CN104586809A - Esomeprazole magnesium enteric pill coated tablet and preparation method thereof - Google Patents
Esomeprazole magnesium enteric pill coated tablet and preparation method thereof Download PDFInfo
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Abstract
The invention discloses an esomeprazole magnesium enteric pill coated tablet. The esomeprazole magnesium enteric pill coated tablet is prepared from the following raw materials in percentage by mass: 4.7-19.7% of a quick-release enteric coated pill, 18.6-30.9% of a slow-release enteric coated pill, 60.7-66.4% of a buffer adjuvant, 1.0% of a lubricant and 2-3% of a thin film coating. The esomeprazole magnesium enteric pill coated tablet is less frequently taken by patients, is reduced in stimulation to the enteric canal, is stable in plasma concentration and is free from peak-valley phenomenon.
Description
Technical field
The present invention relates to a kind of esomeprazole magnesium micropill enteric coatel tablets and preparation method, belong to pharmaceutical preparations technology field.
Background technology
Esomeprazole magnesium is proton pump inhibitor class antiulcerative, has good therapeutical effect for digestive tract ulcer, can treat duodenal ulcer, gastric ulcer and esophagitis, and can eliminate intractable ulcer crisis, and treatment Zollinger-Ellison syndrome is also very effective.Action effect is remarkable, can not the peptic ulcer of onset and the excellent curative of serious esophageal reflux ulcer to routine treatment, and side effect is rarely found.
The chemical name of esomeprazole magnesium is 2 (S-5-methoxyl group-2-(4-methoxyl group-3,5-dimethyl-2-pyridine) methyl) sulfinyl-1 H-benzimidazole) magnesium trihydrate, structural formula is as follows:
Esomeprazole magnesium is easy to degraded at acid and neutral medium, and degradation half life is 10 minutes when pH is less than 4.0, is 18 hours when pH equals 6.5, is about 300 days when pH equals 11.In addition, the stability of esomeprazole magnesium is also subject to the impact of humidity, heat, organic solvent, and in addition, illumination also has the impact of less degree.Even if under normal storage service condition, because the degraded of esomeprazole magnesium, the variable color of preparation also can be found; , there is the problem that onset is slow in esomeprazole magnesium poor solubility simultaneously.
Summary of the invention
A kind of esomeprazole magnesium micropill enteric coatel tablets and preparation method are the object of the present invention is to provide, the esomeprazole magnesium micropill enteric coatel tablets utilizing preparation method of the present invention to prepare decrease patient medication number of times, reduce the zest of medicine to intestinal, and blood drug level is steady, does not have peak valley phenomenon.
For achieving the above object, technical scheme of the present invention is:
A kind of esomeprazole magnesium micropill enteric coatel tablets, comprise the raw material of following mass percent: rapid release enteric coated micropill 4.7-19.7%, enteric-coated sustained release micropill 18.6-30.9%, buffering adjuvant 60.7-66.4%, lubricant 1.0%, outer film coating layer 2-3%.
Described rapid release enteric coated micropill specification selects 10mg, and enteric-coated sustained release micropill specification selects the one in 10mg, 30mg, 70mg; Described buffering adjuvant adopts sodium stearyl fumarate (Germany is auspicious steps on Mel father and son company); Lubricant adopts microcrystalline Cellulose (FMC Corp. of the U.S.).
A kind of preparation method of esomeprazole magnesium micropill enteric coatel tablets, comprise the steps: 1) preparation of rapid release enteric coated micropill and slow release enteric coated micropill, medicine accommodation layer, sealing coat, enteric layer, by medicine accommodation layer, sealing coat, enteric layer composition, are spread evenly across initial vector kind wicking surface with aqueous suspension form by fluidization and spray-drying technology by wherein said rapid release enteric coated micropill and slow release enteric coated micropill respectively; The medicine accommodation layer gain in weight of described rapid release enteric coated micropill is 213.2%-320%, and the medicine accommodation layer gain in weight of described enteric-coated sustained release micropill is 160%-266.67%; Described rapid release enteric coated micropill sealing coat gain in weight is 18.8-24.8%, and described enteric-coated sustained release micropill sealing coat gain in weight is 19.9-28.1%; Described rapid release enteric coated micropill enteric layer coating weight gain amount is 32.1%-45.6%; Described enteric-coated sustained release coating of pellets gain in weight is 17.5%-21.0%.
