CN102631320A - Betahistine hydrochloride liposome and preparation method thereof - Google Patents
Betahistine hydrochloride liposome and preparation method thereof Download PDFInfo
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- CN102631320A CN102631320A CN2012101215162A CN201210121516A CN102631320A CN 102631320 A CN102631320 A CN 102631320A CN 2012101215162 A CN2012101215162 A CN 2012101215162A CN 201210121516 A CN201210121516 A CN 201210121516A CN 102631320 A CN102631320 A CN 102631320A
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Abstract
The invention relates to a betahistine hydrochloride liposome and a preparation method of the betahistine hydrochloride liposome. The preparation method comprises the steps of: firstly dissolving lipide ingredients in methylene dichloride, and carrying out reduced-pressure evaporation in water bath until a film is formed; dissolving the film in diethyl ether, and then adding phosphate buffer containing betahistine into the solution; carrying out ultrasonic treatment on the mixed suspension liquid, placing the treated liquid on a rotary evaporator, and carrying out reduced-pressure vaporization until all the organic reagent is evaporated; and finally, obtaining the betahistine hydrochloride liposome. The betahistine hydrochloride is made into liposome, so that the medicine effect is obviously improved, the permeability of blood capillary can be improved, and the dosage of the medicine reaching blood vessels of the brain can be increased; the betahistine hydrochloride liposome is used for improving the treatment effect of Meniere syndrome, reduces the gastrointestinal irritation and the adverse drug reaction, and is beneficial to reducing the side effects such as stomach upset, nausea, dizziness and the like.
Description
Technical field
The present invention relates to a kind of Betahistine Hydrochloride liposome and preparation method thereof, belong to pharmaceutical preparation and preparation method thereof technical field.
Background technology
Betahistine Hydrochloride is to cerebrovascular, cardiovascular, particularly Arterial system at the bottom of the vertebra had significantly dilating effect, can increase the heart, brain and around blood flow; Improve blood circulation, and reduce systemic blood pressure, this external enwergy increases cochlea and blood flow of the preceding end; Thereby the elimination auditory vertigo, tinnitus and deafness sense can also increase capillary permeability; Promote the absorption of extracellular fluid, eliminate edema in the lymph; Can resist the contract blood vessel function and the reduction arterial pressure of catecholamine, and the clotting of plasma of inhibition and the inductive platelet aggregation effect of ADP are arranged, can prolong rat external thrombus formation time, also have slight diuresis.Simultaneously the Betahistine Hydrochloride of general formulation exist some untoward reaction as, idol has xerostomia, stomach discomfort, cardiopalmus, skin pruritus etc., that indivedual cases idols have is nauseating, dizzy, feeling of fullness in the head, perspiration etc.
Liposome has similar biomembranous bilayer structure, with cell membrane affinity is highly arranged.Particle diameter through the control liposome conducts drugs to specific target site, can improve therapeutic effect, reduces side effects of pharmaceutical drugs.Liposome is the targeting preparation that paid close attention to by people, and people such as Rachanan at first uses liposome as carrier from the sixties, new Liposomal formulation appearance is constantly arranged, like Evacet, the cisplatin liposome of liposome company (TLC).The Liposomal formulation of now existing 2 cancer therapy drugs and 3 antifungal drugs is given the ratification, and other still have the Liposomal formulation of more than ten kind of medicine to enter into clinical experimental stage.For many years, liposome further improving curative effect of medication, is reduced toxicity, doing a lot in aspects such as raising stability, and makes remarkable progress.
Plant sterol is and the mobile relevant important structure factor of biomembrane that the ratio of phytosterol and the flowability of film are the contravariant relation, and influence film fat phase transition temperature with the ratio of content of phospholipid.And all there is an ethylidene to have stronger antiopxidant effect on the plant sterol molecular side chain, blocked the oxidation reaction of fatty acid chain.Existing existing is the control that the clinical medicine of main constituent is used for cardiovascular disorders such as atherosclerosis, hyperlipidemia, coronary atherosclerotic heart disease, uncomfortable in chest, cardiopalmus with the plant sterol.
Summary of the invention
The present invention relates to a kind of method for preparing of Betahistine Hydrochloride liposome, pointed out the characteristics of Betahistine Hydrochloride liposome on pharmacodynamics simultaneously.
