CN101766581B - Diltiazem hydrochloride timing controlled release tablet in group-hole released way and preparation method thereof - Google Patents
Diltiazem hydrochloride timing controlled release tablet in group-hole released way and preparation method thereof Download PDFInfo
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- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
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Abstract
The invention provides a diltiazem hydrochloride timing controlled release tablet in a group-hole released way. The controlled release tablet consists of a tablet core and a controlled release membrane, wherein the tablet core comprises diltiazem hydrochloride, filler and osmotic-pressure active substance; and the controlled release membrane comprises membrane-forming material and a hole-forming agent. The controlled release tablet is characterized in that the weight of the hole-forming agent is 20-29% of that of the controlled release membrane, and the weight of the controlled release membrane is 16-24% of that of the tablet core. The controlled release tablet has the effects of starting releasing medicine after 4h and finishing releasing the medicine within 24h completely at the same time. The invention also provides a preparation method of the controlled release tablet.
Description
Technical field
Controlled release tablets and preparation method thereof belongs to technical field of medicine when the present invention relates to diltiazem hydrochloride that a population hole discharges and selecting.
Background technology
Diltiazem hydrochloride is also referred to as: Diltiazem, diltiazem, diltiazem, Di Erding.Chemical name: suitable-(+)-5-[(2-dimethylamino) ethyl]-2-(4-methoxyphenyl)-3-acetoxyl group-2,3-dihydro-1,5-phenylpropyl alcohol sulfur azatropylidene-4 (5H)-keto hydrochloride.Diltiazem hydrochloride is non-dihydropyridine calcium ion channel blocker, has following effect: (1) is to the effect of myocardial ischemia: through coronary artery dilator trunk and side shoot, inhibition coronary spasm, thereby increase the blood flow of myocardial ischemia part.Alleviate cardiac afterload, reducing heart rate and do not reducing the kinemic myocardial oxygen consumption that reduces simultaneously.Flow into ischemic myocardial cells through suppressing too much calcium ion, protecting myocardial cell improves energy metabolism, dwindles the ischemic region area.
(2) to the effect of blood pressure: normal arterial pressure is not made significant difference, reducing the blood flow that patient's blood pressure does not reduce brain, kidney simultaneously.And can suppress thickening of myocardial hypertrophy that hypertension causes and blood vessel wall.
(3) to the effect of conducting system of heart: sinuatrial node-Xi Shi bundle (A-H) conduction is had prolongation slightly, do not make significant difference to conducting between Xi Shi bundle-Purkinje fiber (A-V).
Diltiazem hydrochloride is widely used in angina pectoris and hypertensive long-term treatment.That the NORDIL that delivered in 2000 research is adopted first is perspective, intervention, contrast large-scale experiment at random the effect of diltiazem prophylaxis of hypertension patient cardiovascular event is estimated.The result confirms: diltiazem is used for the hypertension Primary Care to have and diuretic and/or the same effect of beta-blocker reducing cardiovascular event; Generation to reducing cardiovascular complication obviously is superior to dihydropyridine type calcium antagonists; With the diltiazem is that Primary Care is light, moderate essential hypertension, is that all apoplexy incidence rates of the routine treatment on basis significantly reduce 20% than diuretic/beta-blocker.This has the important clinical meaning for apoplexy national hypertension therapeutics occurred frequently such as picture China, Japan.There are some researches show that in addition diltiazem is suitable for widely the hyperpietic to be used, like complication with diabetes, angina pectoris and the hypertension high-risk patient of myocardial infarction medical history is arranged.
When diltiazem hydrochloride during as angina pectoris and hypertensive long-term treatment drug use, in order to bring into play drug effect better, the clinical research result below needing to consider.Clinical practice and chronopharmacology research show that human blood-pressure presents tangible physiological rhythm undulatory property.When the hypertensive patient woke up, catecholamine discharged and increases sharply in the body, and heart rate is accelerated, hypertension.Therefore angina pectoris, hypertension are higher than other periods at the sickness rate of this time period, and chronopharmacology research simultaneously shows that the best administration time of hypertension drug is about 3:00 AM.Yet common pharmaceutical preparation can not adapt to the human blood-pressure rhythmicity to be changed.According to this principle, releasing osmosis pump sheet when having developed diltiazem hydrochloride and selecting, this controlled release tablet was taken 10 of nights, and begin discharge medicine about the 2-3 point second day morning, and 6 reach treatment blood drug level in the morning, the therapeutical effect of performance medicine.An interval that matches with physiological period is arranged the Time of Administration of this medicine and release time; Hypertension for the rhythmicity morbidity; Overcome traditional constant release controlled release preparation and ignored the deficiency of disease rhythmicity, diseases such as angina pectoris, hypertension have been had excellent curative.
