensure that the enteric coated preparation prepared has good acid-resistant strength in acid, not by stomach acids destroy, can most ofly or whole in intestinal juice discharge fast simultaneously, play due curative effect, specify in Chinese Pharmacopoeia (2010 editions) annex XD drug release determination method, the loss amount of enteric coated preparation in acid (hydrochloric acid solution of PH1.2) during 2h must not be greater than 10% of labelled amount, and the release in buffer (phosphate buffer of PH6.8) during 30min ~ 60min must not be less than 70% of labelled amount; For esomeprazole enteric capsules capsule, the release of American Pharmacopeia (USP35-NF30) then its 30min in the phosphate buffer of PH6.8 of specified in more detail must not be less than 75%.
Except to except acid condition sensitivity, esomeprazole magnesium to wet, heat, light are easily unstable, enteric coated micropill is easily degraded in preparation with storage, variable color, and cause product effective ingredient to reduce, impurity content increases, and affects its clinical therapeutic efficacy.American Pharmacopeia (USP35-NF30) specifies that the total impurities of esomeprazole enteric capsules capsule must not higher than 2%.
The complexity of the unstability special based on esomeprazole magnesium self and enteric coated preparation formulation and technology, preparation simultaneously and the enteric coated preparation for a long time with good acid-resistant strength, release and stability feature is hot technology and the difficult point of research both at home and abroad always.Chinese patent ZL200610136867.5 discloses a kind of enteric coated pellets formulation containing the alkali salt of omeprazole or its single enantiomer, active medicine, excipient sugarcane sugar and starch, antiacid substance oxidation magnesium are prepared into containing pill core, tundish by opacifier, HPMC or/and the sealing coat that forms of PEG6000, outer bag by Pulvis Talci, methacrylic acid copolymer or/and the enteric layer that forms of PEG6000, simple to operate to obtain, the enteric coated preparation of stable in properties.But when adopting the modes such as agitation procedure, extrusion spheronization method, coating pan processes to prepare containing pill core, principal agent easily loses, and product yield is lower; The pill regularity of preparation is poor, easily causes clothing layer to wrap up uneven, thus affect product stability when further bag sealing coat and enteric layer.Esomeprazole enteric capsules capsule prepared by said method is in the hydrochloric acid solution of PH1.2, and during 2h, medicine peracid loss amount is 4.8%, and in the phosphate buffer of PH6.8, the release of 30min is only 63.2%, and content of impurities is 1.39%.
Chinese patent application CN101513403A discloses and a kind of the solid dispersal liquid solution that benzimidazoles residues, surfactant and solid dispersion hydrophilic carrier material are prepared into is coated on inertia ball core, and the method for further bag sealing coat and enteric layer, utilize carrier to keep the high degree of dispersion state of insoluble drug, thus improve its dissolution rate.But easily there is the catabiosis such as crystallization, overgrowth of crystal and dissolution reduction in solid dispersion after a period of time places, a large amount of hydrophilic carrier materials simultaneously owing to using have very strong hygroscopicity, make product moisture-proof poor, in hygrothermal environment, impurity content obviously increases.Present invention applicant is found by research, esomeprazole enteric capsules capsule prepared by said method, cannot ambient temperature and moisture (10 DEG C ~ 30 DEG C, RH45% ~ 75%) under environment long-term (in 3 years effect duration) to maintain in acid 2h loss amount lower than 10%, buffer 30min release is higher than 75%, and impurity content is lower than 2%.
Chinese patent application CN103127026A discloses a kind of increasing containing pill core the method that one deck contains the alkali layer of alkaline sodium salt outward, to increase the acid-resistant strength of medicine, slows down its degraded.Present invention applicant is according to described in embodiment 1, increasing outward containing pill core, the alkalescence be made up of sodium phosphate, starch, magnesium stearate and hypromellose is outer, then bag sealing coat, enteric layer and skin, the esomeprazole enteric capsules capsule of preparation, its 2h loss amount in acid is 7.6%, in buffer, 30min release is 84.3%, and total impurities is 0.88%.Under ambient temperature and moisture, row detection again in 36 months is placed after above-mentioned enteric-coated pellet capsule packaging, find that in acid, 2h loss amount is 8.4%, in buffer, 30min release is 79.6%, total impurities rises to 1.53%, can to meet in acid 2h loss amount lower than 10%, buffer 30min release higher than 75% and impurity content lower than 2% quality standard, but the membership that adds of alkali layer causes production stage to increase, operation sequence is complicated, and the production cycle extends, and production cost is increased greatly.
In addition, present invention applicant also finds in research process, and the former product that lists a company that grinds can keep within the storage life in acid that 2h loss amount is lower than 5%, and the release of buffer 30min is higher than 85%.Method disclosed in part prior art, method disclosed in above-mentioned Chinese patent application CN103127026A, although loss amount obtained when to meet 2h in acid in long-term placement lower than 10%, in buffer during 30min release higher than 75%, and content of impurities is lower than the esomeprazole enteric capsules capsule of 2%, but because its index such as acid-resistant strength, release is all far below the former measured value grinding product, therefore its onset time, clinical efficacy grind compared with commercialized product with former, still have a certain distance.But the former prescription grinding commercialized product is owing to being only applicable to comparatively piller core (0.1mm ~ 0.3mm), compared to large ball core, piller core drop when coating spray is not easily sprawled, and easily cause pill adhesion, production difficulty is large; Meanwhile, piller core specific surface area is comparatively large, easily produces coating material consumption large, the problems such as production cost is high.