Disclosed by the inventionA kind of Betahistine Hydrochloride liposome is characterized in that: comprise Betahistine Hydrochloride and Liposomal formulation, wherein, Betahistine Hydrochloride 5～30mg/mL; Comprise lecithin, two kinds of lipid components of plant sterol in the Liposomal formulation, wherein, the mass ratio of lecithin and plant sterol is 3:1～8:1, and the mass ratio of Betahistine Hydrochloride and TL composition is 1:1～1:15.
The method for preparing of Betahistine Hydrochloride liposome of the present invention is characterized in that, step is following:
(1) take by weighing lecithin, plant sterol by mass ratio 3:1～8:1, then both are dissolved with 20～30mL dichloromethane, after the dissolving, reduction vaporization to thin film forms fully;
(2) with in 40～80mL ether impouring lipid film, be that thin film is dissolved in the ether fully;
(3) preparation contains the phosphate buffer of Betahistine Hydrochloride 5～30mg/mL, and its pH is 5.7～8.0;
(4) with the said solution mix homogeneously in (2) (3), ultrasonic 15～30 minutes;
(5) mixed solution after ultrasonic is put on the Rotary Evaporators reduction vaporization to all organic reagents evaporations;
(6) the above-mentioned suspension that makes is passed through high pressure homogenizer, pressure is 500～1000bar, extrudes appearance (the filter membrane aperture is between 0.2 μ m～10 μ m) through liposome then, promptly gets the Betahistine Hydrochloride liposome.
Said step (3) preparation contains the PBS buffer of Betahistine Hydrochloride 5～30mg/mL, and its pH is 5.7～8.0.
Said step (6) is passed through high pressure homogenizer with the above-mentioned suspension that makes; Pressure is 500～1000bar; Extrude appearance (the filter membrane aperture is between 0.2 μ m～10 μ m) through liposome then, promptly get the Betahistine Hydrochloride liposome, particle diameter is between 0.2 μ m～10 μ m.
Described Betahistine Hydrochloride liposome is characterized in that: can be prepared into the tablet, capsule, oral liquid, the injection that contain the Betahistine Hydrochloride liposome.
Betahistine Hydrochloride liposome mean diameter of the present invention is at 0.2 μ m～10 μ m, and the concentration of Betahistine Hydrochloride is 5～30mg/mL, and liposome is neutral, also can positively charged or negative charge; Envelop rate is 50%～90%, and pH value is 5.8～8.0, and outward appearance is the milky suspension.
The present invention replaces cholesterol with plant sterol and prepares the Betahistine Hydrochloride liposome.Plant sterol character and cholesterol seemingly can angiocardiopathy preventings, and clinical also had research, but never be applied in the liposome preparation technology.Mainly contrasted plant sterol and cholesterol in the description and prepared the difference that liposome arrives rat brain medicine effective content respectively, explained that plant sterol is fit to preparation Betahistine Hydrochloride liposome more.
Good effect of the present invention is:Betahistine Hydrochloride is processed liposome, can obviously strengthen drug effect, can increase the penetrating power of blood capillary; Making medicine arrive cerebrovascular dosage increases; Can be used for improving the therapeutic effect of Meniere's disease, can also reduce GI irritation simultaneously, reduce adverse effect; Help to reduce stomach discomfort, the side effect such as dizziness of feeling sick.The flowability that the cholesterol that appliable plant sterol simultaneously of the present invention replaces traditional liposomal preparation technology is regulated liposome membrane can improve the oxidation resistance of liposome.Plant sterol mainly is the functional activity composition as angiocardiopathy preventing, and plant sterol can be assisted the drug effect that improves Betahistine Hydrochloride among the present invention.
The Betahistine Hydrochloride liposome has stability preferably, can obviously strengthen drug effect, can increase the penetrating power of blood capillary; Making medicine arrive cerebrovascular dosage increases; Can be used for improving the therapeutic effect of Meniere's disease, can also reduce GI irritation simultaneously, reduce adverse effect; Help to reduce stomach discomfort, the side effect such as dizziness of feeling sick.The present invention goes back the flowability that cholesterol that the appliable plant sterol replaces traditional liposomal preparation technology is regulated liposome membrane, can improve the oxidation resistance of liposome, to effective treatment of cardiovascular, cerebrovascular double diseases.
Description of drawings
Fig. 1 is an acid hydrochloride salt betahistine standard curve.