2) according to rapid release enteric coated micropill 4.7-19.7%, enteric-coated sustained release micropill 18.6-30.9%, buffering adjuvant 60.7-66.4%, lubricant 1.0%, the mass percent ratio of outer film coating layer 2-3%, rapid release enteric coated micropill, enteric-coated sustained release micropill are become plain sheet with tabletting after buffering adjuvant, mix lubricant, and then at the outer film coating layer of plain sheet.
Described kind core adopts water-insoluble kind core or water solublity kind core, and wherein said water-insoluble kind core adopts the one in oxide, cellulose, organic polymer; Described water solublity kind core adopts the one in inorganic salt, sugar, starch; Described kind core diameter is 0.1---2 millimeters;
Described medicine accommodation layer is dispersed in binder solution by the esomeprazole magnesium raw material of nanometer particle size to be formed, described nanoscale esomeprazole magnesium raw material is obtained by nano-pulverization technology, the particle diameter of described nanoscale esomeprazole magnesium raw material is at below 50um, and described binding agent adopts the one in hypromellose (German JRS company), hydroxypropyl cellulose (AQUALON company of the U.S.), sodium carboxymethyl cellulose (AQUALON company of the U.S.);
Described sealing coat adopts the one in sugar, Polyethylene Glycol, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl acetate, hydroxypropyl cellulose, methylcellulose, ethyl cellulose, hydroxypropyl emthylcellulose, sodium carboxymethyl cellulose and additive to mix; Described additive adopts plasticizer, one or more in coloring agent, pigment, filler, antitack agent, antistatic agent;
Described enteric layer coating dispersion or be dissolved in water or organic solvent, adopt polymer and plasticizer as enteric coat layer, wherein polymer adopts one or more in methacrylic acid copolymer, hypromellose, ethyl cellulose, ethyl acrylate-methyl methacrylate, Cellacefate, Hydroxypropyl Methylcellulose Phathalate, HPMC-AS, poly-acetate phthalate vinyl acetate, acetic acid benzenetricarboxylic acid cellulose, carboxymethylethylcellulose, lac; Described plasticizer adopts the one in glyceryl triacetate, citric acid three ester, single glycerol distearate, phthalic acid ester, SA dibutyl ester, spermol, Polyethylene Glycol, multi-sorbitol ester; The content of described plasticizer is greater than the 10-50% of enteric coating layer polymer weight.
Described kind core preferably adopts sugar to plant core, microcrystalline Cellulose kind core; Kind core diameter described in (Japanese Asahi Kasei Corporation) is preferably 0.1---and 0.5 millimeter; The particle diameter of described nanoscale esomeprazole magnesium raw material is preferably at below 500nm; Described sealing coat preferably adopts the one in hydroxypropyl cellulose (AQUALON company of the U.S.), hydroxypropyl emthylcellulose (German JRS company), sodium carboxymethyl cellulose (AQUALON company of the U.S.) and additive to mix; Described additive preferably adopts two kinds in magnesium stearate, titanium dioxide, Pulvis Talci; Described polymer preferably adopt in methacrylic acid copolymer, hypromellose (German JRS company), ethyl cellulose (AQUALON company of the U.S.), ethyl acrylate-methyl methacrylate (German goldschmidt chemical corporation) one or more; Described plasticizer adopts the content of citric acid three ester (Bengbu FengYuan TuShan Pharmaceutical Co., Ltd) or the plasticizer described in single glycerol distearate (Hunan Er-kang Pharmaceutical Co., Ltd.) to be preferably greater than the 15-50% of enteric coating layer polymer weight.
Described kind core preferably adopts microcrystalline Cellulose kind core further, and described kind core further preferred diameter is 0.1---and 0.2 millimeter.The particle diameter of described nanoscale esomeprazole magnesium raw material is preferred at below 50nm further; The content of described plasticizer is preferably greater than 20% of enteric coating layer polymer weight further.
The invention has the beneficial effects as follows: the invention discloses a kind of esomeprazole magnesium micropill enteric coatel tablets, there is the good medicament contg uniformity; After tabletting, still can accomplish more than 90% acid-resistant strength, carry out acid-resistant strength with independent rapid release or enteric-coated sustained release micropill and investigate and there is no notable difference; Stripping curve does not have peak valley phenomenon, and drug release peak value reaches 8 hours.Solve the compliance issues of patient medication, avoid the too high and stimulation to gastric mucosa caused of local drug concentration simultaneously, be conducive to the absorption of medicine, thus improve bioavailability, decrease individual variation.Meanwhile, multiple unit dosage form drug release behavior is the summation of multiple piller drug release behaviors of a composition dosage, and the defect in indivedual piller preparation is unlikely to produce the drug release behavior of whole preparation to have a strong impact on, and ensure that the safety of clinical application.This invention simultaneously decreases patient medication number of times, reduces the zest of medicine to intestinal, and blood drug level is steady, does not have peak valley phenomenon, has good release amount of medicine and acid resistance in vivo.