Can meet in acid that 2h loss amount is lower than 10% in view of prior art is difficult to provide, buffer 30min release is higher than 75%, and impurity content is lower than the esomeprazole enteric capsules capsule of 2%, or although the preparation prepared can reach above-mentioned quality standard, this characteristic cannot be maintained within the storage life, or though above-mentioned quality standard can be met within the storage life, but it is too complicated to there is production process, production cycle is longer, the problems such as high cost, exploitation is a kind of can take into account product acid-resistant strength for a long time in put procedure, release and stability, and the esomeprazole enteric capsules capsule reaching high quality standards is as far as possible very necessary, described capsule can meet and be better than existing preparation quality standard, and operation is simple, and larger ball core (0.3mm ~ 1mm) can be applicable to, pill not easily adhesion when making coating, be more suitable for large-scale industrial production, coating material consumption is less simultaneously, and production cost is lower.
Summary of the invention
Being difficult to provide the esomeprazole enteric capsules capsule can for a long time with good acid-resistant strength, release and stability to overcome prior art, the invention provides following technical scheme:
The invention provides a kind of enteric coated micropill containing esomeprazole magnesium, comprise inertia ball core, drug-loaded layer, sealing coat and enteric layer, containing methacrylic acid/ethyl acrylate 1:1 copolymer, glyceryl monostearate, Tween 80 and Pulvis Talci in described enteric layer.
The invention provides a kind of enteric coated micropill containing esomeprazole magnesium specifically, its composition comprises:
。
Methacrylic acid of the present invention/ethyl acrylate 1:1 copolymer is preferably Eudragit L30D-55.
Drug-loaded layer of the present invention can also containing at least one disintegrating agent be selected from carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose, starch, and the disintegrate effect being preferably carboxymethyl starch sodium is best.
Binding agent in drug-loaded layer of the present invention and sealing coat is selected from least one in hypromellose, hydroxypropyl cellulose, polyvinylpyrrolidone or its copolymer, polyvinyl alcohol or its copolymer, methylcellulose.
Plasticizer of the present invention is selected from least one in triethyl citrate, tributyl citrate, glycerol triacetate, diethyl phthalate, Polyethylene Glycol, acetin, caprylin.
The invention provides a kind of preferred enteric coated micropill containing esomeprazole magnesium, its composition comprises:
。
The size of inertia ball core of the present invention is 0.3mm ~ 1mm, and be preferably 0.4mm ~ 0.6mm, the ball core under this scope is more conducive to the adhesion of coating solution and sprawls, there is higher upper ball rate, and due to micropill surface area less, can enteric-coating material be saved, reduce production cost.
The invention provides a kind of enteric coated micropill more preferably containing esomeprazole magnesium, its composition comprises:
。
The preparation method of esomeprazole enteric capsules of the present invention is:
1) bag drug-loaded layer: esomeprazole magnesium, dispensable disintegrating agent, binding agent, appropriate purified water are made into suspension, and spray is wrapped on inertia ball core, regulates temperature of charge to be 25 DEG C ~ 45 DEG C in coating process;
2) bag sealing coat: binding agent, the appropriate purified water of Pulvis Talci are made into suspension, spray is wrapped on the pill of bag drug-loaded layer, regulates temperature of charge to be 25 DEG C ~ 45 DEG C in coating process;
3) bag enteric layer: methacrylic acid/ethyl acrylate 1:1 copolymer, glyceryl monostearate, Tween 80, plasticizer, the appropriate purified water of Pulvis Talci are made into coating solution, spray is wrapped in the pill of bag sealing coat, regulates temperature of charge to be 25 DEG C ~ 35 DEG C in coating process.
In the preparation process of esomeprazole enteric capsules of the present invention, the magnesium stearate of 0.05% ~ 1% of the pill weight of bag drug-loaded layer can be added after drug-loaded layer coating, can avoid producing during bag sealing coat the micropill that a large amount of electrostatic causes mutually assemble or be fluidized barrel absorption, micropill is distributed more dispersed, clothing film parcel is more effectively homogeneous.