The practical implementation method:
Following embodiment is used for further specifying the present invention, but content of the present invention is not limited thereto.
Embodiment 1
Method for preparing of the present invention:
(1) take by weighing lecithin, plant sterol by mass ratio 3:1, then both are dissolved with the 20mL dichloromethane, after the dissolving, reduction vaporization to thin film forms fully;
(2) with in the 40mL ether impouring lipid film, be that thin film is dissolved in the ether fully;
(3) preparation contains the phosphate buffer of Betahistine Hydrochloride 5mg/mL, and its pH is 5.7;
(4) with the said solution mix homogeneously of step (2) (3), ultrasonic 15 minutes;
(5) mixed solution after ultrasonic is put on the Rotary Evaporators reduction vaporization to all organic reagents evaporations;
(6) the above-mentioned suspension that makes is passed through high pressure homogenizer, pressure is 500bar, extrudes appearance (the filter membrane aperture is 0.4 μ m) through liposome then, promptly gets Betahistine Hydrochloride liposome (experimental group one).
The matched group method for preparing:
(1) take by weighing lecithin, cholesterol by mass ratio 3:1, then both are dissolved with the 20mL dichloromethane, after the dissolving, reduction vaporization to thin film forms fully;
(2) with in the 40mL ether impouring lipid film, be that thin film is dissolved in the ether fully;
(3) preparation contains the phosphate buffer of Betahistine Hydrochloride 5mg/mL, and its pH is 5.7;
(4) with the said solution mix homogeneously of step (2) (3), ultrasonic 15 minutes;
(5) mixed solution after ultrasonic is put on the Rotary Evaporators reduction vaporization to all organic reagents evaporations;
(6) the above-mentioned suspension that makes is passed through high pressure homogenizer, pressure is 500bar, extrudes appearance (the filter membrane aperture is 0.4 μ m) through liposome then, promptly gets Betahistine Hydrochloride liposome (matched group one).
Embodiment 2
Method for preparing of the present invention:
(1) take by weighing lecithin, plant sterol by mass ratio 4:1, then both are dissolved with the 25mL dichloromethane, after the dissolving, reduction vaporization to thin film forms fully;
(2) with in the 60mL ether impouring lipid film, be that thin film is dissolved in the ether fully;
(3) preparation contains the phosphate buffer of Betahistine Hydrochloride 10mg/mL, and its pH is 6.5;
(4) with the said solution mix homogeneously of step (2) (3), ultrasonic 20 minutes;
(5) mixed solution after ultrasonic is put on the Rotary Evaporators reduction vaporization to all organic reagents evaporations;
(6) the above-mentioned suspension that makes is passed through high pressure homogenizer, pressure is 800bar, extrudes appearance (the filter membrane aperture is between 0.3 μ m) through liposome then, promptly gets Betahistine Hydrochloride liposome (experimental group two).
The matched group method for preparing:
(1) take by weighing lecithin, cholesterol by mass ratio 4:1, then both are dissolved with the 25mL dichloromethane, after the dissolving, reduction vaporization to thin film forms fully;
(2) with in the 60mL ether impouring lipid film, be that thin film is dissolved in the ether fully;
(3) preparation contains the phosphate buffer of Betahistine Hydrochloride 10mg/mL, and its pH is 6.5;
(4) with the said solution mix homogeneously in (2) (3), ultrasonic 20 minutes;
(5) mixed solution after ultrasonic is put on the Rotary Evaporators reduction vaporization to all organic reagents evaporations;
(6) the above-mentioned suspension that makes is passed through high pressure homogenizer, pressure is 800bar, extrudes appearance (the filter membrane aperture is between 0.3 μ m) through liposome then, promptly gets Betahistine Hydrochloride liposome (matched group two).
Embodiment 3
Method for preparing of the present invention:
(1) take by weighing lecithin, plant sterol by mass ratio 5:1, then both are dissolved with the 25mL dichloromethane, after the dissolving, reduction vaporization to thin film forms fully;
(2) with in the 60mL ether impouring lipid film, be that thin film is dissolved in the ether fully;
(3) preparation contains the phosphate buffer of Betahistine Hydrochloride 20mg/mL, and its pH is 6.8;
(4) with the said solution mix homogeneously in (2) (3), ultrasonic 20 minutes;
(5) mixed solution after ultrasonic is put on the Rotary Evaporators reduction vaporization to all organic reagents evaporations;
(6) the above-mentioned suspension that makes is passed through high pressure homogenizer, pressure is 900bar, extrudes appearance (the filter membrane aperture is between 0.5 μ m) through liposome then, promptly gets Betahistine Hydrochloride liposome (experimental group three).
