CN103417508B - The pharmaceutical composition of release when a kind of candesartan Cilexetil pulse is selected - Google Patents
The pharmaceutical composition of release when a kind of candesartan Cilexetil pulse is selected Download PDFInfo
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- CN103417508B CN103417508B CN201310340678.XA CN201310340678A CN103417508B CN 103417508 B CN103417508 B CN 103417508B CN 201310340678 A CN201310340678 A CN 201310340678A CN 103417508 B CN103417508 B CN 103417508B
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Abstract
The present invention relates to release administration system when a kind of candesartan Cilexetil pulse is selected, release administration system when candesartan Cilexetil pulse of the present invention is selected, it is characterized in that being made up of label and three layers of coating, described three layers of coating refer to that internal layer is enteric coating layer, intermediate layer is organic acid layer, and skin is the mixture of enteric coating layer or insoluble coating and enteric coating.The feature of this medicine is that medicine does not discharge under one's belt, outer coat dissolves after entering intestinal, but under organic acid effect, pH remains on less than 6, and internal layer enteric coating just will start to dissolve release medicine, by controlling the thickness of each layer coating after organic acid layer is dissolved, the particularly thickness of intermediate layer coating, finally reach the object of medicine time controlled released in intestinal, ensure that patient is taking a medicine at bedtime, discharge the characteristic of medicine early morning.
Description
Technical field: the pharmaceutical composition that the present invention relates to release when a kind of candesartan Cilexetil pulse is selected, belongs to medical art.
Background of invention:
Hypertension is a kind of common chronic disease, one independently disease outwardly, be actually the risk factor that of causing Cardial or cerebral vascular diseases and nephropathy is important, if malpractice, the generation of the hypertension complications such as serious apoplexy, myocardial infarction, heart failure or renal failure can be caused.
Clinical observation finds: about when early morning 3, in hyperpietic's body, catecholamine levels starts to increase, and heart, vasoconstriction are strengthened, and blood pressure starts to raise.If controlling of blood pressure is bad, early morning is the time period that hyperpietic's most probable goes wrong, and rises about when therefore hyperpietic's optimal drug onset time is morning 3.
Pulsatile drug delivery system (pulsatilereleasesystem) is a kind of oral medicine, with the mode of time control specific part release medicine in gastrointestinal tract after oral.This based composition is specially adapted to the disease for the treatment of night or needing a blood concentration peak value after waking up at once, as insomnia, ischemic heart disease, hypertension etc.Said composition to be taken at bed time use evening, and m seq can the medicine of release pulses dosage, extremely meets the needs of this hypertension rhythm and pace of moving things change.
Summary of the invention:
Goal of the invention: overcome after existing hypertension medication takes, period in morning blood drug level does not reach the deficiency of disease control requirement, for medical personnel or patient provide a kind of medicine of in good time release, with the generation of the hypertension complication effectively controlling patients' blood and surely cause because of unstable blood pressure.
For realizing goal of the invention, the present inventor has done a large amount of experiments, adopts three layers of packaging technique, and after prolongation patient consumes, the release time of medicine, achieves the present invention.
Technical scheme of the present invention is: release composition when a kind of candesartan Cilexetil pulse is selected, is characterized in that: be made up of label and three layers of coatings.
Release composition when candesartan Cilexetil pulse of the present invention is selected, described three layers of coating refer to that internal layer is enteric coating layer, and intermediate layer is organic acid layer, and skin is the mixture of enteric coating layer or insoluble coating and enteric coating.
Release composition when candesartan Cilexetil pulse of the present invention is selected, the enteric coating layer of internal layer is dissolved in the scope of pH > 6.
When candesartan Cilexetil pulse of the present invention is selected, the feature of release composition is that medicine does not discharge under one's belt, after entering intestinal, outer coating starts to dissolve, but under organic acid effect, pH remains on less than 6, internal layer enteric coating just will start to dissolve release medicine after organic acid layer is dissolved.
The present invention, by controlling the thickness, the particularly thickness of intermediate layer coating of each layer coating, finally reaches the object of medicine time controlled released in intestinal, ensures that patient is taking a medicine at bedtime, discharges the characteristic of medicine early morning, effectively control blood pressure.
The preferred technical scheme of the present invention, is characterized in that, enteric material is selected from cellulose acetate-phthalate, Lac, acrylic resin, Algin etc.