The coating material used due to the enteric layer of enteric coated micropill has acid proof polymer, and the corrosion process of enteric coated micropill in buffer is to sealing coat by enteric layer, then progressive to drug-loaded layer, therefore, enteric material all has impact to a certain degree to the acid-resistant strength of micropill and release.In order to improve acid-resistant strength and the release of esomeprazole enteric capsules, present invention applicant attempts using different enteric-coating materials, as Hydroxypropyl methyl cellulose phtalate, Hydroxypropyl Methyl Cellulose Phthalate, cellulose acetate-phthalate, zein, Lac, cellulose acetate benzenetricarboxylic acid ester, polyvinyl alcohol phthalate ester, carboxymethylethylcelluloses etc. carry out enteric layer coating respectively, to investigate the impact of different enteric material on micropill acid-resistant strength and release, found that, above-mentioned enteric-coating material or to be difficult to be met for a long time in acid 2h loss amount lower than 10%, buffer 30min release is higher than 75%, and impurity content is lower than the esomeprazole enteric capsules capsule of 2%, as zein, polyvinyl alcohol phthalate ester etc., or in coating process, sticky ball is serious, and cause ball rate low, product yield is not high, as Lac, or need to adopt the organic solvent (as 95% ethanol) of high concentration to prepare coating solution, be unfavorable for environmental conservation, and in order to ensure that safety need be equipped with antiknock device thus increase cost, as Hydroxypropyl methyl cellulose phtalate.
In order to improve the dissolution of esomeprazole enteric capsules, make it that there is bioavailability in higher body, present invention applicant adds the disintegrating agent of variety classes and dosage in drug-loaded layer, as carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, cross-linking sodium carboxymethyl cellulose, starch etc., or two or more disintegrating agents of use in conjunction, to observe different disintegrating agent and compatibility thereof to the impact of enteric coated micropill disintegrating property, result of study shows, esomeprazole enteric capsules prepared by said method, its release in buffer during 30min is still lower than 75%, the solubilizing agent adding variety classes and dosage is attempted further in above-mentioned composition, as Tween 80, sodium lauryl sulphate, poloxamer, lecithin etc., find that its release in buffer during 30min can be increased to more than 75%, and in acid during 2h loss amount lower than 10%, total impurities is lower than 2%, but place under ambient temperature and moisture in the process of 36 months after above-mentioned enteric-coated pellet capsule packaging, its acid-resistant strength and stability decline obviously, in acid, loss amount rises to more than 10%, and total impurities is increased to more than 2%, in drug-loaded layer or sealing coat, add a certain amount of basifier further to improving acid-resistant strength and stability, result is still not improved.Research finds, rely in drug-loaded layer and add disintegrating agent and solubilizing agent, although can the release of raising enteric coated micropill in buffer to a certain degree, but obvious effect is not had for product stability, being added in of some solubilizing agents even adds the chance that medicine is revealed in poor environment in some cases, have impact on the acid-resistant strength in the long-term put procedure of product and stability.
When using fluid bed to carry out drug-loaded layer coating, disperse in order to medicaments uniformity can be made and stick on inertia ball core, the particle diameter of medicine often need be less than 25 μm, present invention applicant uses jet mill by about its particle diameter micropowder to 5 μm, then the preparation of enteric coated micropill is carried out, found that, above-mentioned micropill fill capsule is also placed 36 months after packaging under ambient temperature and moisture, in its acid, 2h loss amount is lower than 10%, in buffer, 30min release is greater than 85%, total impurities, lower than 2%, has good acid resistance, release and stability.But comminution by gas stream energy consumption is very big, and processing cost is high, unit disposal ability is poor, yields poorly, is not suitable for large-scale production.
Chinese patent CN101366703B discloses a kind of omeprazole enteric-coated micro-pill; take corn protein as the sealing coat coating material of micropill; the active drug nitride layer of alkalescence and acid enteric material are kept apart; with available protecting active constituents of medicine; adopt alcohol dissolubility acrylic acid resinⅡ as coating material simultaneously; use 98% ethanol as solvent, to reduce moisture on the impact that omeprazole stability produces in preparation process, thus obtain the preparation that stability is better, effect duration is longer.Present invention applicant is with reference to the component of enteric coated preparation described in embodiment 1, prepare esomeprazole enteric capsules capsule, in its acid of testing result, 2h loss amount is 4.3%, in buffer, 30min release is 80.2%, and total impurities is 0.63%, places row detection again in 36 months after above-mentioned enteric-coated pellet capsule packaging under ambient temperature and moisture, in result acid, 2h loss amount is 7.8%, in buffer, 30min release is 72.7%, and total impurities is 1.86%, still can not meet the quality standard of enteric coated micropill.
In addition, present invention applicant also with reference to various kinds of document method, using special binding agent as polyvinyl alcohol/Polyethylene Glycol 3:1 graft copolymer as added basifier, opacifier or sealing coat in the isolation layer, all not obtaining the enteric coated preparation can taking into account acid-resistant strength, release and stability for a long time.