The matched group method for preparing:
(1) take by weighing lecithin, cholesterol by mass ratio 5:1, then both are dissolved with the 25mL dichloromethane, after the dissolving, reduction vaporization to thin film forms fully;
(2) with in the 60mL ether impouring lipid film, be that thin film is dissolved in the ether fully;
(3) preparation contains the phosphate buffer of Betahistine Hydrochloride 20mg/mL, and its pH is 6.8;
(4) with the said solution mix homogeneously in (2) (3), ultrasonic 20 minutes;
(5) mixed solution after ultrasonic is put on the Rotary Evaporators reduction vaporization to all organic reagents evaporations;
(6) the above-mentioned suspension that makes is passed through high pressure homogenizer, pressure is 900bar, extrudes appearance (the filter membrane aperture is between 0.5 μ m) through liposome then, promptly gets Betahistine Hydrochloride liposome (matched group three).
Embodiment 4
Method for preparing of the present invention:
(1) take by weighing lecithin, plant sterol by mass ratio 8:1, then both are dissolved with the 30mL dichloromethane, after the dissolving, reduction vaporization to thin film forms fully;
(2) with in the 80mL ether impouring lipid film, be that thin film is dissolved in the ether fully;
(3) preparation contains the phosphate buffer of Betahistine Hydrochloride 30mg/mL, and its pH is 8.0;
(4) with the said solution mix homogeneously in (2) (3), ultrasonic 30 minutes;
(5) mixed solution after ultrasonic is put on the Rotary Evaporators reduction vaporization to all organic reagents evaporations;
(6) the above-mentioned suspension that makes is passed through high pressure homogenizer, pressure is 1000bar, extrudes appearance (the filter membrane aperture is between 10 μ m) through liposome then, promptly gets Betahistine Hydrochloride liposome (experimental group four).
The matched group method for preparing:
(1) take by weighing lecithin, cholesterol by mass ratio 8:1, then both are dissolved with the 30mL dichloromethane, after the dissolving, reduction vaporization to thin film forms fully;
(2) with in the 80mL ether impouring lipid film, be that thin film is dissolved in the ether fully;
(3) preparation contains the phosphate buffer of Betahistine Hydrochloride 30mg/mL, and its pH is 8.0;
(4) with the said solution mix homogeneously in (2) (3), ultrasonic 30 minutes;
(5) mixed solution after ultrasonic is put on the Rotary Evaporators reduction vaporization to all organic reagents evaporations;
(6) the above-mentioned suspension that makes is passed through high pressure homogenizer, pressure is 1000bar, extrudes appearance (the filter membrane aperture is between 10 μ m) through liposome then, promptly gets Betahistine Hydrochloride liposome (matched group four).
Below experiment shows that acid hydrochloride salt betahistine liposome has higher bioavailability than general formulation, can improve drug effect, and prove that reagent provided by the invention and consumption are optimum condition:
1. chromatographic condition: Agilent HC-C
18Chromatographic column; With acetonitrile: (12% sulphuric acid 10mL, 1% tetrabutylammonium hydroxide amine 40mL and water 650 mL mix the back and add the 2.5g sodium lauryl sulphate acetic acid mixed solution, dissolve, shake up; Regulating pH is 3.3) (28:72) be mobile phase; The ultraviolet detection wavelength is 260nm, and number of theoretical plate calculates by acid hydrochloride salt betahistine peak should be not less than 1500, and sample introduction is counted its RSD of pin less than 20%.