Detailed description of the invention
Embodiment 1
The preparation method of a kind of esomeprazole magnesium micropill enteric coatel tablets of the present embodiment, comprise the steps: 1) preparation of rapid release enteric coated micropill and slow release enteric coated micropill, medicine accommodation layer, sealing coat, enteric layer, by medicine accommodation layer, sealing coat, enteric layer composition, are spread evenly across initial vector kind wicking surface with aqueous suspension form by fluidization and spray-drying technology by wherein said rapid release enteric coated micropill and slow release enteric coated micropill respectively; The medicine accommodation layer gain in weight of described rapid release enteric coated micropill is 213.2%, and the medicine accommodation layer gain in weight of described enteric-coated sustained release micropill is 160%; Described rapid release enteric coated micropill sealing coat gain in weight is 24.8%, and described enteric-coated sustained release micropill sealing coat gain in weight is 28.4%; Described rapid release enteric coated micropill enteric layer coating weight gain amount is 44.92%; Described enteric-coated sustained release coating of pellets gain in weight is 21.16%.
Wherein rapid release enteric coated micropill medicine accommodation layer formula is:
Adopt fluidization and spray-drying technology, the water slurry form containing the binding agent dissolved be sprayed on microcrystalline Cellulose kind core by esomeprazole magnesium and form medicine accommodation layer piller, wherein planting core diameter is 0.15 millimeter, and esomeprazole magnesium particle diameter is at below 50nm.
Rapid release enteric coated micropill sealing coat formula is:
Adopt fluidization and spray-drying technology, after sealing coat coating being carried out to medicine accommodation layer piller with the hydroxypropyl cellulose solution containing Pulvis Talci and magnesium stearate, form isolation piller.
Rapid release enteric coated micropill enteric layer formula is:
Adopt fluidization and spray-drying technology, with the form of dispersion liquid, the enteric coat layer that methacrylic acid copolymer aqueous dispersion, single glycerol distearate, triethyl citrate and Tween 80 form is sprayed on the isolation piller of use sealing coat coating.
The rapid release enteric coated micropill weight now obtained containing esomeprazole 10mg is about 20-50mg.
Enteric-coated sustained release micropill medicine accommodation layer formula is:
Adopt fluidization and spray-drying technology, the water slurry form containing the binding agent dissolved be sprayed on microcrystalline Cellulose kind core by esomeprazole magnesium and form medicine accommodation layer piller, wherein planting core diameter is 0.15 millimeter, and esomeprazole magnesium particle diameter is at below 50nm.
Enteric-coated sustained release micropill sealing coat formula is:
Adopt fluidization and spray-drying technology, after sealing coat coating being carried out to medicine accommodation layer piller with the hydroxypropyl cellulose solution containing Pulvis Talci and magnesium stearate, form isolation piller.
Enteric-coated sustained release micropill enteric layer formula is:
Adopt fluidization and spray-drying technology, by the hypromellose solution spray containing ethyl acrylate-methyl methacrylate aqueous dispersion, ethyl cellulose and titanium dioxide to on the isolation piller of sealing coat coating.
Enteric-coated sustained release micropill weight now containing esomeprazole 10mg is about 30-50mg.
2) according to following formula proportion, rapid release enteric coated micropill, enteric-coated sustained release micropill are become plain sheet with tabletting after buffering adjuvant, mix lubricant, and then at the outer film coating layer of plain sheet.
Tabletting formula
Rapid release enteric coated micropill, enteric-coated sustained release micropill and additional buffering adjuvant are mixed rear tabletting and become plain sheet.
Element coating tablets
Gastric solubleness coating materials 30g
Purified water 160g
Element sheet 1000g
Element film coating of tablets, weightening finish 2-3%.