Summary of the invention
Purpose of the present invention provides diltiazem hydrochloride that a population hole discharges controlled release tablets when selecting.This controlled release tablet has when selecting release characteristics, and after the patient took medicine, medicine postponed release in 4 hours, and the blood drug level of generation is consistent with the physiological rhythm of human body.
The method for preparing of another purpose of the present invention has provided diltiazem hydrochloride that described crowd hole discharges when selecting controlled release tablets.
Diltiazem hydrochloride controlled release tablet provided by the invention is made up of label and the controlled release layer that is wrapped in the label outside.Described label comprises diltiazem hydrochloride, filler, osmotic pressure active substance; Controlled release layer comprises filmogen, plasticizer and porogen.
The present invention finds, the consumption of porogen and the coating of controlled release layer increase weight has initial release time to diltiazem hydrochloride appreciable impact.On the basis of embodiment 1 label, ratio and the controlled release layer coating of PEG6000 in controlled release layer increased weight to investigating the initial release time of diltiazem hydrochloride; Define the release degree less than 5%, and back one hour release degree is initial release time of a point greater than 5% time point; The average weight that deducts label with the average weight of controlled release tablet behind the coating is the coating weightening finish, is the ratio of the relative label of controlled release layer with the increase weight weight ratio of relative label of coating.The prescription of controlled release layer and release result see the following form.
The result shows, the ratio that PEG accounts for controlled release layer in 19.5%～29.8% scope, the controlled release layer coating increases weight in 15.1%～25.7% scope, the time that can control initial release was at 4 hours.Therefore, preferred porogen weight accounts for the 20%-29% of release-controlled film weight, and preferred controlled release layer weight accounts for the 16%-24% of label weight.
In addition, the present invention finds further that also the consumption of osmotic pressure active substance has very big influence to release.The ratio of PEG in prescription increased the consumption of NaCL greater than 25% o'clock, discharged and accelerated; The consumption of PEG increased the consumption of NaCL less than 25% o'clock in controlled release layer, discharged slack-off.EXPERIMENTAL DESIGN and drug release determination result see the following form.
The drug release determination result (%) of test
| Time | Test 1 | Test 2 | Test 3 | |
Test 5 | Test 6 | Test 7 |
| 2h | 0.1 | 0.4 | 0.3 | 0.4 | 0.3 | 0.3 | 0.4 |
| 4h | 0.9 | 2.1 | 1.0 | 0.9 | 0.8 | 2.2 | 3.5 |
| 8h | 32.3 | 31.8 | 22.0 | 35.3 | 33.9 | 40.5 | 42.5 |
| 12h | 62.4 | 58.2 | 47.0 | 58.6 | 59.8 | 63.5 | 65.4 |
| 16h | 85.8 | 83.3 | 74.3 | 71.3 | 72.9 | 75.9 | 77.8 |
| 24h | 97.3 | 98.3 | 80.3 | 83.9 | 84.9 | 89.2 | 93.2 |
The present invention preferably weight of osmotic pressure active substance accounts for label weight between 14%-20%, and the consumption of filler should account between the 28%-36% of label weight.
Preferably, above-mentioned described diltiazem hydrochloride controlled release tablet, wherein said filmogen is a cellulose acetate, described porogen is selected from Polyethylene Glycol.
Preferably, above-mentioned described diltiazem hydrochloride controlled release tablet, wherein said controlled release layer also comprises plasticizer.
Preferably, above-mentioned described diltiazem hydrochloride controlled release tablet, wherein said plasticizer is selected from one or more in triethyl citrate, dibutyl sebacate, the phthalic acid ester.
Preferably, above-mentioned diltiazem hydrochloride controlled release tablet, wherein said filler is selected from one or more in microcrystalline Cellulose, lactose, sucrose, polymerization sugar and the calcium phosphate.
