CN106031713A - Ketoprofen sustained-release pellet and preparation method thereof - Google Patents
Ketoprofen sustained-release pellet and preparation method thereof Download PDFInfo
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Abstract
The invention relates to a ketoprofen sustained-release pellet and a preparation method thereof. The pellet comprises a blank pill core, a sustained-release layer and a medicine-feeding layer. The invention adopts a process including twice medicine feeding and twice coating of sustained-release coating. The process not only controls the content proportion and speed of the medicine feeding, but also uses the combination of skeleton and membrane controlled-release; while oil is added in the sustained-release coating, so that the medicine feeding efficiency and coating efficiency are increased, and the content uniformity and reproducibility of process are better, and easy to control; the release is uniform and the release energy curve is basically the same as the preparation on the market. The coating layer has better stability, and reaches in vitro release effect similar to that of the brand-name drug. The invention improves production efficiency and is applicable to large-scale production.
Description
Technical field
The present invention relates to pharmaceutical preparation containing ketoprofen and preparation method thereof, more particularly to slow-release micro-pill containing ketoprofen and preparation method thereof.
Background technology
Ketoprofen, English name: ketoprofen, chemical name: Alpha-Methyl-3-benzoyl-phenylacetic acid, structural formula is as follows:
Molecular formula: C16H14O3, molecular weight: 254.29.
In daily life, pain is one of most common reason of seeking medical advice of patient, and rheumatism, arthritis are also diseases common under existing living environment, the prevalence of current China only rheumatoid arthritis just reaches about 5 ‰, and rheumatism and rheumatoid disease patient numbers are more than 10,000,000 people.
Ketoprofen is a kind of NSAID (non-steroidal anti-inflammatory drug) (NSAID), have another name called ketone ibuprofen, there is analgesia and antipyretic properties, it is the upgrading products of ibuprofen, more preponderate on therapeutic effect and untoward reaction than ibuprofen, it has been generally acknowledged that NSAID is by suppression Cycloxygenase (cyclooxygenase, COX) play a role, research shows, internal COX is made up of two kinds of enzymes of COX1 and COX2, COX1 is present in normal structure, especially gastric mucosa and kidney, produces prostaglandin (PG) by catalysis and maintains normal physiological function.And electrophysiologic studies shows, ketoprofen has clear and definite Central Analgesic Effect to human body, and intravenous injection ketoprofen can pass through rapidly blood brain barrier, reduces the spinal levels impression threshold value to nociceptive reflex.Ketoprofen has more than the Clinical practice experience of 40 years, and its easing pain and diminishing inflammation antiinflammatory action is better than the Motrin of existing market main flow.Dosage form aspect, ketoprofen slow-release agent is because simplicity of taking medicine, untoward reaction are little and make patient be prone to accept, and therefore inventor has carried out the exploitation of ketoprofen slow release preparation.
Investigate through substantial amounts of test and data, existing relate to ketoprofen slow release preparation have Chinese patent CN102000032 B, Chinese patent CN1203787 A, only disclose the prescription of a kind of slow releasing tablet, belong to the slow releasing preparation-tablet of a unit, and multiunit slow-release micro-pill is advantageously, can take with multiple dose, and a certain junior unit can't produce big impact to total release, and tablet is only a unit, Unit one directly influences the quality of product, the risk produced is bigger, is not suitable for multiple dose and takes, does not preponderate；nullDomestic patent is for ketoprofen slow-release micropill and has no publication，United States Patent (USP) US6613361 B1 discloses the preparation method of a kind of ketoprofen slow-release micropill，Celphere is used to add medicine to the usual manner of bag extended release coatings again，Coating solution has used Eudragit NE30D、Eudragit RS30D、Eudragit RL30D、Pulvis Talci、Colloidal silica、Triethyl citrate，But produce and need to use special equipment，And used substantial amounts of colloidal silica，Wherein colloidal silica due to its density too small thus very light and be prone to swim in aerial，The biggest impact all can be caused on producing and transporting，Possibly even set off an explosion，And its technique filmogen and framework material addition binding agent spray into and the particularity of framework material，It is easy in coating process produce adhesion phenomenon and the generation of electrostatic，The present inventor can find part piller adhesion in coating process in repetition process of the test，Also it is not easy after heating and cooling to recover，Even add antiplastering aids many again can not escape by luck，Requirement to environment and equipment is the highest，It is relatively difficult in technique control.And ketoprofen raw material inherent character: electrostatic is serious, easily gathering is agglomerating, be not easy molding etc., it is easily caused that gained pellet size differs, yield is low, bulk density is little, slow-release pill to be prepared as needs correspondingly to transform equipment, to add substantial amounts of anlistatig adjuvant, this is also the problem that prior art exists simultaneously.
Therefore the present inventor has invented a kind of ketoprofen slow-release micropill, both can avoid the risk only having a unit of slow releasing tablet and can not take the impact caused by multiple dose, and being avoided that again and use the too much safety risks existing for colloidal silica.While ensureing production efficiency, also can guarantee that smoothly completing and the stability of film layer of coating, reduce the requirement to equipment, more improve the controlling extent to technique, the technique being suitable for the production of scale.
The mode that the present inventor have employed framework material and film controlled release combines, 2 medicine-feedings and 2 coatings are carried out, on celphere, namely carry out solid medicine-feeding, carry out sustained-release coating layer coating for the first time, carry out second time the most again to add medicine to, the last mode carrying out second time coating again so that the uniformity of dosage units of micropill is the best, the release uniformity is the highest.In technique, medicine-feeding for the first time and second time medicine-feeding all having been carried out strict control, medicine-feeding efficiency is high, and the uniformity of dosage units of micropill is not affected by medicine-feeding speed.
The present inventor adds oils and fats in coating process in coating constituents and improves the easy bonding phenomenon produced due to electrostatic in coating process, the stability of sustained-release coating layer is also had big improvement, the most all demonstrates this advantage by substantial amounts of experiment.
The present inventor prepares ketoprofen slow-release piller by this technique of the present invention and need not use special equipment, using common centrifugal granulating seed-coating machine, production efficiency is high, and uniformity of dosage units is good, discharge homogeneous, it is possible to reach same reference preparation and discharge similar and discharge more homogeneous.
And present invention process is simple, easily operates, process stabilizing, reproducible, it is suitable for large-scale production.