A kind of esomeprazole magnesium micropill enteric coatel tablets of the present embodiment, have the good medicament contg uniformity; After tabletting, still can accomplish more than 90% acid-resistant strength, carry out acid-resistant strength with independent rapid release or enteric-coated sustained release micropill and investigate and there is no notable difference; Stripping curve does not have peak valley phenomenon, and drug release peak value reaches 8 hours.Solve the compliance issues of patient medication, avoid the too high and stimulation to gastric mucosa caused of local drug concentration simultaneously, be conducive to the absorption of medicine, thus improve bioavailability, decrease individual variation.Meanwhile, multiple unit dosage form drug release behavior is the summation of multiple piller drug release behaviors of a composition dosage, and the defect in indivedual piller preparation is unlikely to produce the drug release behavior of whole preparation to have a strong impact on, and ensure that the safety of clinical application.This invention simultaneously decreases patient medication number of times, reduces the zest of medicine to intestinal, and blood drug level is steady, does not have peak valley phenomenon, has good release amount of medicine and acid resistance in vivo.
Embodiment 2
The preparation method of a kind of esomeprazole magnesium micropill enteric coatel tablets of the present embodiment, comprise the steps: 1) preparation of rapid release enteric coated micropill and slow release enteric coated micropill, medicine accommodation layer, sealing coat, enteric layer, by medicine accommodation layer, sealing coat, enteric layer composition, are spread evenly across initial vector kind wicking surface with aqueous suspension form by fluidization and spray-drying technology by wherein said rapid release enteric coated micropill and slow release enteric coated micropill respectively; The medicine accommodation layer gain in weight of described rapid release enteric coated micropill is 266.8%, and the medicine accommodation layer gain in weight of described enteric-coated sustained release micropill is 160%; Described rapid release enteric coated micropill sealing coat gain in weight is 22.4%, and described enteric-coated sustained release micropill sealing coat gain in weight is 28.4%; Described rapid release enteric coated micropill enteric layer coating weight gain amount is 38.4%; Described enteric-coated sustained release coating of pellets gain in weight is 21.16%.
Wherein rapid release enteric coated micropill medicine accommodation layer formula is:
Adopt fluidization and spray-drying technology, the water slurry form containing the binding agent dissolved be sprayed on microcrystalline Cellulose kind core by esomeprazole magnesium and form medicine accommodation layer piller, wherein planting core diameter is 0.1 millimeter, and esomeprazole magnesium particle diameter is at below 500nm.
Rapid release enteric coated micropill sealing coat formula is:
Adopt fluidization and spray-drying technology, after sealing coat coating being carried out to medicine accommodation layer piller with the hydroxypropyl cellulose solution containing Pulvis Talci and magnesium stearate, form isolation piller.
Rapid release enteric coated micropill enteric layer formula is
Adopt fluidization and spray-drying technology, with the form of dispersion liquid, the enteric coat layer that methacrylic acid copolymer aqueous dispersion (by especially strange L30D-55), single glycerol distearate, triethyl citrate and Tween 80 forms is sprayed on the isolation piller of use sealing coat coating.
Rapid release enteric coated micropill weight now containing esomeprazole 20mg is about 20-50mg.
Enteric-coated sustained release micropill medicine accommodation layer formula is:
Adopt fluidization and spray-drying technology, the water slurry form containing the binding agent dissolved be sprayed on microcrystalline Cellulose kind core by esomeprazole magnesium and form medicine accommodation layer piller, wherein planting core diameter is 0.15 millimeter, and esomeprazole magnesium particle diameter is at below 50nm.
Enteric-coated sustained release micropill sealing coat formula is:
Adopt fluidization and spray-drying technology, after sealing coat coating being carried out to medicine accommodation layer piller with the hydroxypropyl cellulose solution containing Pulvis Talci and magnesium stearate, form isolation piller.
Enteric-coated sustained release micropill enteric layer formula is:
Adopt fluidization and spray-drying technology, by the hypromellose solution spray containing ethyl acrylate-methyl methacrylate aqueous dispersion, ethyl cellulose and titanium dioxide to on the isolation piller of sealing coat coating.
Enteric-coated sustained release micropill weight now containing esomeprazole 30mg is about 90-110mg.
2) according to following formula proportion, rapid release enteric coated micropill, enteric-coated sustained release micropill are become plain sheet with tabletting after buffering adjuvant, mix lubricant, and then at the outer film coating layer of plain sheet.
Tabletting formula is:
Rapid release enteric coated micropill, enteric-coated sustained release micropill and additional buffering adjuvant are mixed rear tabletting and become plain sheet.
Element coating tablets formula is:
Gastric solubleness coating materials 60g
Purified water 320g
Element sheet 2000g
Element film coating of tablets, weightening finish 2-3%.