Present invention applicant chances on through a large amount of experiments, when after the complete drug-loaded layer of inertia ball core bag and sealing coat, use containing methacrylic acid/ethyl acrylate 1:1 copolymer, glyceryl monostearate, Tween 80 and talcous enteric coating liquid carry out coating, can make us preparing uncannily and have good acid-resistant strength simultaneously concurrently, the enteric coated preparation of release and stability, and larger ball core (0.3mm ~ 1mm) can be applicable to, pill not easily adhesion when making coating, coating material consumption is less simultaneously, production cost is lower, be more suitable for large-scale industrial production, described enteric coated micropill specific embodiment can be 20% ~ 40% inertia ball core, bag one deck includes 7.5% ~ 22.5% esomeprazole magnesium, the drug-loaded layer of 1% ~ 3.5% binding agent, bag one deck comprises 1.5% ~ 3.5% binding agent again, 3% ~ 6% talcous sealing coat, finally bag one deck comprises 15% ~ 30% methacrylic acid/ethyl acrylate 1:1 copolymer, 1.5% ~ 9% plasticizer, 0.3% ~ 3% glyceryl monostearate, 0.03% ~ 1.8% Tween 80 and 1.5% ~ 30% talcous enteric layer, after the enteric coated micropill fill capsule now prepared, in acid during 2h loss amount lower than 10%, in buffer during 30min release higher than 75%, content of impurities is lower than 2%.Unexpected, even if be not generally used for improving containing basifier (as sodium hydroxide) etc. the composition drawing azole enteric coated preparation stability in compositions of the present invention, product of the present invention character in long-term put procedure is amazing stable, its acid-resistant strength, release and stability are without significant change, still can meet above-mentioned quality standard, significantly improve end product quality.Realize above-mentioned technique effect, need simultaneously containing methacrylic acid/ethyl acrylate 1:1 copolymer, glyceryl monostearate, Tween 80 and Pulvis Talci in enteric layer, and the consumption of each composition of prescription is in scope of the present invention, and when lack in above-mentioned four kinds of compositions in enteric layer any one, or the consumption of prescription each composition is when exceeding scope of the present invention, then can not obtain the esomeprazole enteric capsules taking into account acid-resistant strength, release and stability for a long time.
Methacrylic acid of the present invention/ethyl acrylate 1:1 copolymer can participate in the configuration of enteric coating liquid with the form of solid or aqueous dispersion, and can be never directly purchase available commodity with place of production firm: as Eudragit L30D-55, Eudragit L100-55, Kolicoat MAE30DP, Kolicoat MAE 100P, Eastacryl 30D, be preferably Eudragit L30D-55.
Inertia ball core of the present invention; can be by excipient such as the mixture of starch, sugar and starch or microcrystalline Cellulose; being obtained by equipment such as centrifugal coating granulator, extrusion spheronization machine, fluidized bed coating granulator, also can be never directly purchase available commodity with place of production firm.According to the present invention, the size of inertia ball core is 0.3mm ~ 1mm, particularly during 0.4mm ~ 0.6mm, be conducive to obtaining the enteric coated micropill with good acid-resistant strength, release and stability, and the realization of above-mentioned technique effect, be not only the restriction of its separate sources and preparation method by the size of inertia ball core.
Esomeprazole enteric capsules of the present invention, can adopt the equipment preparations such as centrifugal coating granulator, fluidized bed coating granulator, atresia or porose efficient film coating pan.
Esomeprazole enteric capsules of the present invention, loads hard capsule by standard quantity, obtains esomeprazole enteric capsules capsule.
comparative example
In following comparative example, the weight of esomeprazole magnesium is all in esomeprazole, and the inertia ball core of use is Ethispheres
?cP250 microcrystalline Cellulose type fine pellet core.
comparative example 1
comparative example 2
comparative example 3
comparative example 4
comparative example 5
comparative example 6
comparative example 7
comparative example 8
comparative example 9
comparative example 10
According to formula described in comparative example 1 ~ 10, first prepare drug-loaded layer coating solution, spray is wrapped on inertia ball core, prepare sealing coat coating solution again, spray is wrapped on the pill of bag drug-loaded layer, finally prepares enteric layer coating solution, spray is wrapped on the pill of bag sealing coat, be prepared into enteric coated micropill, fill, in hard capsule, obtains esomeprazole enteric capsules capsule.
Peracid loss amount when placing 36 months after measuring above-mentioned enteric-coated pellet capsule packaging as follows respectively 0 time and under ambient temperature and moisture (10 DEG C ~ 30 DEG C, RH45% ~ 75%) environment, release and content of impurities in buffer.