Summary of the invention
What the present invention described is a kind of ketoprofen slow-release micropill and preparation method thereof, reduce the differences between batches that Ketoprofen Sustained Released Tablet in Healthy causes less because of unit, intergranular difference and can not the risk taken of multiple dose, solve slow-release micro-pill inefficiency in coating process, repeatability is bad, unmanageable problem, also improve the efficiency of medicine-feeding simultaneously, and use conventional equipment centrifugal granulating seed-coating machine just can complete medicine-feeding and enrobing processes expeditiously, and process stabilizing, reproducible, uniformity of dosage units is good, prepare the uniform ketoprofen slow-release micropill of release, solve the disadvantage that similar products conventional equipment is difficult to reappear, highly shortened the process time, it is suitable for large-scale production.
Ketoprofen slow-release micropill of the present invention, is made up of capsule core, twice medicine accommodation layer, twice coatings；
Wherein said capsule core is the one in sucrose capsule core, microcrystalline Cellulose capsule core, and particle diameter is 0.35mm～1.0mm.
Wherein coatings is become with line of oils by slow release filmogen, plasticizer, antiplastering aid, diluent, wetting agent.
Wherein, described oil is soybean oil, Oleum Arachidis hypogaeae semen or medium chain fatty acid three fat.
Further, described oil number in coatings is 2.0 ~ 5.0.
Wherein, described slow release filmogen is the one in Eudragit RL30D, Eudragit RS30D or a combination of both thing；Described antiplastering aid is Pulvis Talci, and plasticizer is triethyl citrate, and wetting agent is water.On ketoprofen slow-release micropill of the present invention twice, dose is content 55-65% for the first time, and second time medicine-feeding content is 70-80%.Described upper dose refers to the mass fraction in ketoprofen slow-release micropill of all the components weight in medicine accommodation layer.Described ketoprofen slow-release micropill, it is characterized in that the mode using framework material and film controlled release to combine controls release, framework material adds along with wetting agent together in the process added medicine to, film controlled release is carried out again by coating, while control this product uniformly discharges, substantially increase release homogeneity and decrease the phenomenon of burst release of each time point；
Owing to ketoprofen is big at comparision contents shared by ketoprofen slow-release micropill, more than 65% is all ketoprofen, therefore need in technique to carry out pressed powder medicine-feeding, and the inherent character of ketoprofen raw material be that electrostatic phenomenon is very serious, be easy to assemble agglomerating, be not easy molding, it is desirable to obtain uniform content and bulk density meets the requirements, smooth appearance, release are homogeneous slow-release micro-pill be not easy very much.Current domestic temporary nothing is correlated with the report of ketoprofen slow-release micropill and patent; part relates to the method in the paper of ketoprofen slow-release micropill; also it is only capable of being used in the lab scale stage through trial; cannot be carried out large-scale production at all, and external patent is the equipment by special transformation just can complete this medicine-feeding coating process.The present inventor proves through substantial amounts of experiment, only by common equipment-centrifugal granulating seed-coating machine, through twice medicine-feeding, twice coating, use the production technology that framework material and film controlled release combine, uniform content can not only be obtained, the piller of smooth appearance, and more can reach the purpose uniformly discharged, and it is adjusted medicine-feeding speed and other parameters, medicine-feeding speed speed is the fastest, about in 100-150 gram/minute, medicine-feeding speed can cause because medicine-feeding time length causes yield on the low side slowly the most on the contrary, adjusting medicine-feeding coating parameters makes medicine-feeding rate reach more than 95%.By this kind of combination, it is possible to make uniform content degree the best, and production efficiency is higher, discharge more uniform.
Ketoprofen slow-release micropill in the present invention, capsule core content is 16-20%.In medicine accommodation layer, drug content is 70～80%, and framework material content is 0.4-3.0%.In coatings, sustained-release matrix material content is 0.7-3.5%, and plasticizer loading is 0.4-2.0%, and antiplastering aid content is 1.0～the content of 3.0%, oil is 0.4%-2.6%.Described content refers to each solid constituent mass fraction in all solids composition summation.
Further, coatings each coating solution composition and ratio is: slow release filmogen 0-30 part, plasticizer 0.5-2.5 part, antiplastering aid 1-4 part, oil 2.0-5.0, wetting agent 80-100 part.
The present invention typically uses high-shearing dispersion emulsifying machine during preparation coating solution, the shearing of each for coating solution composition is dispersed to uniform while, also oil phase and aqueous phase homogenizing are defined simple emulsion, add lubricity, improve because electrostatic interaction causes piller adhesion phenomenon in coating process, in present invention process, serve the effect of stabilizer simultaneously, oil being added in ketoprofen slow-release micropill of the present invention at coating solution is may indicate that through substantial amounts of test, greatly reduce the bonding phenomenon that electrostatic phenomenon occurs in coating process, also improve the stability of release membranes, improve production efficiency.Ketoprofen slow-release micropill of the present invention, is likely to not have similar effect at other medicines, relevant with the characteristic of ketoprofen raw material exactly just can play this effect, these at home and abroad pertinent literature do not reported.
The technique that ketoprofen slow-release micropill of the present invention is taked is twice medicine-feeding, twice coating, concrete technology is as follows: prepared by (1) medicine accommodation layer for the first time: weigh recipe quantity fine pellet core, it is placed in centrifugal granulating seed-coating machine, weigh recipe quantity ketoprofen raw material, raw material particle size D90 ＜ 20 μm, open machine, adjust parameters, ketoprofen medicated powder is added while adding with the form of spraying with framework material and purified water mixed solution, dosing speed and hydrojet speed coordinate accordingly, the speed of guarantee dosing is 100-150g/ minute, the too low loss that can increase material of speed, too high meeting causes uniformity of dosage units bad, and cause the piller outward appearance of preparation coarse, operation below is produced impact.After treating dosing, piller is dried, collects the piller of required mesh number；(2) for the first time prepared by coating:Coating solution is prepared: weigh each coating solution components: first stirring is sheared 10-15 minute for 30 minutes again with wetting agent high-shearing dispersion emulsifying machine, standby under stirring.Coating: being placed in centrifugal granulating seed-coating machine by medicine-feeding piller for the first time, unlocking turntable, adjust parameters, temperature of charge controls at 25-45 DEG C, adjusts hydrojet speed according to material state in good time, and coating carries out heat treatment after terminating.(3) second time medicine-feeding: preparation method is with medicine-feeding for the first time.(4) coating for the second time: weighing second time medicine-feeding piller, remaining preparation method is with coating for the first time.