2. get the about 0.1g of acid hydrochloride salt betahistine reference substance, being dissolved in water and being settled to 100mL is stock solution.Get stock solution 1.5,2.0,2.25,2.5,2.75mL, add mobile phase, get each concentration liquid 10 μ L and inject chromatograph of liquid, draw peak area separately to 25mL.With concentration is abscissa, and peak area is that vertical coordinate gets regression equation: y=11977x-16799, R
2=0.9992.Above presentation of results acid hydrochloride salt betahistine concentration is good in the concentration range internal linear relation of 100～170 mg/mL.Like Fig. 1
3. getting body weight is 180～220g male rat, is divided into two groups at random.Press 4.32mgkg for one group
-1Dosage irritate stomach and give the Betahistine Hydrochloride liposome turbid liquor, another group gives isodose commercially available Betahistine Hydrochloride tablet.Behind the successive administration 7 days, behind the last administration 1h, put to death rat, get cerebral tissue, clean with normal saline flushing, filter paper blots, and weighs; The accurate title, be placed in the homogenizer surely, add an amount of normal saline (internal organs weight: normal saline=1g:10mL) homogenate, get homogenate and all place centrifuge tube, add 2mL25% hydrochloric acid solution vortex and mixed 3 minutes, be placed in 40 ℃ of water-baths hydrolysis 30 minutes.Put coldly, add the 5mL deionized water, vortex mixed 3 minutes, 8000rmin
-1Centrifugal 15min draws supernatant, and the accurate 20 μ L sample introductions of drawing inject chromatograph of liquid, the record peak area.Contrast mark curve draws the Betahistine Hydrochloride content of each cerebral tissue.
4. result
The Betahistine Hydrochloride liposome of method of the present invention preparation after administration, the medicament contg such as the table 1 of rat cerebral tissue,
Table 1 experimental group rat cerebral tissue Betahistine Hydrochloride content (n=10)
| ? | Betahistine Hydrochloride liposome group (%) | Betahistine Hydrochloride tablet group (%) |
| Experimental group one | 0.3420±0.0046 | 0.0872±0.0148 |
| Experimental group two | 0.3543±0.0547 | 0.0997±0.0186 |
| Experimental group three | 0.3681±0.0458 | 0.1072±0.0143 |
| Experimental group four | 0.3726±0.0843 | 0.1192±0.0376 |
The Betahistine Hydrochloride liposome of contrast method preparation after administration, the medicine assay such as the table 2 of rat cerebral tissue,
Table 2 control rats cerebral tissue Betahistine Hydrochloride content (n=10)
| ? | Betahistine Hydrochloride liposome group (%) | Betahistine Hydrochloride tablet group (%) |
| Matched group one | 0.2034±0.0058 | 0.0872±0.0148 |
| Matched group two | 0.2883±0.0148 | 0.0997±0.0186 |
| Matched group three | 0.3068±0.0862 | 0.1072±0.0143 |
| Matched group four | 0.3187±0.0057 | 0.1192±0.0376 |
Above-mentioned experiment shows that the Betahistine Hydrochloride liposome has high bioavailability than conventional tablet, more helps increasing the penetrating power of blood capillary, and making medicine arrive cerebrovascular effective dose increases.Can be used for treating Meniere disease, vascular headache and cerebral arteriosclerosis, and can be used for treating acute cerebrovascular disease, like cerebral thrombosis, cerebral embolism etc.The Betahistine Hydrochloride liposome that the present invention relates to also can be prepared into tablet, capsule, oral liquid and injection.
Table 3. experimental group and control rats cerebral tissue Betahistine Hydrochloride content are relatively
| ? | Experimental group (%) | Matched group (%) |
| One | 0.3420±0.0046 | 0.2034±0.0058 |
| Two | 0.3543±0.0547 | 0.2883±0.0148 |
| Three | 0.3681±0.0458 | 0.3068±0.0862 |
| Four | 0.3726±0.0843 | 0.3187±0.0057 |
The cholesterol that experimental group appliable plant sterol substitutes matched group prepares liposome; From table 3, can find out; Betahistine Hydrochloride content contained in the experimental group rat is higher; Explain that plant sterol is more suitable for as preparation Betahistine Hydrochloride liposome than cholesterol, and the application of plant sterol can improve the drug effect of Betahistine Hydrochloride.
Betahistine Hydrochloride liposome of the present invention has bigger advantage in application, liposome dosage form itself has the advantage that reduces drug toxicity simultaneously.The present invention provides new thinking for the medicine of treatment cardiovascular and cerebrovascular disease.
Claims (5)
1. Betahistine Hydrochloride liposome is characterized in that: comprise Betahistine Hydrochloride and Liposomal formulation, wherein, Betahistine Hydrochloride 5～30mg/mL; Comprise lecithin, two kinds of lipid components of plant sterol in the Liposomal formulation, wherein, the mass ratio of lecithin and plant sterol is 3:1～8:1, and the mass ratio of Betahistine Hydrochloride and TL composition is 1:1～1:15.