peracid loss amount:
Get esomeprazole enteric capsules capsule, according to drug release determination method (Chinese Pharmacopoeia version in 2010 two annex X D second methods), adopt dissolution method (Chinese Pharmacopoeia 2010 editions annex XC first methods) device, with 0.1mol/L hydrochloric acid solution 300ml for dissolution medium, rotating speed is 100 turns, operate in accordance with the law, through 120 minutes time, add 0.1mol/L sodium hydroxide solution 300ml, phosphate buffer (pH11.0) [gets 95.0g/L trisodium phosphate solution 11ml and 179.1g/L disodium phosphate soln 22ml, be diluted with water to 1000ml, mix and get final product] 400ml, continue to operate in accordance with the law, through 30 minutes time, get solution 10ml, filter, as need testing solution, separately get omeprazole reference substance, accurately weighed, put in 100ml measuring bottle, add 10ml ethanol and make dissolving, add phosphate buffer (pH11.0) and be diluted to scale, shake up, precision measures 10ml, puts in 50ml measuring bottle, be diluted with water to scale, shake up, in contrast product solution.Precision measures reference substance solution and each 20 μ l of need testing solution, respectively injection liquid chromatography, and chromatographic condition is as follows:
Be filler with octadecylsilane chemically bonded silica, mobile phase is that acetonitrile-phosphate buffer (pH7.3) [gets 1.0mol/L sodium dihydrogen phosphate 10.5ml and 0.5mol/L disodium phosphate soln 60ml, be diluted with water to 1000ml, shake up, adjust ph to 7.3]-water (35:50:15), determined wavelength is 302nm, and flow velocity is 1.0ml/min.The retention time at omeprazole peak is about 4 minutes, and record chromatogram is to 1.5 times of main peak retention time.Be calculated as follows peracid loss amount:
Peracid loss amount=
Wherein, A
supplyfor test sample main peak area, A
rightfor reference substance main peak area, C
rightfor the concentration of reference substance solution, unit is mg/ml; V is the cumulative volume of dissolution medium, is 1000ml herein.W
rulefor the specification of every capsules, i.e. the labelled amount (in esomeprazole) of esomeprazole magnesium.
release in buffer:
Get esomeprazole enteric capsules capsule, according to drug release determination method (Chinese Pharmacopoeia version in 2010 two annex X D second methods), adopt dissolution method (Chinese Pharmacopoeia version in 2010 two annex X C second methods) device, with 0.1mol/L hydrochloric acid solution 300ml for dissolution medium, rotating speed is 75 turns per minute, operate in accordance with the law, through 120 minutes time, add the 0.086mol/L disodium phosphate soln 700ml of 37 DEG C, continue to operate in accordance with the law, through 30 minutes time, get solution 10ml, filter, precision measures subsequent filtrate 5ml, precision adds 0.25mol/L sodium hydroxide solution 1ml immediately, mixing, as need testing solution, separately get omeprazole reference substance, accurately weighed, put in 100ml measuring bottle, add ethanol 10ml and make dissolving, (get 0.1mol/L hydrochloric acid solution 300ml and 0.086mol/L disodium phosphate soln 700ml with phosphate buffer (pH6.8), mixing) be diluted to scale, shake up, precision measures 10 ml, puts in 50ml measuring bottle, be diluted to scale with phosphate buffer (pH6.8), shake up, precision measures 5ml, and precision adds 0.25mol/L sodium hydroxide solution 1ml immediately, shakes up, in contrast product solution.Precision measures reference substance solution and each 20 μ l of need testing solution, and injection liquid chromatography, tests according to the chromatographic condition under peracid loss amount detection respectively, and record chromatogram, calculates the release of every capsules in buffer according to the following formula:
Buffer release=
Wherein, A
supplyfor test sample main peak area; A
rightfor reference substance main peak area; C
rightfor the concentration of reference substance solution, unit is mg/ml; V is the cumulative volume of dissolution medium, is 1000ml herein.W
rulefor the specification of every capsules, i.e. the labelled amount (in esomeprazole) of esomeprazole magnesium.
content of impurities:
Measure according to high performance liquid chromatography (Chinese Pharmacopoeia 2010 editions two annex VD).
Get esomeprazole enteric capsules capsule 's content porphyrize, get fine powder appropriate (being about equivalent to esomeprazole 14mg), put in 50ml measuring bottle, add phosphate buffer (pH11.0) 1ml, jolting makes dispersion, adds methanol 15ml, jolting 30 seconds, 25 DEG C of supersound process 5 minutes, add phosphate buffer (pH11.0) 15ml, be diluted with water to scale, shake up, filtering, getting subsequent filtrate as need testing solution (facing with newly joining); Precision measures need testing solution 1ml, puts in 100ml measuring bottle, is diluted with water to scale, shake up, in contrast solution.Get contrast solution 20ul, injection liquid chromatography, regulate detector sensitivity, make the peak height of main constituent chromatographic peak be about 20% of full scale, then precision measures need testing solution and each 20ul of contrast solution, injection liquid chromatography respectively, chromatographic condition is: take octadecylsilane chemically bonded silica as filler, is mobile phase A with phosphate buffer (pH8.0) [1.4g/L disodium phosphate soln is 8.0 with phosphoric acid adjust pH], acetonitrile is Mobile phase B, carries out gradient elution according to following ratio:
Determined wavelength is 280nm, and flow velocity is 1.0ml/min.Record chromatogram, calculates content of impurities according to the following formula:
Content of impurities=Σ A
assorted/ A
right
Wherein, Σ A
assortedfor each impurity peaks peak area sum, A
rightfor the peak area of contrast solution main peak.