The ketoprofen slow-release micropill of gained of the present invention, smooth appearance, uniformly, intergranular difference is little in release, and release is stable, finally can carry out capsule filling according to different size, dosage and be prepared as capsule preparations.
By substantial amounts of experiment, and the investigation to exemplary embodiments contrasts, can be seen that when oil occupies certain ratio in coating solution, the electrostatic phenomenon that ketoprofen micropill produces in coating process can be reduced, it is above listing preparation by twice coating of twice medicine-feeding, uniformity of dosage units and release homogeneity.Phenomenon and result during piller coating are superior to according to listing the piller that formulation patent ratio is made, and allow the stability of coating membrane be greatly improved.Use oil perhaps can not reach the effect above with other active medicine micropills.
Detailed description of the invention:
Embodiment 1:
(1) for the first time prepared by medicine accommodation layer: weigh recipe quantity Eudragit NE30D and purified water by embodiment 1, stir 45 minutes preparation suspensions standby as binding agent, weigh recipe quantity medicinal fine pellet core (cane sugar type, 0.35-0.55mm) it is placed in centrifugal granulating seed-coating machine, weigh recipe quantity ketoprofen raw material, raw material particle size D90 ＜ 20 μm, open machine, adjust parameters, binding agent sprays into spray pattern, control parameters according to practical situation simultaneously, dosing speed controlling was at 100-150g/ minute, dosing is complete to be dried, it is dried to moisture≤3.0%, collect required mesh number piller and carry out next step operation.(2) for the first time prepared by coating: weighs each coating solution components according to embodiment 1 proportioning and prescription and first stirs 30 minutes again with high-shearing dispersion emulsifying machine shearing 10-15 minute, under stirring standby, medicine-feeding piller for the first time is placed in centrifugal granulating seed-coating machine, open machine and adjust parameters, temperature of charge controls at 25-45 DEG C, adjust hydrojet speed according to material state, coating terminates to carry out heat treatment in good time.(3) second time medicine-feeding: weigh Eudragit NE30D and purified water by embodiment 1 recipe quantity, stir 45 minutes standby, first time coated pellets is placed in centrifugal granulating seed-coating machine, corresponding recipe quantity ketoprofen raw material is weighed by embodiment 1, open machine, adjust parameters, with binding agent with addition of spraying, control parameters according to practical situation simultaneously, dosing speed controlling was at 100-150g/ minute, preparation method, with medicine-feeding for the first time, is dried to moisture≤3.0%, collects required mesh number piller and carries out next step operation.(4) coating for the second time: weigh each coating solution components according to embodiment 1 and first stir 30 minutes and shear 10-15 minute with high-shearing dispersion emulsifying machine again, under stirring standby, second time medicine-feeding piller is placed in centrifugal granulating seed-coating machine, open machine and adjust parameters, temperature of charge controls at 25-45 DEG C, adjust hydrojet speed according to material state, coating terminates to carry out heat treatment in good time.
Embodiment 1
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Embodiment 2:
(1) for the first time prepared by medicine accommodation layer: weigh Eudragit NE30D and purified water by embodiment 2 recipe quantity, stir 45 minutes preparation suspensions standby as binding agent, weigh recipe quantity medicinal fine pellet core (microcrystalline Cellulose capsule core, 0.35-0.55mm) it is placed in centrifugal granulating seed-coating machine, weigh recipe quantity ketoprofen raw material, raw material particle size D90 ＜ 20 μm, open machine, adjust parameters, binding agent is with addition of spraying, control parameters according to practical situation simultaneously, dosing speed controlling was at 100-150g/ minute, dosing is complete to be dried, it is dried to moisture≤3.0%, collect required mesh number piller and carry out next step operation.(2) for the first time prepared by coating: weighs each coating solution components according to embodiment 1 and first stirs 30 minutes again with high-shearing dispersion emulsifying machine shearing 10-15 minute, under stirring standby, medicine-feeding piller for the first time is placed in centrifugal granulating seed-coating machine, open machine and adjust parameters, temperature of charge controls at 25-45 DEG C, adjust hydrojet speed according to material state, coating terminates to carry out heat treatment in good time.(3) second time medicine-feeding: weigh Eudragit NE30D and purified water by embodiment 2 recipe quantity, stir 45 minutes standby, first time coated pellets is placed in centrifugal granulating seed-coating machine, weigh corresponding recipe quantity ketoprofen raw material by embodiment 1 and open machine, adjust parameters, binding agent is with addition of spraying, control parameters according to practical situation simultaneously, dosing speed controlling was at 100-150g/ minute, dosing is complete to be dried, it is dried to moisture≤3.0%, collects required mesh number piller and carry out next step operation.(4) coating for the second time: weigh each coating solution components according to embodiment 2 and first stir 30 minutes and shear 10-15 minute with high-shearing dispersion emulsifying machine again, under stirring standby, second time medicine-feeding piller is placed in centrifugal granulating seed-coating machine, open machine and adjust parameters, temperature of charge controls at 25-45 DEG C, adjust hydrojet speed according to material state, coating terminates to carry out heat treatment in good time.
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Embodiment 3:
(1) for the first time prepared by medicine accommodation layer: weigh hypromellose (5cp) and purified water by embodiment 3 recipe quantity, stir 45 minutes preparation solution standby as binding agent, weigh recipe quantity medicinal celphere (starch type, particle diameter: 0.5-0.6mm) it is placed in centrifugal granulating seed-coating machine, weigh recipe quantity ketoprofen raw material, raw material particle size D90 ＜ 20 μm, open machine, adjust parameters, with binding agent with addition of spraying, control parameters according to practical situation simultaneously, dosing speed controlling was at 100-150g/ minute, dosing is complete to be dried, it is dried to moisture≤3.0%, collect required mesh number piller and carry out next step operation.(2) for the first time prepared by coating: weighs each coating solution components according to embodiment 1 and first stirs 30 minutes again with high-shearing dispersion emulsifying machine shearing 10-15 minute, under stirring standby, medicine-feeding piller for the first time is placed in centrifugal granulating seed-coating machine, open machine and adjust parameters, temperature of charge controls at 25-45 DEG C, adjust hydrojet speed according to material state, coating terminates to carry out heat treatment in good time.(3) second time medicine-feeding: weigh Eudragit NE30D and purified water by embodiment 3 recipe quantity, stir 45 minutes standby, first time coated pellets is placed in centrifugal granulating seed-coating machine, weigh corresponding recipe quantity ketoprofen raw material by embodiment 1 and open machine, adjust parameters, with binding agent with addition of spraying, control parameters according to practical situation simultaneously, dosing speed controlling was at 100-150g/ minute, dosing is complete to be dried, it is dried to moisture≤3.0%, collects required mesh number piller and carry out next step operation.(4) coating for the second time: weigh each coating solution components according to embodiment 3 and first stir 30 minutes and shear 10-15 minute with high-shearing dispersion emulsifying machine again, under stirring standby, second time medicine-feeding piller is placed in centrifugal granulating seed-coating machine, open machine and adjust parameters, temperature of charge controls at 25-45 DEG C, adjust hydrojet speed according to material state, coating terminates to carry out heat treatment in good time.