The preferred technical scheme of the present invention, is characterized in that, organic acid is selected from the water-soluble organic acids etc. such as succinic acid, fumaric acid, citric acid.
The preferred technical scheme of the present invention is: release composition when a kind of candesartan Cilexetil pulse is selected, it is characterized in that: each label is by candesartan Cilexetil 4 ~ 12mg, polyethylene glycol 6000 4 ~ 12mg, lactose, 60 ~ 90mg, microcrystalline Cellulose 10 ~ 30mg, low-substituted hydroxypropyl cellulose 5 ~ 15mg, 6% PVP-K30 50% alcoholic solution 15 ~ 30mg, magnesium stearate 0.5 ~ 1.0mg;
The preferred technical scheme of the present invention is: by regulating the coating thickness in intermediate layer (relative label weightening finish 5%-10%), obtain discharging the different coated tablet of time lag.
Beneficial effect: the present invention, by carrying out coating to label, obtains a kind of compositions of time controlled released in intestinal, ensures that patient is taking a medicine at bedtime, discharges the characteristic of medicine early morning.
Accompanying drawing illustrates: Fig. 1, the release in vitro data of embodiment 1, embodiment 2, label.
Fig. 2, the release in vitro data of embodiment 3, embodiment 4, label.
Fig. 3, the release in vitro data of embodiment 5, embodiment 6, label.
Fig. 4, the release in vitro data of embodiment 7, embodiment 8, label.
Embodiment 1:
Prescription (1000) label: candesartan Cilexetil 8g, polyethylene glycol 6000 8g, lactose 75g, microcrystalline Cellulose 25g, low-substituted hydroxypropyl cellulose 10g, 6% PVP-K30 50% alcoholic solution 25g, magnesium stearate 0.5g.
Preparation: (1) material process: candesartan Cilexetil, polyethylene glycol 6000, microcrystalline Cellulose, low-substituted hydroxypropyl cellulose cross 80 mesh sieves, 100 orders selected by lactose;
(2) binding agent preparation: preparation 6%w/w PVP-K30 solution for standby;
(3) mix: by candesartan Cilexetil and polyethylene glycol 6000 in measurements of the chest, waist and hips mixer premix, after other adjuvants of recipe quantity are together mixed;
(4) soft material processed: recipe quantity binding agent is sprayed in wet granulator, mixing;
(5) granulate: adopt 22 eye mesh screens to granulate;
(6) dry: less than 50 DEG C oven dry to moisture are less than 4%;
(7) granulate: 20 order granulate;
(8) always mix: add magnesium stearate, always mix;
(9) adopt the stamping of Φ 7mm scrobicula, tabletting controls at the heavy 50N of average sheet
(10) coating:
Internal layer: adopt 6% Hydroxypropyl Methyl Cellulose Phthalate 75% ethanol coating, 10% of coatings Chong Shi plate core weight; Intermediate layer: the ethyl cellulose succinic acid 80% alcoholic solution coating adopting solid content 20%, relative label weightening finish 5%, wherein ethyl cellulose: succinic acid: tributyl citrate=5: 3: 2;
Outer: the polyacrylic resin II90% alcoholic solution coating adopting solid content 15%, wherein polyacrylic resin II: tributyl citrate: Pulvis Talci=10: 1: 4, relative label weightening finish 5%.
Embodiment 2, formula preparation method are with embodiment 1, and relative label weightening finish 10%, other are identical.
Test example 1, stripping curve assay method:
Measure according to method under 2010 editions " Chinese Pharmacopoeia " dissolution determination method items, adopt paddle method 50 turns, prior to measuring 2 hours in the hydrochloric acid solution of pH1.2, the buffer solution putting into pH6.8 again discharges, observe label, embodiment 1, embodiment 2 sample release time lag situation, concrete release in vitro data as table 1, and draw In-vitro release curves Fig. 1.
Table 1 label, embodiment 1, embodiment 2 sample In-vitro release curves tables of data
Embodiment 3:
Prescription (1000) label: candesartan Cilexetil 4g, polyethylene glycol 6000 4g, lactose 70g, microcrystalline Cellulose 15g, low-substituted hydroxypropyl cellulose 8g, 6% PVP-K30 50% alcoholic solution 15g, magnesium stearate 0.58g.