Comparative example 1 ~ 10 enteric-coated pellet capsule 0 time and 36 months time acid-resistant strength, release and content of impurities the results are shown in following table:
In comparative example 1 ~ 3, disintegrating agent and solubilizing agent is increased in drug-loaded layer, or basifier is added in drug-loaded layer, add basifier and opacifier in sealing coat, the esomeprazole enteric capsules simultaneously with good acid-resistant strength, release and stability can not be obtained; In comparative example 4 ~ 5, use polyvinyl alcohol/Polyethylene Glycol 3:1 graft copolymer as insolated layer materials, or enteric layer coating material to be replaced with acrylic acid resinⅡ, still cannot significantly improve dissolution and the acid-resistant strength of micropill; Comparative example 6, by about the particle diameter micropowder to 5 of principal agent μm, can be met the micropill of preparation quality standard for a long time, but this method energy consumption is large, process high, yield poorly, be not suitable for large-scale production; In comparative example 7 ~ 10, use and carry out coating containing the enteric liquid of any 3 kinds of compositions in methacrylic acid/ethyl acrylate 1:1 copolymer, glyceryl monostearate, Tween 80 and Pulvis Talci, when can not obtain 2h in acid, loss amount is lower than 10%, in buffer during 30min release higher than 75%, content of impurities lower than 2% enteric coated micropill, only when enteric layer is simultaneously containing above-mentioned 4 kinds of compositions, the preparation of esomeprazole enteric capsules capsule quality standard just can be met.
comparative example 11
According to formula described in comparative example 10, first prepare drug-loaded layer coating solution, spray is wrapped on inertia ball core, then prepares sealing coat coating solution, and spray is wrapped on the pill of bag drug-loaded layer.
comparative example 12
According to formula described in comparative example 10, first prepare drug-loaded layer coating solution, spray is wrapped on inertia ball core, then prepares sealing coat coating solution, and in sealing coat coating solution, adding the antistatic additive sodium lauryl sulphate of hypromellose weight 0.1%, after mix homogeneously, spray is wrapped on the pill of bag drug-loaded layer.
comparative example 13
According to formula described in comparative example 10, first prepare drug-loaded layer coating solution, spray is wrapped on inertia ball core, then prepares sealing coat coating solution, spray be wrapped on the pill of bag drug-loaded layer, and in bag sealing coat process every Pulvis Talci adding the pill weight 0.01% of bag drug-loaded layer for 5 minutes.
comparative example 14
According to formula described in comparative example 10, first prepare drug-loaded layer coating solution, spray is wrapped on inertia ball core, after drug-loaded layer coating, in pill, add the magnesium stearate of 0.05% of the pill weight of bag drug-loaded layer, then prepare sealing coat coating solution, spray is wrapped on the pill of the above-mentioned drug-loaded layer of bag.
Respectively when comparative example 11 ~ 14 bag sealing coat, observe the absorption situation of pill in fluid bed, and contrast its electrostatic size produced by the following method: single bar-shaped contact-type electrostatic probe is placed in fluid bed inwall, respectively when seething with excitement fluidisation 5 minutes, 10 minutes and 15 minutes, platinized platinum electroscope is placed in distance electrostatic probe 0.5cm place and measures its platinized platinum irrelevance, platinized platinum irrelevance is larger, shows that the electrostatic electricity produced is larger.
Testing result sees the following form:
The testing result of comparative example 11 ~ 14 shows, adopt the method for electrostatic in removal coating process conventional in current commercial production, as added antistatic additive sodium lauryl sulphate in sealing coat coating solution, or repeatedly Pulvis Talci is added in sealing coat coating process, can not significantly reduce the electrostatic produced in sealing coat coating process, micropill in fluid bed when seething with excitement fluidisation because electrostatic attracts each other gathering, and part is fluidized barrel absorption, cannot be dispersed, thus affect clothing film covered effect, and adopt the preparation method described in present patent application, after drug-loaded layer coating completes, the magnesium stearate of 0.05% ~ 1% of the pill weight of bag drug-loaded layer is added in pill, carry out the coating of sealing coat again, then obviously can improve electrostatic phenomenon, improve coating efficiency.
Detailed description of the invention
Below in conjunction with specific embodiment, set forth the present invention further.But these embodiments are only limitted to the present invention instead of the further restriction to protection scope of the present invention are described.
embodiment 1
In the present embodiment, inertia ball core is the cane sugar type fine pellet core purchased from Gaocheng Biologic Nutrition Technology Co Ltd, Hangzhou.
embodiment 2
In the present embodiment, inertia ball core is the microcrystalline Cellulose type fine pellet core tieing up brilliant pharmaceutic adjuvant technological development company limited purchased from Haining.
embodiment 3
In the present embodiment, inertia ball core is for using the homemade starch type fine pellet core of centrifugal coating granulator.
embodiment 4
In the present embodiment, inertia ball core is the cane sugar type fine pellet core purchased from weights Tyke, Changzhou pharmaceutic adjuvant company limited.
embodiment 5
In the present embodiment, inertia ball core is the starch type fine pellet core purchased from Linan, Hangzhou Dechang Chemical Co., Ltd..
embodiment 6
In the present embodiment, inertia ball core is for using the homemade cane sugar type fine pellet core of extrusion spheronization machine.
embodiment 7
In the present embodiment, inertia ball core is Suglets
?cP-405E cane sugar type fine pellet core.