A kind of esomeprazole magnesium micropill enteric coatel tablets of the present embodiment, have the good medicament contg uniformity; After tabletting, still can accomplish more than 90% acid-resistant strength, carry out acid-resistant strength with independent rapid release or enteric-coated sustained release micropill and investigate and there is no notable difference; Stripping curve does not have peak valley phenomenon, and drug release peak value reaches 8 hours.Solve the compliance issues of patient medication, avoid the too high and stimulation to gastric mucosa caused of local drug concentration simultaneously, be conducive to the absorption of medicine, thus improve bioavailability, decrease individual variation.Meanwhile, multiple unit dosage form drug release behavior is the summation of multiple piller drug release behaviors of a composition dosage, and the defect in indivedual piller preparation is unlikely to produce the drug release behavior of whole preparation to have a strong impact on, and ensure that the safety of clinical application.This invention simultaneously decreases patient medication number of times, reduces the zest of medicine to intestinal, and blood drug level is steady, does not have peak valley phenomenon, has good release amount of medicine and acid resistance in vivo.
Embodiment 3
The preparation method of a kind of esomeprazole magnesium micropill enteric coatel tablets of the present embodiment, comprise the steps: 1) preparation of rapid release enteric coated micropill and slow release enteric coated micropill, medicine accommodation layer, sealing coat, enteric layer, by medicine accommodation layer, sealing coat, enteric layer composition, are spread evenly across initial vector kind wicking surface with aqueous suspension form by fluidization and spray-drying technology by wherein said rapid release enteric coated micropill and slow release enteric coated micropill respectively; The medicine accommodation layer gain in weight of described rapid release enteric coated micropill is 320%, and the medicine accommodation layer gain in weight of described enteric-coated sustained release micropill is 266.8%; Described rapid release enteric coated micropill sealing coat gain in weight is 18.8%, and described enteric-coated sustained release micropill sealing coat gain in weight is 19.8%; Described rapid release enteric coated micropill enteric layer coating weight gain amount is 32.12%; Described enteric-coated sustained release coating of pellets gain in weight is 17.56%.
Wherein rapid release enteric coated micropill medicine accommodation layer formula is:
Adopt fluidization and spray-drying technology, the water slurry form containing the binding agent dissolved be sprayed on microcrystalline Cellulose kind core by esomeprazole magnesium and form medicine accommodation layer piller, wherein planting core diameter is 0.2 millimeter, and esomeprazole magnesium particle diameter is at below 50um.
Rapid release enteric coated micropill sealing coat formula is:
Adopt fluidization and spray-drying technology, after sealing coat coating being carried out to medicine accommodation layer piller with the hydroxypropyl cellulose solution containing Pulvis Talci and magnesium stearate, form isolation piller.
Rapid release enteric coated micropill enteric layer formula is:
Adopt fluidization and spray-drying technology, with the form of dispersion liquid, the enteric coat layer that methacrylic acid copolymer aqueous dispersion (by especially strange L30D-55), single glycerol distearate, triethyl citrate and Tween 80 forms is sprayed on the isolation piller of use sealing coat coating.
Rapid release enteric coated micropill weight now containing esomeprazole 20mg is about 20-50mg.
Enteric-coated sustained release micropill medicine accommodation layer formula is:
Adopt fluidization and spray-drying technology, the water slurry form containing the binding agent dissolved be sprayed on microcrystalline Cellulose kind core by esomeprazole magnesium and form medicine accommodation layer piller, wherein planting core diameter is 0.15 millimeter, and esomeprazole magnesium particle diameter is at below 50nm.
Enteric-coated sustained release micropill sealing coat formula is:
Adopt fluidization and spray-drying technology, after sealing coat coating being carried out to medicine accommodation layer piller with the hydroxypropyl cellulose solution containing Pulvis Talci and magnesium stearate, form isolation piller.
Enteric-coated sustained release micropill enteric layer formula is:
Adopt fluidization and spray-drying technology, by the hypromellose solution spray containing ethyl acrylate-methyl methacrylate aqueous dispersion, ethyl cellulose and titanium dioxide to on the isolation piller of sealing coat coating.
Enteric-coated sustained release micropill weight now containing esomeprazole 20mg is about 180-220mg.
2) according to following formula proportion, rapid release enteric coated micropill, enteric-coated sustained release micropill are become plain sheet with tabletting after buffering adjuvant, mix lubricant, and then at the outer film coating layer of plain sheet.