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Embodiment 4:
(1) for the first time prepared by medicine accommodation layer: weigh Eudragit NE30D and purified water by embodiment 4 recipe quantity, stir 45 minutes preparation suspensions standby as binding agent, weigh recipe quantity medicinal fine pellet core (cane sugar type, 0.8-1.0mm) it is placed in centrifugal granulating seed-coating machine, weigh recipe quantity ketoprofen raw material, raw material particle size D90 ＜ 20 μm, open machine, adjust parameters, binding agent is with addition of spraying, control parameters according to practical situation simultaneously, dosing speed controlling was at 100-150g/ minute, dosing is complete to be dried, it is dried to moisture≤3.0%, collect required mesh number piller and carry out next step operation.(2) for the first time prepared by coating: weighs each coating solution components according to embodiment 1 and first stirs 30 minutes again with high-shearing dispersion emulsifying machine shearing 10-15 minute, under stirring standby, medicine-feeding piller for the first time is placed in centrifugal granulating seed-coating machine, open machine and adjust parameters, temperature of charge controls at 25-45 DEG C, adjust hydrojet speed according to material state, coating terminates to carry out heat treatment in good time.(3) second time medicine-feeding: weigh Eudragit NE30D and purified water by embodiment 1 recipe quantity, stir 45 minutes standby, first time coated pellets is placed in centrifugal granulating seed-coating machine, weigh corresponding recipe quantity ketoprofen raw material by embodiment 1 and open machine, adjust parameters, binding agent is with addition of spraying, control parameters according to practical situation simultaneously, dosing speed controlling was at 100-150g/ minute, dosing is complete to be dried, it is dried to moisture≤3.0%, collects required mesh number piller and carry out next step operation.(4) coating for the second time: weigh each coating solution components according to embodiment 4 and first stir 30 minutes and shear 10-15 minute with high-shearing dispersion emulsifying machine again, under stirring standby, second time medicine-feeding piller is placed in centrifugal granulating seed-coating machine, open machine and adjust parameters, temperature of charge controls at 25-45 DEG C, adjust hydrojet speed according to material state, coating terminates to carry out heat treatment in good time.
。
Embodiment 5:
(1) for the first time prepared by medicine accommodation layer: weigh Eudragit NE30D and purified water by embodiment 5 recipe quantity, stir 45 minutes preparation suspensions standby as binding agent, weigh recipe quantity medicinal fine pellet core (starch type, 0.7-0.8mm) it is placed in centrifugal granulating seed-coating machine, weigh recipe quantity ketoprofen raw material, raw material particle size D90 ＜ 20 μm, open machine, adjust parameters, binding agent is with addition of spraying, with binding agent with addition of spraying, control parameters according to practical situation simultaneously, dosing speed controlling was at 100-150g/ minute, dosing is complete to be dried, it is dried to moisture≤3.0%, collect required mesh number piller and carry out next step operation.(2) for the first time prepared by coating: weighs each coating solution components according to embodiment 1 and first stirs 30 minutes again with high-shearing dispersion emulsifying machine shearing 10-15 minute, under stirring standby, medicine-feeding piller for the first time is placed in centrifugal granulating seed-coating machine, open machine and adjust parameters, temperature of charge controls at 25-45 DEG C, adjust hydrojet speed according to material state, coating terminates to carry out heat treatment in good time.(3) second time medicine-feeding: weigh Eudragit NE30D and purified water by embodiment 5 recipe quantity, stir 45 minutes standby, first time coated pellets is placed in centrifugal granulating seed-coating machine, weigh corresponding recipe quantity ketoprofen raw material by embodiment 5 and open machine, adjust parameters, with binding agent with addition of spraying, control parameters according to practical situation simultaneously, dosing speed controlling was at 100-150g/ minute, dosing is complete to be dried, it is dried to moisture≤3.0%, collects required mesh number piller and carry out next step operation.(4) coating for the second time: weigh each coating solution components according to embodiment 1 and first stir 30 minutes and shear 10-15 minute with high-shearing dispersion emulsifying machine again, under stirring standby, second time medicine-feeding piller is placed in centrifugal granulating seed-coating machine, open machine and adjust parameters, temperature of charge controls at 25-45 DEG C, adjust hydrojet speed according to material state, coating terminates to carry out heat treatment in good time.
。
Embodiment 6:
(1) for the first time prepared by medicine accommodation layer: weigh Eudragit NE30D and purified water by embodiment 6 recipe quantity, stir 45 minutes preparation suspensions standby as binding agent, weigh recipe quantity medicinal fine pellet core (cane sugar type, 0.5-0.6mm) it is placed in centrifugal granulating seed-coating machine, weigh recipe quantity ketoprofen raw material, raw material particle size D90 ＜ 20 μm, open machine, adjust parameters, binding agent is with addition of spraying, control parameters according to practical situation simultaneously, dosing speed controlling was at 100-150g/ minute, dosing is complete to be dried, it is dried to moisture≤3.0%, collect required mesh number piller and carry out next step operation.(2) for the first time prepared by coating: weighs each coating solution components according to embodiment 6 and first stirs 30 minutes again with high-shearing dispersion emulsifying machine shearing 10-15 minute, under stirring standby, medicine-feeding piller for the first time is placed in centrifugal granulating seed-coating machine, open machine and adjust parameters, temperature of charge controls at 25-45 DEG C, adjust hydrojet speed according to material state, coating terminates to carry out heat treatment in good time.(3) second time medicine-feeding: weigh Eudragit NE30D and purified water by embodiment 6 recipe quantity, stir 45 minutes standby, first time coated pellets is placed in centrifugal granulating seed-coating machine, weigh corresponding recipe quantity ketoprofen raw material by embodiment 1 and open machine, adjust parameters, binding agent is with addition of spraying, control parameters according to practical situation simultaneously, dosing speed controlling was at 100-150g/ minute, dosing is complete to be dried, it is dried to moisture≤3.0%, collects required mesh number piller and carry out next step operation.(4) coating for the second time: weigh each coating solution components according to embodiment 6 and first stir 30 minutes and shear 10-15 minute with high-shearing dispersion emulsifying machine again, under stirring standby, second time medicine-feeding piller is placed in centrifugal granulating seed-coating machine, open machine and adjust parameters, temperature of charge controls at 25-45 DEG C, adjust hydrojet speed according to material state, coating terminates to carry out heat treatment in good time.