embodiment 8
In the present embodiment, inertia ball core is the cane sugar type fine pellet core purchased from Anhui Shanhe Medicinal Subsidiary Material Co., Ltd..
embodiment 9
In the present embodiment, inertia ball core is the microcrystalline Cellulose type fine pellet core purchased from Gaocheng Biologic Nutrition Technology Co Ltd, Hangzhou.
embodiment 10
In the present embodiment, inertia ball core is the cane sugar type fine pellet core purchased from the special Science and Technology Ltd. in Xinyi, Shenzhen.
embodiment 11
In the present embodiment, inertia ball core is for using the homemade cane sugar type fine pellet core of fluidized bed coating granulator.
embodiment 12
In the present embodiment, inertia ball core is Ethispheres
?cP250 microcrystalline Cellulose type fine pellet core.
embodiment 13
In the present embodiment, inertia ball core is Ethispheres
?cP250 microcrystalline Cellulose type fine pellet core.
According to formula described in embodiment 1 ~ 11, first prepare drug-loaded layer coating solution, spray is wrapped on inertia ball core, prepare sealing coat coating solution again, spray is wrapped on the pill of bag drug-loaded layer, finally prepares enteric layer coating solution, spray is wrapped on the pill of bag sealing coat, be prepared into enteric coated micropill, fill, in hard capsule, obtains esomeprazole enteric capsules capsule.
According to formula described in embodiment 12, first prepare drug-loaded layer coating solution, spray is wrapped on inertia ball core, after drug-loaded layer coating, the magnesium stearate of 0.1% of the pill weight of bag drug-loaded layer is added in pill, prepare sealing coat coating solution again, spray is wrapped on the pill of the above-mentioned drug-loaded layer of bag, finally prepares enteric layer coating solution, spray is wrapped on the pill of bag sealing coat, be prepared into enteric coated micropill, fill, in hard capsule, obtains esomeprazole enteric capsules capsule.
According to formula described in embodiment 13, first prepare drug-loaded layer coating solution, spray is wrapped on inertia ball core, after drug-loaded layer coating, the magnesium stearate of 1% of the pill weight of bag drug-loaded layer is added in pill, prepare sealing coat coating solution again, spray is wrapped on the pill of the above-mentioned drug-loaded layer of bag, finally prepares enteric layer coating solution, spray is wrapped on the pill of bag sealing coat, be prepared into enteric coated micropill, fill, in hard capsule, obtains esomeprazole enteric capsules capsule.
Respectively when embodiment 1 ~ 13 bag sealing coat, observe the absorption situation of pill in fluid bed, and measured its platinized platinum irrelevance in 5 minutes, 10 minutes, 15 minutes time.Testing result sees the following form:
。
Peracid loss amount when placing 36 months after measuring above-mentioned enteric-coated pellet capsule packaging respectively 0 time and under ambient temperature and moisture (10 DEG C ~ 30 DEG C, RH45% ~ 75%) environment, release and content of impurities in buffer, the results are shown in following table:
。
Claims (10)
1. the enteric coated micropill containing esomeprazole magnesium, comprise inertia ball core, drug-loaded layer, sealing coat and enteric layer, it is characterized in that in described enteric layer containing methacrylic acid/ethyl acrylate 1:1 copolymer, glyceryl monostearate, Tween 80 and Pulvis Talci.
2. the enteric coated micropill containing esomeprazole magnesium according to claim 1, is characterized in that the composition of described enteric coated micropill comprises:
。
3. the enteric coated micropill containing esomeprazole magnesium according to claim 1 and 2, is characterized in that described methacrylic acid/ethyl acrylate 1:1 copolymer is Eudragit L30D-55.
4. the enteric coated micropill containing esomeprazole magnesium according to claim 2, it is characterized in that described drug-loaded layer can also containing be selected from carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose, starch one or more; Be preferably carboxymethyl starch sodium.
5. the enteric coated micropill containing esomeprazole magnesium according to claim 2, the binding agent that it is characterized in that in described drug-loaded layer and sealing coat is selected from least one in hypromellose, hydroxypropyl cellulose, polyvinylpyrrolidone or its copolymer, polyvinyl alcohol or its copolymer, methylcellulose.
6. the enteric coated micropill containing esomeprazole magnesium according to claim 2, is characterized in that described plasticizer is selected from least one in triethyl citrate, tributyl citrate, glycerol triacetate, diethyl phthalate, Polyethylene Glycol, acetin, caprylin.
7. the enteric coated micropill containing esomeprazole magnesium according to claim 3, is characterized in that the composition of described enteric coated micropill comprises:
。
8. the enteric coated micropill containing esomeprazole magnesium according to any one of claim 1 ~ 7, is characterized in that the size of described inertia ball core is 0.3mm ~ 1mm, is preferably 0.4mm ~ 0.6mm.
9. the enteric coated micropill containing esomeprazole magnesium according to claim 8, is characterized in that the composition of described enteric coated micropill comprises:
The particle diameter of wherein said inertia ball core is 0.4mm ~ 0.6mm.