Tabletting formula is:
Rapid release enteric coated micropill, enteric-coated sustained release micropill and additional buffering adjuvant are mixed rear tabletting and become plain sheet.
Element coating tablets formula is:
Gastric solubleness coating materials 100g
Purified water 525g
Element sheet 3250g
Element film coating of tablets, weightening finish 2-3%.
A kind of esomeprazole magnesium micropill enteric coatel tablets of the present embodiment, have the good medicament contg uniformity; After tabletting, still can accomplish more than 90% acid-resistant strength, carry out acid-resistant strength with independent rapid release or enteric-coated sustained release micropill and investigate and there is no notable difference; Stripping curve does not have peak valley phenomenon, and drug release peak value reaches 8 hours.Solve the compliance issues of patient medication, avoid the too high and stimulation to gastric mucosa caused of local drug concentration simultaneously, be conducive to the absorption of medicine, thus improve bioavailability, decrease individual variation.Meanwhile, multiple unit dosage form drug release behavior is the summation of multiple piller drug release behaviors of a composition dosage, and the defect in indivedual piller preparation is unlikely to produce the drug release behavior of whole preparation to have a strong impact on, and ensure that the safety of clinical application.This invention simultaneously decreases patient medication number of times, reduces the zest of medicine to intestinal, and blood drug level is steady, does not have peak valley phenomenon, has good release amount of medicine and acid resistance in vivo.
Checking embodiment
For the content uniformity of medicine after clear and definite compaction of pellet, uniformity of dosage units detection is carried out to it, detection method is: adopt detection method of content, calculate detect medicament contg and the rapid release enteric coated micropill of gained and the specification sum of slow release enteric coated micropill ratio as acid-resistant strength result, result is as following table 1, as can be seen from Table 1, the uniformity of dosage units of embodiment 1,2,3 all shows well.
For the integrity of coating membrane after clear and definite compaction of pellet, acid-resistant strength detection is carried out to it, detection method is: slurry processes, 100 turns, independent micropill, coated tablet carries out independent detection respectively, investigate hydrochloric acid solution and PH4.5 acetum 500ml that medium selects the PH1.2 of 37 ± 0.5 DEG C, turn after 2 hours, sampling, detect by detection method, the ratio of the specification sum of the medicament contg of coated tablet gained and rapid release enteric coated micropill and slow release enteric coated micropill is as acid-resistant strength result, result is as following table 2, as can be seen from Table 2, independent rapid release enteric coated micropill, enteric-coated sustained release pellet and coated tablet are acidproof in PH1.2 hydrochloric acid solution and PH4.5 acetum respectively all to be showed well.
For clear and definite drug release behavior, rapid release in embodiment and enteric-coated sustained release micropill are measured release, rapid release enteric coated micropill dissolution test method: slurry processes, 100 turns, in the hydrochloric acid solution 500ml of 37 ± 0.5 DEG C of sodium chloride after 2 hours, add the 0.235mol/l disodium phosphate soln 400ml being preheated to 37 ± 0.5 DEG C, littlely sample detection constantly, release more than 80% 1.Testing result is in table 3, and table 3 is independent rapid release enteric coated micropill medicine Cumulative release amount (mg); As seen from Table 3, rapid release enteric coated micropill medicine discharges for 1 hour completely.
Enteric-coated sustained release micropill dissolution test method: slurry processes, 100 turns, in the hydrochloric acid solution 500ml of 37 ± 0.5 DEG C of sodium chloride after 2 hours, add the 0.235mol/l disodium phosphate soln 400ml being preheated to 37 ± 0.5 DEG C, continue to stir, drip clear two sodium solutions of phosphoric acid (simulated intestinal fluid secretion) with 1ml/min constant-velocity, drop to 8 hours always, detect in 1h, 2h, 4h, 8h sampling respectively, testing result is in table 4; Table 4 is enteric-coated sustained release micropill medicine Cumulative release amount (mg) separately; As seen from Table 4, enteric-coated sustained release micropill sustained release, slow release effect is obvious.