。
Embodiment 7:
(1) for the first time prepared by medicine accommodation layer: weigh Eudragit NE30D and purified water by embodiment 7 recipe quantity, stir 45 minutes preparation suspensions standby as binding agent, weigh recipe quantity medicinal fine pellet core (cane sugar type, 0.8-1.0mm) it is placed in centrifugal granulating seed-coating machine, weigh recipe quantity ketoprofen raw material, raw material particle size D90 ＜ 20 μm, open machine, adjust parameters, binding agent is with addition of spraying, control parameters according to practical situation simultaneously, dosing speed controlling was at 100-150g/ minute, dosing is complete to be dried, it is dried to moisture≤3.0%, collect required mesh number piller and carry out next step operation.(2) for the first time prepared by coating: weighs each coating solution components according to embodiment 7 and first stirs 30 minutes again with high-shearing dispersion emulsifying machine shearing 10-15 minute, under stirring standby, medicine-feeding piller for the first time is placed in centrifugal granulating seed-coating machine, open machine and adjust parameters, temperature of charge controls at 25-45 DEG C, adjust hydrojet speed according to material state, coating terminates to carry out heat treatment in good time.(3) second time medicine-feeding: weigh Eudragit NE30D and purified water by embodiment 7 recipe quantity, stir 45 minutes standby, first time coated pellets is placed in centrifugal granulating seed-coating machine, weigh corresponding recipe quantity ketoprofen raw material by embodiment 7 and open machine, adjust parameters, binding agent is with addition of spraying, control parameters according to practical situation simultaneously, dosing speed controlling was at 100-150g/ minute, dosing is complete to be dried, it is dried to moisture≤3.0%, collects required mesh number piller and carry out next step operation.(4) coating for the second time: take each coating solution components according to embodiment 7 and first stir 30 minutes and shear 10-15 minute with high-shearing dispersion emulsifying machine again, under stirring standby, second time medicine-feeding piller is placed in centrifugal granulating seed-coating machine, open machine and adjust parameters, temperature of charge controls at 25-45 DEG C, adjust hydrojet speed according to material state, coating terminates to carry out heat treatment in good time.
。
Embodiment 8:
(1) for the first time prepared by medicine accommodation layer: weigh Eudragit NE30D and purified water by embodiment 8 recipe quantity, stir 45 minutes preparation suspensions standby as binding agent, weigh recipe quantity medicinal fine pellet core (cane sugar type, 0.5-0.6mm) it is placed in centrifugal granulating seed-coating machine, weigh recipe quantity ketoprofen raw material, raw material particle size D90 ＜ 20 μm, open machine, adjust parameters, binding agent is with addition of spraying, control parameters according to practical situation simultaneously, dosing speed controlling was at 100-150g/ minute, dosing is complete to be dried, it is dried to moisture≤3.0%, collect required mesh number piller and carry out next step operation.(2) for the first time prepared by coating: takes each coating solution components according to embodiment 8 and first stirs 30 minutes again with high-shearing dispersion emulsifying machine shearing 10-15 minute, under stirring standby, medicine-feeding piller for the first time is placed in centrifugal granulating seed-coating machine, open machine and adjust parameters, temperature of charge controls at 25-45 DEG C, adjust hydrojet speed according to material state, coating terminates to carry out heat treatment in good time.(3) second time medicine-feeding: weigh Eudragit NE30D and purified water by embodiment 8 recipe quantity, stir 45 minutes standby, first time coated pellets is placed in centrifugal granulating seed-coating machine, weigh corresponding recipe quantity ketoprofen raw material by embodiment 8 and open machine, adjust parameters, binding agent is with addition of spraying, control parameters according to practical situation simultaneously, dosing speed controlling was at 100-150g/ minute, dosing is complete to be dried, it is dried to moisture≤3.0%, collects required mesh number piller and carry out next step operation.(4) coating for the second time: weigh each coating solution components according to embodiment 8 and first stir 30 minutes and shear 10-15 minute with high-shearing dispersion emulsifying machine again, under stirring standby, second time medicine-feeding piller is placed in centrifugal granulating seed-coating machine, open machine and adjust parameters, temperature of charge controls at 25-45 DEG C, adjust hydrojet speed according to material state, coating terminates to carry out heat treatment in good time.
。
Embodiment 9:
(1) for the first time prepared by medicine accommodation layer: weigh Eudragit NE30D and purified water by embodiment 9 recipe quantity, stir 45 minutes preparation suspensions standby as binding agent, weigh recipe quantity medicinal fine pellet core (cane sugar type, 0.5-0.6mm) it is placed in centrifugal granulating seed-coating machine, weigh recipe quantity ketoprofen raw material, raw material particle size D90 ＜ 20 μm, open machine, adjust parameters, binding agent is with addition of spraying, control parameters according to practical situation simultaneously, dosing speed controlling was at 100-150g/ minute, dosing is complete to be dried, it is dried to moisture≤3.0%, collect required mesh number piller and carry out next step operation.(2) for the first time prepared by coating: weighs each coating solution components according to embodiment 9 and first stirs 30 minutes again with high-shearing dispersion emulsifying machine shearing 10-15 minute, under stirring standby, medicine-feeding piller for the first time is placed in centrifugal granulating seed-coating machine, open machine and adjust parameters, temperature of charge controls at 25-45 DEG C, adjust hydrojet speed according to material state, coating terminates to carry out heat treatment in good time.(3) second time medicine-feeding: weigh Eudragit NE30D and purified water by embodiment 9 recipe quantity, stir 45 minutes standby, first time coated pellets is placed in centrifugal granulating seed-coating machine, weigh corresponding recipe quantity ketoprofen raw material by embodiment 9 and open machine, adjust parameters, binding agent is with addition of spraying, control parameters according to practical situation simultaneously, dosing speed controlling was at 100-150g/ minute, dosing is complete to be dried, it is dried to piller moisture≤3.0%, collects required mesh number piller and carry out next step operation.(4) coating for the second time: take each coating solution components according to embodiment 9 and first stir 30 minutes and shear 10-15 minute with high-shearing dispersion emulsifying machine again, under stirring standby, second time medicine-feeding piller is placed in centrifugal granulating seed-coating machine, open machine and adjust parameters, temperature of charge controls at 25-45 DEG C, adjust hydrojet speed according to material state, coating carries out heat treatment after terminating in good time.