10. the enteric coated micropill containing esomeprazole magnesium according to any one of claim 1 ~ 9, is characterized in that the preparation method of described enteric coated micropill is:
1) bag drug-loaded layer: esomeprazole magnesium, dispensable disintegrating agent, binding agent, appropriate purified water are made into suspension, and spray is wrapped on inertia ball core, regulates temperature of charge to be 25 DEG C ~ 45 DEG C in coating process;
2) bag sealing coat: binding agent, the appropriate purified water of Pulvis Talci are made into suspension, spray is wrapped on the pill of bag drug-loaded layer, regulates temperature of charge to be 25 DEG C ~ 45 DEG C in coating process;
3) bag enteric layer: methacrylic acid/ethyl acrylate 1:1 copolymer, glyceryl monostearate, Tween 80, plasticizer, the appropriate purified water of Pulvis Talci are made into coating solution, spray is wrapped in the pill of bag sealing coat, regulates temperature of charge to be 25 DEG C ~ 35 DEG C in coating process;
In the preparation process of preferred described enteric coated micropill, after drug-loaded layer coating, add the magnesium stearate of 0.05% ~ 1% of the pill weight of bag drug-loaded layer.
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Cited By (10)
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| CN104906565A (en) * | 2015-05-13 | 2015-09-16 | 西南大学 | Pancreatin enteric coating pellet and preparation method therefor |
| CN105106168A (en) * | 2015-08-19 | 2015-12-02 | 德州德药制药有限公司 | Esomeprazole magnesium enteric capsules and preparation method thereof |
| CN105125517A (en) * | 2015-07-16 | 2015-12-09 | 广东彼迪药业有限公司 | Esomeprazole magnesium enteric pellet capsule and preparation method thereof |
| CN105193767A (en) * | 2015-08-25 | 2015-12-30 | 江苏中邦制药有限公司 | Preparation method of esomeprazole magnesium enteric-coated pellets |
| CN105326801A (en) * | 2015-11-26 | 2016-02-17 | 河北神威药业有限公司 | Preparation process and use method of esomeprazole enteric coating solution |
| CN107737342A (en) * | 2017-11-30 | 2018-02-27 | 江苏昕宇药业有限公司 | A kind of enteric solubility speed collapses pre-mixing agent |
| CN108042506A (en) * | 2018-01-09 | 2018-05-18 | 上海祺宇生物科技有限公司 | A kind of enteric plant capsule and its capsule |
| CN111481525A (en) * | 2020-04-21 | 2020-08-04 | 广东一力罗定制药有限公司 | Omeprazole enteric-coated pellet and production process thereof |
| CN112999188A (en) * | 2019-12-19 | 2021-06-22 | 康普药业股份有限公司 | Omeprazole enteric-coated pellet and preparation method thereof |
| CN116898825A (en) * | 2023-09-13 | 2023-10-20 | 北京罗诺强施医药技术研发中心有限公司 | Pancreatin enteric-coated capsule, preparation method and application thereof |
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| CN104906565A (en) * | 2015-05-13 | 2015-09-16 | 西南大学 | Pancreatin enteric coating pellet and preparation method therefor |
| CN105125517A (en) * | 2015-07-16 | 2015-12-09 | 广东彼迪药业有限公司 | Esomeprazole magnesium enteric pellet capsule and preparation method thereof |
| CN105106168A (en) * | 2015-08-19 | 2015-12-02 | 德州德药制药有限公司 | Esomeprazole magnesium enteric capsules and preparation method thereof |
| CN105106168B (en) * | 2015-08-19 | 2018-03-06 | 德州德药制药有限公司 | A kind of esomeprazole magnesium intestines capsule and preparation method thereof |
| CN105193767A (en) * | 2015-08-25 | 2015-12-30 | 江苏中邦制药有限公司 | Preparation method of esomeprazole magnesium enteric-coated pellets |
| CN105326801A (en) * | 2015-11-26 | 2016-02-17 | 河北神威药业有限公司 | Preparation process and use method of esomeprazole enteric coating solution |
| CN105326801B (en) * | 2015-11-26 | 2019-03-01 | 河北神威药业有限公司 | A kind of preparing process and application method of esomeprazole enteric coating liquid |
| CN107737342A (en) * | 2017-11-30 | 2018-02-27 | 江苏昕宇药业有限公司 | A kind of enteric solubility speed collapses pre-mixing agent |
| CN108042506A (en) * | 2018-01-09 | 2018-05-18 | 上海祺宇生物科技有限公司 | A kind of enteric plant capsule and its capsule |
| CN112999188A (en) * | 2019-12-19 | 2021-06-22 | 康普药业股份有限公司 | Omeprazole enteric-coated pellet and preparation method thereof |
| CN111481525A (en) * | 2020-04-21 | 2020-08-04 | 广东一力罗定制药有限公司 | Omeprazole enteric-coated pellet and production process thereof |
| CN116898825A (en) * | 2023-09-13 | 2023-10-20 | 北京罗诺强施医药技术研发中心有限公司 | Pancreatin enteric-coated capsule, preparation method and application thereof |
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