Coated tablet dissolution test method: slurry processes, 100 turns, in the hydrochloric acid solution 500ml of 37 ± 0.5 DEG C of sodium chloride after 2 hours, add the 0.235mol/l disodium phosphate soln 400ml being preheated to 37 ± 0.5 DEG C, littlely detection is sampled constantly 1, release more than 80%, continue to stir, clear two sodium solutions of phosphoric acid (simulated intestinal fluid secretion) is dripped with 1ml/min constant-velocity, drop to 8 hours always, respectively at 2h, 4h, 8h samples detection, calculate the Cumulative release amount of deduction after 1 hour to be shown in Table 5, table 5 is coated tablet medicine Cumulative release amount (mg) in embodiment, it is the Cumulative release amount after deduction 1h after 2h.As can be seen from Table 5, the rapid release enteric coated micropill of 1 hour discharges completely, medicine rapid-onset, then sustained release to 8 hour, and maintaining treatment concentration dose, reaches the object of the invention.
In a word, the present invention discharges steadily, reduces times for spraying, and simultaneously in release terminal stage, related substance is still less, and medicine is substantially without degraded.
Table 1
| Numbering | Embodiment 1 | Embodiment 2 | Embodiment 3 |
| 1 | 101.1 | 99.4 | 98.9 |
| 2 | 97.5 | 99.6 | 103.3 |
| 3 | 98.3 | 105.4 | 105.4 |
| 4 | 102.5 | 101.1 | 100.1 |
| 5 | 103.4 | 97.7 | 99.3 |
| 6 | 100.2 | 99.9 | 94.3 |
| 7 | 95.8 | 100 | 99.6 |
| 8 | 99.2 | 102.2 | 100.2 |
| 9 | 100 | 103.9 | 100 |
| 10 | 100.1 | 96.1 | 100 |
| Uniformity of dosage units A+1.8S | 4.27 | 5.50 | 5.28 |
Table 2
| Title | PH1.2 hydrochloric acid solution | PH4.5 acetum |
| Embodiment 1 rapid release enteric coated micropill | 98.7 | 99.2 |
| Embodiment 2 rapid release enteric coated micropill | 98.4 | 98.2 |
| Embodiment 3 rapid release enteric coated micropill | 98.5 | 96.7 |
| Embodiment 1 enteric-coated sustained release micropill | 97.2 | 98.1 |
| Embodiment 2 enteric-coated sustained release micropill | 98.8 | 97.5 |
| Embodiment 3 enteric-coated sustained release micropill | 99.2 | 98.4 |
| Embodiment 1 coated tablet | 97.3 | 98.2 |
| Embodiment 2 coated tablet | 96.8 | 97.6 |
| Embodiment 3 coated tablet | 98.1 | 96.9 |
Table 3
| Embodiment | 1 hour burst size (mg) |
| Embodiment 1 | 10.0 |
| Embodiment 2 | 9.9 |
| Embodiment 3 | 9.9 |
Table 4
| Embodiment | Specification | 1 hour | 2 hours | 4 hours | 8 hours |
| Embodiment 1 | 10mg | 0.9 | 2.8 | 5.9 | 9.8 |
| Embodiment 2 | 30mg | 2.8 | 7.1 | 18.2 | 29.7 |
| Embodiment 3 | 70mg | 4.2 | 8.2 | 26.2 | 68.9 |
Table 5
| Embodiment | Specification | 1 hour | 2 hours | 4 hours | 8 hours |
| Embodiment 1 | 10mg：10mg | 10.8 | 3.1 | 6.2 | 9.5 |
| Embodiment 2 | 10mg：30mg | 12.9 | 6.8 | 17.9 | 29.2 |
| Embodiment 3 | 10mg：70mg | 13.9 | 8.0 | 25.3 | 68.5 |
Claims (6)
1. esomeprazole magnesium micropill enteric coatel tablets, is characterized in that, comprise the raw material of following mass percent: rapid release enteric coated micropill 4.7-19.7%, enteric-coated sustained release micropill 18.6-30.9%, buffering adjuvant 60.7-66.4%, lubricant 1.0%, outer film coating layer 2-3%.
2. a kind of esomeprazole magnesium micropill enteric coatel tablets as claimed in claim 1, is characterized in that, described rapid release enteric coated micropill specification selects 10mg, and enteric-coated sustained release micropill specification selects the one in 10mg, 30mg, 70mg; Described buffering adjuvant adopts microcrystalline Cellulose; Lubricant adopts sodium stearyl fumarate.