。
Embodiment 10:
(1) for the first time prepared by medicine accommodation layer: weigh Eudragit NE30D and purified water by embodiment 10 recipe quantity, stir 45 minutes preparation suspensions standby as binding agent, weigh recipe quantity medicinal fine pellet core (cane sugar type, 0.5-0.6mm) it is placed in centrifugal granulating seed-coating machine, weigh recipe quantity ketoprofen raw material, raw material particle size D90 ＜ 20 μm, open machine, adjust parameters, binding agent is with addition of spraying, control parameters according to practical situation simultaneously, dosing speed controlling was at 100-150g/ minute, dosing is complete to be dried, it is dried to moisture≤3.0%, collect required mesh number piller and carry out next step operation.(2) for the first time prepared by coating: takes each coating solution components according to embodiment 10 and first stirs 30 minutes again with high-shearing dispersion emulsifying machine shearing 10-15 minute, under stirring standby, medicine-feeding piller for the first time is placed in centrifugal granulating seed-coating machine, open machine and adjust parameters, temperature of charge controls at 25-45 DEG C, adjust hydrojet speed according to material state, coating terminates to carry out heat treatment in good time.(3) second time medicine-feeding: weigh Eudragit NE30D and purified water by embodiment 10 recipe quantity, stir 45 minutes standby, first time coated pellets is placed in centrifugal granulating seed-coating machine, weigh corresponding recipe quantity ketoprofen raw material by embodiment 10 and open machine, adjust parameters, binding agent is with addition of spraying, control parameters according to practical situation simultaneously, dosing speed controlling was at 100-150g/ minute, dosing is complete to be dried, it is dried to moisture≤3.0%, collects required mesh number piller and carry out next step operation.(4) coating for the second time: weigh each coating solution components according to embodiment 10 and first stir 30 minutes and shear 10-15 minute with high-shearing dispersion emulsifying machine again, under stirring standby, second time medicine-feeding piller is placed in centrifugal granulating seed-coating machine, open machine and adjust parameters, temperature of charge controls at 25-45 DEG C, adjust hydrojet speed according to material state, coating carries out heat treatment after terminating in good time.
。
Embodiment 11:
(1)
For the first time prepared by medicine accommodation layer: weigh Eudragit NE30D and purified water by embodiment 11 recipe quantity, stir 45 minutes preparation suspensions standby as binding agent, weigh recipe quantity medicinal fine pellet core (cane sugar type, 0.5-0.6mm) as being placed in centrifugal granulating seed-coating machine, weigh recipe quantity ketoprofen raw material, raw material particle size D90 ＜ 20 μm, open machine, adjust parameters, binding agent is with addition of spraying, control parameters according to practical situation simultaneously, dosing speed controlling was at 100-150g/ minute, dosing is complete to be dried, it is dried to moisture≤3.0%, collect required mesh number piller and carry out next step operation.(2) for the first time prepared by coating: weighs each coating solution components according to embodiment 11 and first stirs 30 minutes again with high-shearing dispersion emulsifying machine shearing 10-15 minute, under stirring standby, medicine-feeding piller for the first time is placed in centrifugal granulating seed-coating machine, open machine and adjust parameters, temperature of charge controls at 25-45 DEG C, adjust hydrojet speed according to material state, coating terminates to carry out heat treatment in good time.(3) second time medicine-feeding: weigh Eudragit NE30D and purified water by embodiment 11 recipe quantity, stir 45 minutes standby, first time coated pellets is placed in centrifugal granulating seed-coating machine, weigh corresponding recipe quantity ketoprofen raw material by embodiment 11 and open machine, adjust parameters, binding agent is with addition of spraying, control parameters according to practical situation simultaneously, dosing speed controlling was at 100-150g/ minute, dosing is complete to be dried, it is dried to moisture≤3.0%, collects required mesh number piller and carry out next step operation.(4) coating for the second time: weigh each coating solution components according to embodiment 11 and first stir 30 minutes and shear 10-15 minute with high-shearing dispersion emulsifying machine again, under stirring standby, second time medicine-feeding piller is placed in centrifugal granulating seed-coating machine, open machine and adjust parameters, temperature of charge controls at 25-45 DEG C, adjust hydrojet speed according to material state, coating carries out heat treatment after terminating in good time.
。
Embodiment 12:
Release result and the ketoprofen sustained release capsules of its listing that in the United States Patent (USP) US6613361 B1 of listing ketoprofen sustained release capsules, embodiment 1 is embodied are basically identical, therefore we are coated according to coating constituents weight ratio in embodiment 1 (Eudragit RS30D:eudragit RL30D:trietyl citrate:aerosol 200:talc=1.83%:0.21%:0.40%:0.49%), contrast with other embodiments of the present invention, technique still uses twice coating of twice medicine-feeding of the present invention, and preparation method is as follows
(1) for the first time prepared by medicine accommodation layer: weigh Eudragit NE30D and purified water by the recipe quantity of embodiment 12, stir 45 minutes preparation suspensions standby as binding agent, weigh recipe quantity medicinal fine pellet core (cane sugar type, 0.5-0.6mm) it is placed in centrifugal granulating seed-coating machine, weigh recipe quantity ketoprofen raw material, raw material particle size D90 ＜ 20 μm, open machine, adjust parameters, binding agent is with addition of spraying, parameters is controlled according to practical situation, dosing speed controlling was at 100-150g/ minute, dosing is complete to be dried, it is dried to moisture≤3.0%, collect required mesh number piller and carry out next step operation.(2) for the first time prepared by coating: weighs each coating solution components according to embodiment 1 and first stirs 30 minutes again with high-shearing dispersion emulsifying machine shearing 10-15 minute, under stirring standby, medicine-feeding piller for the first time is placed in centrifugal granulating seed-coating machine, open machine and adjust parameters, temperature of charge controls at 25-45 DEG C, adjust hydrojet speed according to material state, coating terminates to carry out heat treatment in good time.(3) second time medicine-feeding: weigh Eudragit NE30D and purified water by embodiment 1 recipe quantity, stir 45 minutes standby, first time coated pellets is placed in centrifugal granulating seed-coating machine, weigh corresponding recipe quantity ketoprofen raw material by embodiment 1 and open machine, adjust parameters, binding agent is with addition of spraying, parameters is controlled according to practical situation, dosing speed controlling was at 100-150g/ minute, dosing is complete to be dried, it is dried to moisture≤3.0%, collects required mesh number piller and carry out next step operation.(4) coating for the second time: weigh each coating solution components according to embodiment 12 and first stir 30 minutes and shear 10-15 minute with high-shearing dispersion emulsifying machine again, under stirring standby, second time medicine-feeding piller is placed in centrifugal granulating seed-coating machine, open machine and adjust parameters, temperature of charge controls at 25-45 DEG C, adjust hydrojet speed according to material state, coating carries out heat treatment after terminating in good time.