Preparation: (1) ~ (9) step is with embodiment 1
(10) coating:
Internal layer: adopt 15% Lac ethanol coating, relative label weightening finish 8%;
Intermediate layer: the ethyl cellulose fumaric acid 80% alcoholic solution coating adopting solid content 20%, 5% of coatings Chong Shi plate core weight, wherein ethyl cellulose: fumaric acid: tributyl citrate=5: 3: 2;
Outer: the polyacrylic resin II90% alcoholic solution coating adopting solid content 15%, wherein polyacrylic resin II: ethyl cellulose: tributyl citrate: Pulvis Talci=7: 3: 1: 4, relative label weightening finish 5%.
Embodiment 4, intermediate layer coating weight gain 10%, other are with embodiment 3.
Test example 2, embodiment 3, embodiment 4 stripping curve assay method are with test example 1, and concrete data in table 2, and draw In-vitro release curves Fig. 2.
Table 2 embodiment 3, embodiment 4 sample release in vitro situation
Embodiment 5: prescription (1000) label: candesartan Cilexetil 12g, polyethylene glycol 6000 12g, lactose 60g, microcrystalline Cellulose 30g, low-substituted hydroxypropyl cellulose 15g, 6% PVP-K30 50% alcoholic solution 30g, magnesium stearate 1.0g.
Preparation: (1) ~ (9) step is with embodiment 1.
(10) coating:
Internal layer: adopt 15% acrylic resin II90% ethanol coating, relative label weightening finish 10%;
Intermediate layer: the ethyl cellulose citric acid 80% alcoholic solution coating adopting solid content 20%, weightening finish 5%, wherein ethyl cellulose: citric acid: tributyl citrate=5: 3: 2;
Outer: the polyacrylic resin II90% alcoholic solution coating adopting solid content 15%, wherein polyacrylic resin II: ethyl cellulose: tributyl citrate: Pulvis Talci=7: 3: 1: 4, relative label weightening finish 5%.
Embodiment 6, intermediate layer coating weight gain 10%, other are with embodiment 5.
Test example 3, embodiment 5, embodiment 6 stripping curve assay method: with test example 1, concrete data in table 3, and draw In-vitro release curves Fig. 3.
Table 3
Embodiment 7:
Prescription (1000) label: candesartan Cilexetil 8g, polyethylene glycol 6000 8g, lactose 90g, microcrystalline Cellulose 10g, low-substituted hydroxypropyl cellulose 5g, 6% PVP-K30 50% alcoholic solution 20g, magnesium stearate 0.5g.
Preparation: (1) ~ (9) step is with embodiment 1
(10) coating:
Internal layer: adopt 15% Algin 90% ethanol coating, relative label weightening finish 10%;
Intermediate layer: the ethyl cellulose fumaric acid 80% alcoholic solution coating adopting solid content 20%, weightening finish 5%, wherein ethyl cellulose: fumaric acid: tributyl citrate=5: 3: 2;
Outer: the polyacrylic resin II90% alcoholic solution coating adopting solid content 15%, wherein polyacrylic resin II: tributyl citrate: Pulvis Talci=10: 1: 4, relative label weightening finish 5%.
The relative label weightening finish 10% of embodiment 8, intermediate layer coating, other are with embodiment 7.
Test example 4, embodiment 7, embodiment 8 stripping curve assay method: with test example 1, concrete data in table 4, and draw In-vitro release curves Fig. 4.
Table 4
As can be seen from accompanying drawing 1, Fig. 2, Fig. 3, Fig. 4, the present composition, obviously can postpone drug release, and can discharge fast and reach therapeutic effect in pulsed in the set time, when this is selected, the Slack time of releasing piece can be controlled by intermediate layer coating weight gain, can adjust as the case may be to ensure that patient is taking a medicine at bedtime, discharge the characteristic of medicine early morning, effectively control blood pressure.Positive meaning is had to clinical treatment.