3. the preparation method of esomeprazole magnesium micropill enteric coatel tablets, it is characterized in that comprising the steps: 1) preparation of rapid release enteric coated micropill and slow release enteric coated micropill, medicine accommodation layer, sealing coat, enteric layer, by medicine accommodation layer, sealing coat, enteric layer composition, are spread evenly across initial vector kind wicking surface with aqueous suspension form by fluidization and spray-drying technology by wherein said rapid release enteric coated micropill and slow release enteric coated micropill respectively; The medicine accommodation layer gain in weight of described rapid release enteric coated micropill is 213.2%-320%, and the medicine accommodation layer gain in weight of described enteric-coated sustained release micropill is 160%-266.8%; Described rapid release enteric coated micropill sealing coat gain in weight is 18.8-24.8%, and described enteric-coated sustained release micropill sealing coat gain in weight is 19.8-28.4%; Described rapid release enteric coated micropill enteric layer coating weight gain amount is 32.1%-44.9%; Described enteric-coated sustained release coating of pellets gain in weight is 17.6%-21.2%;
2) according to rapid release enteric coated micropill 4.5-19.1%, enteric-coated sustained release micropill 18.1-29.9%, buffering adjuvant 58.9-64.4%, lubricant 1.0%, the mass percent ratio of outer film coating layer 2-3%, rapid release enteric coated micropill, enteric-coated sustained release micropill are become plain sheet with tabletting after buffering adjuvant, mix lubricant, and then at the outer film coating layer of plain sheet.
4. the preparation method of a kind of esomeprazole magnesium micropill enteric coatel tablets as claimed in claim 3, it is characterized in that: described kind core adopts water-insoluble kind core or water solublity kind core, wherein said water-insoluble kind core adopts the one in oxide, cellulose, organic polymer; Described water solublity kind core adopts the one in inorganic salt, sugar, starch; Described kind core diameter is 0.1---2 millimeters;
Described medicine accommodation layer is dispersed in binder solution by the esomeprazole magnesium raw material of nanometer particle size to be formed, described nanoscale esomeprazole magnesium raw material is obtained by nano-pulverization technology, the particle diameter of described nanoscale esomeprazole magnesium raw material is at below 50um, and described binding agent adopts the one in hypromellose, hydroxypropyl cellulose, sodium carboxymethyl cellulose;
Described sealing coat adopts the one in sugar, Polyethylene Glycol, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl acetate, hydroxypropyl cellulose, methylcellulose, ethyl cellulose, hydroxypropyl emthylcellulose, sodium carboxymethyl cellulose and additive to mix; Described additive adopts plasticizer, one or more in coloring agent, pigment, filler, antitack agent, antistatic agent;
Described enteric layer coating dispersion or be dissolved in water or organic solvent, adopt polymer and plasticizer as enteric coat layer, wherein polymer adopts one or more in methacrylic acid copolymer, hypromellose, ethyl cellulose, ethyl acrylate-methyl methacrylate, Cellacefate, Hydroxypropyl Methylcellulose Phathalate, HPMC-AS, poly-acetate phthalate vinyl acetate, acetic acid benzenetricarboxylic acid cellulose, carboxymethylethylcellulose, lac; Described plasticizer adopts the one in glyceryl triacetate, triethyl citrate, single glycerol distearate, phthalic acid ester, SA dibutyl ester, spermol, Polyethylene Glycol, multi-sorbitol ester; The content of described plasticizer is greater than the 10-50% of enteric coating layer polymer weight.
5. the preparation method of a kind of esomeprazole magnesium micropill enteric coatel tablets as claimed in claim 4, is characterized in that: described kind core adopts sugar to plant core, microcrystalline Cellulose kind core; Described kind core diameter is 0.1---0.5 millimeter; The particle diameter of described nanoscale esomeprazole magnesium raw material is at below 500nm; Described sealing coat adopts the one in hydroxypropyl cellulose, hydroxypropyl emthylcellulose, sodium carboxymethyl cellulose and additive to mix; Described additive adopts two kinds in magnesium stearate, titanium dioxide, Pulvis Talci; Described polymer adopt in methacrylic acid copolymer, hypromellose, ethyl cellulose, ethyl acrylate-methyl methacrylate one or more; Described plasticizer adopts triethyl citrate or single glycerol distearate; The content of described plasticizer is greater than the 15-50% of enteric coating layer polymer weight.
6. the preparation method of a kind of esomeprazole magnesium micropill enteric coatel tablets as claimed in claim 5, is characterized in that: described kind core adopts microcrystalline Cellulose kind core, and described kind core diameter is 0.1---0.2 millimeter; The particle diameter of described nanoscale esomeprazole magnesium raw material is at below 50nm; The content of described plasticizer is greater than 20% of enteric coating layer polymer weight.
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Application publication date: 20150506 |