Preferably, above-mentioned described diltiazem hydrochloride controlled release tablet, wherein said osmotic pressure active substance is selected from one or more in sodium chloride, potassium chloride, mannitol and the sorbitol.
Preferably, above-mentioned diltiazem hydrochloride controlled release tablet, wherein said lubricant is selected from one or more in stearic acid, magnesium stearate, hydrogenated vegetable oil and the sodium stearyl fumarate.
Preferably, diltiazem hydrochloride controlled release tablet of the present invention, diltiazem hydrochloride began the about 3-4 of release relay hour in the wherein said controlled release tablet, preferably postponed about 4 hours, and 24 h drug discharge and are not less than 80%, discharge fully near.
The present invention also provides a kind of method for preparing said controlled release tablet on the other hand, and this method may further comprise the steps:
A. granulate: at first diltiazem hydrochloride, filler and osmotic pressure active substance are put mix homogeneously in the comminutor, add binding agent and process granule, subsequent use behind drying, granulate;
B. tabletting: granule and mix lubricant that step a is obtained are even, and carry out tabletting, obtain label;
C. prepare the controlled release layer coating solution: with described filmogen, porogen and optional plasticizer and solvent, obtain coating solution, preferably, wherein said solvent is acetone or the acetone soln that contains low amounts of water;
D. wrap controlled release layer: the coating solution that obtains with step c carries out coating to the label that step b obtains, and is label weight 15%-21% up to release-controlled film weight, obtains the semi-finished product of controlled release tablet;
E. controlled release layer is aging: the semi-finished product of the controlled release tablet that steps d is obtained are dry, remove solvent wherein, obtain described controlled release tablet.
Preferably, described step a carries out in wet granulator or in the fluid bed, and described steps d is carried out in high-efficiency coating machine.
The preferred invention that the present invention formerly makes on the patent application CN1923184A basis the applicant.The present invention is through the repeated multiple times experiment; Find unexpectedly; Through the porogen in the diltiazem hydrochloride controlled release tablet of confirming the release of crowd hole and the approrpiate wts of release-controlled film; Postpone to begin in about 4 hours to discharge thereby reach patient's back medicine of taking medicine, simultaneously within 24 hours that drug release is closely complete, the purpose that the blood drug level of generation is consistent with the physiological rhythm of human body.Further, the present invention also through the amount of osmotic pressure active substance and filler in the control controlled release tablet label, can play the effect that control lag discharges better.
The mode that the present invention uses group hole to discharge is first prepared the osmotic pump controlled release tablet with release function when selecting; It is the combination of group hole release tech and basic osmotic pump controlled release tablet technology of preparing; Beyond thoughtly be that the combination of these two technology has not only kept the effect of original technology; The more important thing is to have produced the delay releasing effect to have the effect that discharges when selecting.Because the drug release of these article has the interval that matches with the human blood-pressure physiological period, can discharge medicine according to the physiological rhythm of human blood-pressure, satisfy the needs of division of day and night treatment clinically.In addition, the present invention also has following effect:
Simplified production process: the preparation technology of this product does not need laser boring, has simplified the industrialization production that production process helps realizing osmotic pump controlled release tablet.
Do not need new equipment input: this project provides a kind of releasing osmosis pump sheet when need not to carry out the selecting of laser boring, the input 1,000 ten thousand of saving laser drilling device; These article both can be produced in the tablet manufacturing workshop of routine, need not acquire new equipment, were particularly suitable for the existing working condition of Chinese pharmacy corporation.
Improved the safety of medicine: because the mode that adopts the crowd hole to discharge; The risk of having avoided single drug release hole to be stopped up by food easily, can the mode drug release hole by the food betting contest after the label osmotic pressure can't discharge, cause the release-controlled film explosion; Medicine is prominent to be released; A large amount of medicines are emitted fast, reach the problem of poisoning concentration rapidly, have improved the safety of preparation greatly.
Reduced production link: compare with the basic osmotic pumps of laser boring, reduced laser boring link and hand inspection punch sample and two production links of no marking hole sample more; Shorten the production cycle greatly, reduced cost of labor and production cost, improved yield rate.