。
Embodiment 13:
Coating solution components antiplastering aid Pulvis Talci in embodiment 1 in US patent US6613361 B1 and colloidal silica amount are increased, sees whether to make moderate progress, still use twice coating of twice medicine-feeding of the present invention.
(1) for the first time prepared by medicine accommodation layer: weigh Eudragit NE30D and purified water by embodiment 13 recipe quantity, stir 45 minutes preparation suspensions standby as binding agent, weigh recipe quantity medicinal fine pellet core (cane sugar type, 0.5-0.6mm) it is placed in centrifugal granulating seed-coating machine, weigh recipe quantity ketoprofen raw material, raw material particle size D90 ＜ 20 μm, open machine, adjust parameters, binding agent is with addition of spraying, parameters is controlled according to practical situation, dosing speed controlling was at 100-150g/ minute, dosing is complete to be dried, it is dried to moisture≤3.0%, collect required mesh number piller and carry out next step operation.(2) for the first time prepared by coating: weighs each coating solution components according to embodiment 1 and first stirs 30 minutes again with high-shearing dispersion emulsifying machine shearing 10-15 minute, under stirring standby, medicine-feeding piller for the first time is placed in centrifugal granulating seed-coating machine, open machine and adjust parameters, temperature of charge controls at 25-45 DEG C, adjust hydrojet speed according to material state, coating terminates to carry out heat treatment in good time.(3) second time medicine-feeding: weigh Eudragit NE30D and purified water by embodiment 13 recipe quantity, stir 45 minutes standby, first time coated pellets is placed in centrifugal granulating seed-coating machine, weigh corresponding recipe quantity ketoprofen raw material by embodiment 1 and open machine, adjust parameters, binding agent is with addition of spraying, control parameters according to practical situation simultaneously, dosing speed controlling was at 100-150g/ minute, dosing is complete to be dried, it is dried to piller moisture≤3.0%, collects required mesh number piller and carry out next step operation.(4) coating for the second time: according to embodiment 13 weigh each coating solution components under stirring standby, second time medicine-feeding piller is placed in centrifugal granulating seed-coating machine, open machine and adjust parameters, temperature of charge controls at 25-45 DEG C, adjust hydrojet speed according to material state, coating carries out heat treatment after terminating in good time.
。
Embodiment 14:
Embodiment 1-13 is carried out release investigation, and ibid city's preparation contrasts.nullSpecific implementation method: dissolution determination method: take this product，Carry out encapsulating capsule according to specification 0.2g to be measured，According to drug release determination method (Chinese Pharmacopoeia two annex X D the first methods of version in 2010)，Use the device of dissolution method the second method，With pH value 6.9 phosphate buffer 900ml for dissolution medium agent，Slurry processes，Rotating speed is 75 turns per minute，Operate in accordance with the law，Through 0.5、1，2、4、5、6、7、8、10、12、14、16、18、24 little constantly，Sample 10 milliliters，According to spectrophotography (Chinese Pharmacopoeia two annex IV A of version in 2010)，Trap is measured at the wavelength of 260nm，External standard method also calculates the release of 12 each time points，Finally by release result and similar factors，And release homogeneity RSD value evaluate.Result sees attached list three, four.Result shows: dissolution of the present invention release can reach to list the releasing effect that preparation is close.Coating process Phenomena Observation result shows: embodiment 1,2,3,4,5,6,7,10 adds oil owing to employing in the coating solution of the present invention so that in coating process adhesion phenomenon cause less release can the most ibid city's preparation similar.In embodiment 8,9,11 coating solution, the usage amount of oil is fewer, more or does not adds and all causes coating adhesion, embodiment 8,9,11 only exemplary embodiments oil in coating solution, accounts for 2-5%(w/w) outside release membranes material screening process in embodiment do not put into, although add more slow release filmogen still make release can not with listing preparation similar.Embodiment 12,13 is coating solution components and the ratio that have references to list preparation producer patent, colloidal silica has been arrived owing to using, in coating process, adhesion phenomenon makes moderate progress, adhesion can't cause rupturing of film, release can be reached and to list preparation close, but from release homogeneity it can be seen that owing to adhesion causes the became uneven of film even, cause discharging homogeneity and be deteriorated.
Embodiment 15:
Embodiment 1-13 technical process is monitored, coating phenomenon is observed and evaluated, the uniformity of dosage units of each layer medicine-feeding content and last piller is comprehensively analyzed, and final gained piller is carried out the mensuration of bulk density.Specific implementation method: (1) uniformity of dosage units: take the medicine-feeding for the first time of each embodiment and second time each 10 of sample of medicine-feeding, the most finely ground, precision weighs in right amount (being approximately equivalent to ketoprofen 60mg) respectively, put in 200ml measuring bottle, add water-methanol (1:3) about 150ml, shake well makes ketoprofen dissolve, add water-methanol (1:3) and be diluted to scale, shake up, filter, it is appropriate that precision measures subsequent filtrate, add water-methanol (1:3) dilution and make in every 1ml the solution containing about 6 μ g, according to spectrophotography (Chinese Pharmacopoeia two annex IV A of version in 2010, trap is measured at 257nm wavelength；The ketoprofen reference substance that another precision weighs through 60 DEG C of drying under reduced pressure to constant weight is appropriate, add water-methanol (1:3) dissolve and quantitatively dilute the solution made in every 1ml containing about 6 μ g, it is measured in the same method trap, external standard method calculates each embodiment sample size, the relative standard deviation (RSD) of each embodiment calculating content, as uniformity of dosage units, is evaluated.(2) bulk density: weigh each embodiment final sample and be placed in 10 milliliters of graduated cylinders, weigh the weight of 10 milliliters of samples, calculate bulk density, and carry out the comparison of each embodiment.Result sees attached list one, two.Result shows: the off-limits final products of ratio of oil during coating solution does not adds oil and coating solution in embodiment, its bulk density all can reach requirement, but less than normal compared with the embodiment bulk density of the oil of (2-5%) ratio within the scope of adding in coating solution, the last gained piller uniformity of dosage units of oil adding a certain amount of (2-5%) in coating solution is good compared with reference preparation.