Claims (2)
1.
release composition when a kind of candesartan Cilexetil pulse is selected, it is characterized in that, every 1000 labels are by candesartan Cilexetil 8g, polyethylene glycol 6000 8g, lactose 75g, microcrystalline Cellulose 25g, low-substituted hydroxypropyl cellulose 10g, 6% PVP-K30 50% alcoholic solution 25g, magnesium stearate 0.5g form, and prepare by the following method:
(1) material process: candesartan Cilexetil, polyethylene glycol 6000, microcrystalline Cellulose, low-substituted hydroxypropyl cellulose cross 80 mesh sieves, 100 orders selected by lactose;
(2) binding agent preparation: preparation 6%w/w PVP-K30 solution for standby;
(3) mix: by candesartan Cilexetil and polyethylene glycol 6000 in measurements of the chest, waist and hips mixer premix, after other adjuvants of recipe quantity are together mixed;
(4) soft material processed: recipe quantity binding agent is sprayed in wet granulator, mixing;
(5) granulate: adopt 22 eye mesh screens to granulate;
(6) dry: less than 50 DEG C oven dry to moisture are less than 4%;
(7) granulate: 20 order granulate;
(8) always mix: add magnesium stearate, always mix;
(9) adopt the stamping of Φ 7mm scrobicula, tabletting controls at the heavy 50N of average sheet;
(10) coating:
internal layer: adopt 6% Hydroxypropyl Methyl Cellulose Phthalate 75% ethanol coating, 10% of coatings Chong Shi plate core weight;
intermediate layer: the ethyl cellulose succinic acid 80% alcoholic solution coating adopting solid content 20%, relative label weightening finish 5%, wherein ethyl cellulose: succinic acid: tributyl citrate=5: 3: 2;
outer: the polyacrylic resin II90% alcoholic solution coating adopting solid content 15%, wherein polyacrylic resin II: tributyl citrate: Pulvis Talci=10: 1: 4, relative label weightening finish 5%.
2.
release composition when a kind of candesartan Cilexetil pulse is selected, it is characterized in that, every 1000 labels are by candesartan Cilexetil 4g, polyethylene glycol 6000 4g, lactose 70g, microcrystalline Cellulose 15g, low-substituted hydroxypropyl cellulose 8g, 6% PVP-K30 50% alcoholic solution 15g, magnesium stearate 0.58g form, and prepare by the following method:
(1) material process: candesartan Cilexetil, polyethylene glycol 6000, microcrystalline Cellulose, low-substituted hydroxypropyl cellulose cross 80 mesh sieves, 100 orders selected by lactose;
(2) binding agent preparation: preparation 6%w/w PVP-K30 solution for standby;
(3) mix: by candesartan Cilexetil and polyethylene glycol 6000 in measurements of the chest, waist and hips mixer premix, after other adjuvants of recipe quantity are together mixed;
(4) soft material processed: recipe quantity binding agent is sprayed in wet granulator, mixing;
(5) granulate: adopt 22 eye mesh screens to granulate;
(6) dry: less than 50 DEG C oven dry to moisture are less than 4%;
(7) granulate: 20 order granulate;
(8) always mix: add magnesium stearate, always mix;
(9) adopt the stamping of Φ 7mm scrobicula, tabletting controls at the heavy 50N of average sheet;
(10) coating:
internal layer: adopt 15% Lac ethanol coating, relative label weightening finish 8%;
intermediate layer: the ethyl cellulose fumaric acid 80% alcoholic solution coating adopting solid content 20%, 5% of coatings Chong Shi plate core weight, wherein ethyl cellulose: fumaric acid: tributyl citrate=5: 3: 2;
outer: the polyacrylic resin II90% alcoholic solution coating adopting solid content 15%, wherein polyacrylic resin II: ethyl cellulose: tributyl citrate: Pulvis Talci=7: 3: 1: 4, relative label weightening finish 5%.
3.