Production cycle shortens: the laser boring osmotic pump controlled release tablet is processed controlled release tablet and is needed 3 days from being dosed into, and the many punchings of hand inspection are during with no marking hole sample, and every lot sample article need the workman with the 7 day time of macroscopy in 500,000, altogether need 10 day time.This product does not need laser boring, and the production time of every lot sample article shortens to 3 days, has shortened the production cycle greatly, has reduced labor intensity.
Process repeatability improves: production process of this project and basic osmotic pumps have relatively reduced by 2 production links; Compare with double-layer osmotic pump controlled-release tablet; Reduced by 5 production links, produced and be more prone to control, suitability for industrialized production can be easy to duplication of production and go out the uniform product of quality.
Cost reduces: owing to need not carry out the transformation, with short production cycle etc. of the acquiring of laser boring and laser drilling device, workshop; Greatly reduce power consumption; The direct cost of production processes such as manpower consumption has improved the output capacity of workman's unit interval, and work efficiency improves greatly.
Description of drawings
The release profiles of Fig. 1 embodiment 1 and embodiment 2
The release profiles of Fig. 2 embodiment 3
The specific embodiment
The present invention is elaborated with the specific embodiment, and following examples do not constitute restriction of the present invention.
Embodiment 1
The label prescription:
Diltiazem hydrochloride 90g
Microcrystalline Cellulose 60g
Sodium chloride 40g
Magnesium stearate 2g
15% polyvidone aqueous solution is an amount of
Process 1000
The release-controlled film prescription:
Cellulose acetate 20g
Polyethylene Glycol 8.5g
Dibutyl sebacate 2.0g
Acetone 800 (ml)
Water 40g
Method for preparing:
(1) pulverizes: get sodium chloride and pulverize subsequent use;
(2) granulate: diltiazem hydrochloride, sodium chloride fine powder and the microcrystalline Cellulose of getting recipe quantity are put into the granulator mix homogeneously, are binding agent with 15% povidone solution, granulate, and wet granular is at 40 ℃ of dryings, granulate; Granule that makes and magnesium stearate mix homogeneously is subsequent use;
(3) tabletting: get the granule of mix homogeneously, with the circular scrobicula stamping of diameter 8mm, Hardness Control is about 6kg;
(4) preparation controlled release layer coating solution: cellulose acetate is added in the acetone, soak, stir and make whole dissolvings, subsequent use; Taking polyethylene glycol is added to the water, and stirs and makes dissolving, joins in foregoing cellulose acetate-acetone soln, adds dibutyl sebacate again, and mix homogeneously is subsequent use;
(5) label that makes is put in the high-efficiency coating machine, EAT is controlled at below 35 ℃, sprays into the controlled release layer coating solution, and the sheet bed tempertaure remains on below 30 ℃, is 15% of plate core weight up to the weight of release-controlled film;
(6) controlled release layer is aging: the controlled release tablet of getting behind the coating is put in 40 ℃ of thermostatic drying chambers, dry 12 hours, removes acetone.
The label prescription:
Diltiazem hydrochloride 90g
Lactose 30g
Microcrystalline Cellulose 30g
Sorbitol 50g
Magnesium stearate 2g
15% povidone solution is an amount of
Controlled release layer coating solution prescription:
Cellulose acetate 20g
Polyethylene Glycol 8g
Triethyl citrate 2.4g
Acetone 800 (ml)
Water 40g
Method for preparing:
(1) granulates: diltiazem hydrochloride, lactose, microcrystalline Cellulose, sodium chloride fine powder are put into the fluid bed mix homogeneously, use 15% polyvidone aqueous solution to be binding agent top spray grain, add the magnesium stearate mix homogeneously;
(2) tabletting: with the circular scrobicula stamping of diameter 8mm, Hardness Control is at 7kg;
(3) preparation controlled release layer coating solution: cellulose acetate is added in the acetone, soak, make whole dissolvings, add Polyethylene Glycol, stir and make its dissolving, add triethyl citrate again, mix homogeneously, subsequent use;
(4) controlled release layer coating: the label that makes is put in the high-efficiency coating machine, and EAT is controlled at below 35 ℃, sprays into coating solution, forms release-controlled film, and the sheet bed tempertaure remains on below 30 ℃, is 19% of label weight up to release-controlled film weight;
(5) aging: the controlled release tablet of getting the bag controlled release layer is put in the drying baker, 40～50 ℃ of dryings, removes acetone.