2. the method for preparing of the described Betahistine Hydrochloride liposome of claim 1 is characterized in that step is following:
(1) take by weighing lecithin, plant sterol by mass ratio 3:1～8:1, then both are dissolved with 20～30mL dichloromethane, after the dissolving, reduction vaporization to thin film forms fully;
(2) with in 40～80mL ether impouring lipid film, be that thin film is dissolved in the ether fully;
(3) preparation contains the phosphate buffer of Betahistine Hydrochloride 5～30mg/mL, and its pH is 5.7～8.0;
(4) with the said solution mix homogeneously in (2) (3), ultrasonic 15～30 minutes;
(5) mixed solution after ultrasonic is put on the Rotary Evaporators reduction vaporization to all organic reagents evaporations;
(6) the above-mentioned suspension that makes is passed through high pressure homogenizer, pressure is 500～1000bar, extrudes appearance (the filter membrane aperture is between 0.2 μ m～10 μ m) through liposome then, promptly gets the Betahistine Hydrochloride liposome.
3. the method for preparing of the described Betahistine Hydrochloride liposome of claim 2 is characterized in that: said step (3) preparation contains the PBS buffer of Betahistine Hydrochloride 5～30mg/mL, and its pH is 5.7～8.0.
4. the method for preparing of the described Betahistine Hydrochloride liposome of claim 2; It is characterized in that: said step (6) is passed through high pressure homogenizer with the above-mentioned suspension that makes; Pressure is 500～1000bar; Extrude appearance (the filter membrane aperture is between 0.2 μ m～10 μ m) through liposome then, promptly get the Betahistine Hydrochloride liposome, particle diameter is between 0.2 μ m～10 μ m.
5. the described Betahistine Hydrochloride liposome of claim 1 is characterized in that: can be prepared into the tablet, capsule, oral liquid, the injection that contain the Betahistine Hydrochloride liposome.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108553421A (en) * | 2018-07-20 | 2018-09-21 | 中国海洋大学 | A kind of selenka nano liposomes and preparation method thereof |
| CN110559263A (en) * | 2019-10-10 | 2019-12-13 | 中国海洋大学 | Delta 5-cholest sulfate compound liposome and preparation method thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101559039A (en) * | 2009-05-27 | 2009-10-21 | 中国农业科学院油料作物研究所 | Method for producing nattokinase liposome from phytosterol |
| CN102366400A (en) * | 2011-09-28 | 2012-03-07 | 河南辅仁怀庆堂制药有限公司 | Betahistine hydrochloride injection and its production technology |
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2012
- 2012-04-24 CN CN201210121516.2A patent/CN102631320B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101559039A (en) * | 2009-05-27 | 2009-10-21 | 中国农业科学院油料作物研究所 | Method for producing nattokinase liposome from phytosterol |
| CN102366400A (en) * | 2011-09-28 | 2012-03-07 | 河南辅仁怀庆堂制药有限公司 | Betahistine hydrochloride injection and its production technology |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108553421A (en) * | 2018-07-20 | 2018-09-21 | 中国海洋大学 | A kind of selenka nano liposomes and preparation method thereof |
| CN110559263A (en) * | 2019-10-10 | 2019-12-13 | 中国海洋大学 | Delta 5-cholest sulfate compound liposome and preparation method thereof |
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Effective date of registration: 20230111 Address after: 518110 708, Huiyi building, 9 Zhongxin Road, Taoyuan community, Dalang street, Longhua District, Shenzhen City, Guangdong Province Patentee after: Shenzhen Hongyue Enterprise Management Consulting Co.,Ltd. Address before: 519041 Jinhai Road, Shenzhen, Guangdong Province Patentee before: ZHUHAI COLLEGE OF JILIN University Effective date of registration: 20230111 Address after: Committee 9, Xicheng Street, Tieli Town, Tieli City, Yichun City, Heilongjiang Province, 152500 (in the hospital of Shanghai Huangxiang Tieli Lantian Pharmaceutical Co., Ltd.) Patentee after: Heilongjiang Yidahong Pharmaceutical Co.,Ltd. Address before: 518110 708, Huiyi building, 9 Zhongxin Road, Taoyuan community, Dalang street, Longhua District, Shenzhen City, Guangdong Province Patentee before: Shenzhen Hongyue Enterprise Management Consulting Co.,Ltd. |
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