release composition when a kind of candesartan Cilexetil pulse is selected, it is characterized in that, every 1000 labels are by candesartan Cilexetil 12g, polyethylene glycol 6000 12g, lactose 60g, microcrystalline Cellulose 30g, low-substituted hydroxypropyl cellulose 15g, 6% PVP-K30 50% alcoholic solution 30g, magnesium stearate 1.0g form, and prepare by the following method:
(1) material process: candesartan Cilexetil, polyethylene glycol 6000, microcrystalline Cellulose, low-substituted hydroxypropyl cellulose cross 80 mesh sieves, 100 orders selected by lactose;
(2) binding agent preparation: preparation 6%w/w PVP-K30 solution for standby;
(3) mix: by candesartan Cilexetil and polyethylene glycol 6000 in measurements of the chest, waist and hips mixer premix, after other adjuvants of recipe quantity are together mixed;
(4) soft material processed: recipe quantity binding agent is sprayed in wet granulator, mixing;
(5) granulate: adopt 22 eye mesh screens to granulate;
(6) dry: less than 50 DEG C oven dry to moisture are less than 4%;
(7) granulate: 20 order granulate;
(8) always mix: add magnesium stearate, always mix;
(9) adopt the stamping of Φ 7mm scrobicula, tabletting controls at the heavy 50N of average sheet;
(10) coating:
internal layer: adopt 15% acrylic resin II90% ethanol coating, relative label weightening finish 10%;
intermediate layer: the ethyl cellulose citric acid 80% alcoholic solution coating adopting solid content 20%, weightening finish 5%, wherein ethyl cellulose: citric acid: tributyl citrate=5: 3: 2;
outer: the polyacrylic resin II90% alcoholic solution coating adopting solid content 15%, wherein polyacrylic resin II: ethyl cellulose: tributyl citrate: Pulvis Talci=7: 3: 1: 4, relative label weightening finish 5%.
4.
release composition when a kind of candesartan Cilexetil pulse is selected, it is characterized in that, every 1000 labels are by candesartan Cilexetil 8g, polyethylene glycol 6000 8g, lactose 90g, microcrystalline Cellulose 10g, low-substituted hydroxypropyl cellulose 5g, 6% PVP-K30 50% alcoholic solution 20g, magnesium stearate 0.5g form, and prepare by the following method:
(1) material process: candesartan Cilexetil, polyethylene glycol 6000, microcrystalline Cellulose, low-substituted hydroxypropyl cellulose cross 80 mesh sieves, 100 orders selected by lactose;
(2) binding agent preparation: preparation 6%w/w PVP-K30 solution for standby;
(3) mix: by candesartan Cilexetil and polyethylene glycol 6000 in measurements of the chest, waist and hips mixer premix, after other adjuvants of recipe quantity are together mixed;
(4) soft material processed: recipe quantity binding agent is sprayed in wet granulator, mixing;
(5) granulate: adopt 22 eye mesh screens to granulate;
(6) dry: less than 50 DEG C oven dry to moisture are less than 4%;
(7) granulate: 20 order granulate;
(8) always mix: add magnesium stearate, always mix;
(9) adopt the stamping of Φ 7mm scrobicula, tabletting controls at the heavy 50N of average sheet;
(10) coating:
internal layer: adopt 15% Algin 90% ethanol coating, relative label weightening finish 10%;
intermediate layer: the ethyl cellulose fumaric acid 80% alcoholic solution coating adopting solid content 20%, weightening finish 5%, wherein ethyl cellulose: fumaric acid: tributyl citrate=5: 3: 2;
outer: the polyacrylic resin II90% alcoholic solution coating adopting solid content 15%, wherein polyacrylic resin II: tributyl citrate: Pulvis Talci=10: 1: 4, relative label weightening finish 5%.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1404389A (en) * | 2000-02-11 | 2003-03-19 | 欧兰德制药有限公司 | Timed pulsatile drug delivery systems |
| CN101031290A (en) * | 2003-09-18 | 2007-09-05 | 赛福伦公司 | Modafinil modified release pharmaceutical compositions |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1404389A (en) * | 2000-02-11 | 2003-03-19 | 欧兰德制药有限公司 | Timed pulsatile drug delivery systems |
| CN101031290A (en) * | 2003-09-18 | 2007-09-05 | 赛福伦公司 | Modafinil modified release pharmaceutical compositions |
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Effective date of registration: 20160729 Address after: 264205, Weihai economic and Technological Zone, Shandong Province, Qingdao South Road, No. 1 Patentee after: Disha Pharmaceutical Industry Group Corp., Ltd. Address before: 264205, Weihai economic and Technological Zone, Shandong Province, Qingdao South Road, No. 1 Patentee before: Disha Pharmaceutical Industry Group Corp., Ltd. Patentee before: Disha Pharmaceutical Group Shandong Disha Pharmaceutical Co., Ltd. |
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| CB02 | Change of applicant information |
Inventor after: Gao Yongji Inventor after: Xu Lei Inventor after: Long Lianqing Inventor before: Xu Lei Inventor before: Long Lianqing |
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