Embodiment 3
The label prescription:
Diltiazem hydrochloride 90g
Microcrystalline Cellulose 60g
Sodium chloride 25g
Magnesium stearate 2g
15% povidone solution is an amount of
Controlled release layer coating solution prescription:
Cellulose acetate 30g
Polyethylene glycol 6000 10g
Dibutyl sebacate 3g
Acetone 900 (g)
Water 30g
Method for preparing:
(1) granulate: diltiazem hydrochloride, microcrystalline Cellulose, sodium chloride fine powder are put into the granulator mix homogeneously, use 15% polyvidone aqueous solution to granulate as binding agent, drying, granulate adds the magnesium stearate mix homogeneously;
(2) tabletting: with the circular scrobicula stamping of diameter 8mm, Hardness Control is at 6 ~ 7kg;
(3) preparation controlled release layer coating solution: cellulose acetate is added in the acetone, soak, make whole dissolvings, add Polyethylene Glycol, stir and make its dissolving, add dibutyl sebacate again, mix homogeneously, subsequent use;
(4) controlled release layer coating: the label that makes is put in the high-efficiency coating machine, and EAT is controlled at below 30 ℃, sprays into coating solution, forms release-controlled film, and the sheet bed tempertaure remains on below 28 ℃, is 18% of label weight up to release-controlled film weight;
(5) aging: the controlled release tablet of getting the bag controlled release layer is put in the drying baker, 40～50 ℃ of dryings, removes acetone.The mensuration of release degree:
Drug release determination method: the release degree that adopts drug release determination first method mensuration diltiazem hydrochloride timing and controlled release sheet of Chinese Pharmacopoeia regulation.Adopt dissolution determination first subtraction unit; With water 900ml is release medium, and rotating speed was that per minute 100 changes, sampling in 4,8,12,16 and 24 hours; At the wavelength working sample of 236nm and the absorbance of reference substance, method calculates the burst size of different time with ultraviolet spectrophotometry.
The drug release determination result (%) of embodiment
Claims (11)
1. the diltiazem hydrochloride timing and controlled release sheet that discharges of a population hole; This controlled release tablet is made up of label and release-controlled film; Described label comprises diltiazem hydrochloride, filler and osmotic pressure active substance; Described release-controlled film comprises filmogen and porogen, it is characterized in that porogen weight in the said release-controlled film accounts for the 20%-25% of release-controlled film weight, and release-controlled film weight accounts for the 16%-24% of label weight; Osmotic pressure active substance weight accounts for the 14%-20% of label weight in the described label, and filler weight accounts for 28%～36% of label weight; Wherein, described filmogen is a cellulose acetate, and described porogen is a Polyethylene Glycol;
And diltiazem hydrochloride began the about 3-4 of release relay hour, and 24 h drug discharge and are not less than 80%.
2. diltiazem hydrochloride controlled release tablet according to claim 1, wherein said release-controlled film also comprises plasticizer, and described plasticizer is selected from one or more in triethyl citrate, dibutyl sebacate, phthalic acid ester, glycerin and the propylene glycol.
3. diltiazem hydrochloride controlled release tablet according to claim 2, wherein said filler is selected from one or more in microcrystalline Cellulose, lactose, starch, sucrose and the polymerization sugar.
4. according to each described diltiazem hydrochloride controlled release tablet of claim 1-3, wherein said osmotic pressure active substance is selected from one or more in sodium chloride, potassium chloride, mannitol and the sorbitol.
5. diltiazem hydrochloride controlled release tablet according to claim 2, wherein said osmotic pressure active substance is selected from one or more in sodium chloride, potassium chloride, mannitol and the sorbitol.
6. diltiazem hydrochloride controlled release tablet according to claim 5, wherein said label also comprises lubricant and binding agent.
7. diltiazem hydrochloride controlled release tablet according to claim 6, described lubricant is selected from one or more in stearic acid, magnesium stearate, hydrogenated vegetable oil and the sodium stearyl fumarate.
8. diltiazem hydrochloride controlled release tablet according to claim 6, described binding agent are polyvidone.