Embodiment 16:
The coating stability of embodiment 1-13 is carried out comprehensive assessment, each embodiment is under conditions of temperature 40 DEG C ± 2 DEG C, relative humidity 75% ± 5%, investigate 3,6 months respectively, investigate the change of each embodiment release with this understanding, carrying out similarity comparison with self release of 0 month respectively, result sees appendix table five.
Result shows: the addition of oil in coating solution, the stability of extended release coatings film has been significantly greatly increased, but also need to be in certain scope, in extraneous embodiment, (embodiment 8,9 is less than 2%, embodiment 11 is more than 5%) expected value that stability does not reach, after comparing the embodiment coating solution formula coating according to United States Patent (USP), little stability is more excellent.
Embodiment 17:
To embodiment 1-13 in twice coating process, phenomenon is observed, each coating gained piller outward appearance is observed, and the adhesion phenomenon in coating process is evaluated, evaluation methodology sees attached list a little note, result sees attached list one, and adding a range of oil in coating solution has certain change to coating outward appearance and the adhesion phenomenon that causes because of electrostatic.
Twice coating Phenomena Observation result of each embodiment of table one
Note: outward appearance symbol represents: the brightest and the cleanest: +++；2. outward appearance: brighter and cleaner: ++；3. outward appearance: general, fineness is poor；
Adhesion phenomenon symbol represents: 1. adhesion is less than 2%:++++；2. adhesion phenomenon 2-5%, +++；3. adhesion phenomenon 5-9%, ++；；Adhesion phenomenon is more than 10%:+.
The each embodiment of table two each layer medicine-feeding content, the final uniformity and bulk density testing result
Table three each embodiment cumulative release result:
*Note: ibid city's preparation compares f2 It is worth the least, shows the most dissimilar, meet 50 More than turn out similar.
4 12, table release homogeneity
(being measured % with specification 0.2g encapsulating capsule)
。
The results of stability (accelerated test, similar factors f2 compared with 0 month) of table five dressing seed
| Compared with 0 month | Embodiment 1 | Embodiment 2 | Embodiment 3 | Embodiment 4 | Embodiment 5 | Embodiment 6 | Embodiment 7 | Embodiment 8 | Embodiment 9 | Embodiment 10 | Embodiment 11 | Embodiment 12 | Embodiment 13 |
| 3 months | 98.6 | 98.4 | 98.8 | 98.7 | 98.1 | 99.5 | 98.4 | 75.2 | 74.1 | 97.7 | 79.6 | 94.5 | 95.6 |
| 6 months | 98.5 | 98.8 | 98.7 | 98.9 | 98.5 | 99.1 | 95.8 | 52.3 | 56.8 | 94.6 | 55.1 | 85.5 | 82.1 |
Claims (10)
1. a ketoprofen slow-release micropill, it is characterised in that be made up of celphere, twice medicine accommodation layer, twice coatings.
Ketoprofen slow-release micropill the most according to claim 1, it is characterised in that described medicine accommodation layer is by principal agent ketoprofen, framework material and wetting agent composition.
Ketoprofen slow-release micropill the most according to claim 1, it is characterised in that described coatings is become with line of oils by slow release filmogen, plasticizer, antiplastering aid, wetting agent.
Ketoprofen slow-release micropill the most according to claim 3, it is characterised in that described oil is soybean oil, Oleum Arachidis hypogaeae semen or medium chain fatty acid three fat.
5., according to the ketoprofen slow-release micropill described in claims 1, it is characterised in that described capsule core is sucrose capsule core or microcrystalline Cellulose capsule core, described capsule core content is 16-20%.
6., according to the ketoprofen slow-release micropill described in claims 2, it is characterised in that the content of described principal agent ketoprofen is 70～80%, described framework material content is 0.4-3.0%.
7. according to the ketoprofen slow-release micropill described in claims 3, it is characterised in that described slow release filmogen content is 0.7-3.5%, and plasticizer loading is 0.5-2.0%, and antiplastering aid content is 1.0～3.0%.
8. according to the ketoprofen slow-release micropill described in claims 3 or 4, it is characterised in that described oil content is 0.5%-2.5%.
9. according to the ketoprofen slow-release micropill described in claims 3, it is characterised in that each coatings composition and ratio is: slow release filmogen 0-30 part, plasticizer 0.5-2.5 part, antiplastering aid 1-4 part, oil 2.0-5.0, wetting agent 80-100 part.
10. according to the ketoprofen slow-release micropill described in claim 3 or 9, it is characterised in that described slow release filmogen is Eudragit RL30D or the one in Eudragit RS30D or a combination of both thing；Described antiplastering aid is Pulvis Talci, and described plasticizer is triethyl citrate；Described wetting agent is purified water；Described oil is soybean oil, Oleum Arachidis hypogaeae semen or medium chain fatty acid three fat.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6613361B1 (en) * | 1999-04-22 | 2003-09-02 | Laboratoires Des Produits Ethiques Ethypharm | Ketoprofen microgranules, method for preparing same and pharmaceutical compositions |
| CN101279091A (en) * | 2007-04-04 | 2008-10-08 | 常州市第四制药厂有限公司 | Pancreatic enzymes enteric coated pellets and preparation |
| CN103989638A (en) * | 2014-04-29 | 2014-08-20 | 常州市第四制药厂有限公司 | Mesalazine slow-release granules and preparation method thereof |
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2015
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6613361B1 (en) * | 1999-04-22 | 2003-09-02 | Laboratoires Des Produits Ethiques Ethypharm | Ketoprofen microgranules, method for preparing same and pharmaceutical compositions |
| CN101279091A (en) * | 2007-04-04 | 2008-10-08 | 常州市第四制药厂有限公司 | Pancreatic enzymes enteric coated pellets and preparation |
| CN103989638A (en) * | 2014-04-29 | 2014-08-20 | 常州市第四制药厂有限公司 | Mesalazine slow-release granules and preparation method thereof |
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