9. method for preparing each said diltiazem hydrochloride controlled release tablet among the claim 1-8, this method may further comprise the steps:
A. at first diltiazem hydrochloride, filler and osmotic pressure active substance are mixed, add binding agent and process granule;
B. the granule and the mix lubricant that step a are obtained are even, and carry out tabletting, obtain label;
C. with filmogen, porogen and optional plasticizer and the solvent that exists, obtain coating solution;
D. the coating solution that obtains with step c carries out coating to the label that step b obtains, and obtains the semi-finished product of controlled release tablet;
The semi-finished product of the controlled release tablet that e. steps d is obtained are dry, remove solvent wherein, obtain described controlled release tablet.
10. method according to claim 9, wherein said solvent are the mixed solution of acetone or acetone-water.
11. method according to claim 10, wherein said step a carries out in wet granulator or in the fluid bed, and described steps d is carried out in the coating machine.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2008102467319A CN101766581B (en) | 2008-12-30 | 2008-12-30 | Diltiazem hydrochloride timing controlled release tablet in group-hole released way and preparation method thereof |
| PCT/CN2009/001575 WO2010081286A1 (en) | 2008-12-30 | 2009-12-29 | Timing controlled – release porous tablet of diltiazem hydrochloride and the preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2008102467319A CN101766581B (en) | 2008-12-30 | 2008-12-30 | Diltiazem hydrochloride timing controlled release tablet in group-hole released way and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101766581A CN101766581A (en) | 2010-07-07 |
| CN101766581B true CN101766581B (en) | 2012-08-15 |
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| CN2008102467319A Active CN101766581B (en) | 2008-12-30 | 2008-12-30 | Diltiazem hydrochloride timing controlled release tablet in group-hole released way and preparation method thereof |
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| CN (1) | CN101766581B (en) |
| WO (1) | WO2010081286A1 (en) |
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| CN112220771B (en) * | 2020-11-10 | 2023-03-31 | 成都大学 | Zalcitabine osmotic pump type controlled release tablet and preparation method thereof |
| CN113171351A (en) * | 2021-04-02 | 2021-07-27 | 海南锦瑞制药有限公司 | Diltiazem hydrochloride controlled-release pill and preparation method thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1546039A (en) * | 2003-12-15 | 2004-11-17 | 中国药科大学 | Sustained releasing minipills of diltiazem hydrochloride and its preparation |
| CN1771965A (en) * | 2005-11-04 | 2006-05-17 | 陈茜 | Diltiazem hydrochloride and its prepn |
| CN1923184A (en) * | 2006-10-16 | 2007-03-07 | 北京科信必成医药科技发展有限公司 | Multiple apertures releasing osmosis pump and preparation process thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NZ226179A (en) * | 1987-09-24 | 1991-04-26 | Merck & Co Inc | Controlled porosity osmotic pump for sustained release of pharmaceutical agents |
| SE0001151D0 (en) * | 2000-03-31 | 2000-03-31 | Amarin Dev Ab | Method of producing a controlled-release composition |
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2008
- 2008-12-30 CN CN2008102467319A patent/CN101766581B/en active Active
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2009
- 2009-12-29 WO PCT/CN2009/001575 patent/WO2010081286A1/en active Application Filing
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1546039A (en) * | 2003-12-15 | 2004-11-17 | 中国药科大学 | Sustained releasing minipills of diltiazem hydrochloride and its preparation |
| CN1771965A (en) * | 2005-11-04 | 2006-05-17 | 陈茜 | Diltiazem hydrochloride and its prepn |
| CN1923184A (en) * | 2006-10-16 | 2007-03-07 | 北京科信必成医药科技发展有限公司 | Multiple apertures releasing osmosis pump and preparation process thereof |
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| Publication number | Publication date |
|---|---|
| WO2010081286A1 (en) | 2010-07-22 |
| CN101766581A (en) | 2010-07-07 |
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Address after: 100083 Haidian District, Xueyuan Road, No. 30, A building, room No. 15, room, room 15 Patentee after: Beijing Kexin Bicheng Medicine Science & Technology Developing Co., Ltd. Address before: 100190, room 1410, satellite building, No. 63, Zhichun Road, Beijing, Haidian District Patentee before: Beijing Kexin Bicheng Medicine Science & Technology Developing Co., Ltd. |