CN102755637B - Composition for preventing and treating ischemia reperfusion injury - Google Patents
Composition for preventing and treating ischemia reperfusion injury Download PDFInfo
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- CN102755637B CN102755637B CN2012101426163A CN201210142616A CN102755637B CN 102755637 B CN102755637 B CN 102755637B CN 2012101426163 A CN2012101426163 A CN 2012101426163A CN 201210142616 A CN201210142616 A CN 201210142616A CN 102755637 B CN102755637 B CN 102755637B
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Abstract
The invention discloses a composition for preventing and treating ischemia reperfusion injury. The composition is prepared by combining erythropoietin (EPO) with selenium in the ratio of (10,000 IU):(28.5-7,310.6 mug). The composition rationality of EPO and selenium is based on the organ protecting function of EPO and the anti-oxidation function of selenium. The compound composition has a coordinating protection effect on ischemia reperfusion injury, and has the effects of lowering the BUN (Blood Urea Nitrogen) level of blood serum, reducing nephric tubule injury and improving kidney pathologic changes on the aspect of kidney; the EPO has a more remarkable effect, and serves as a primary medicament; sodium selenite has a smaller effect than EPO, and serves as an auxiliary medicament; and the curative effect of the composition of the EPO and sodium selenite is remarkably superior to that of the EPO or sodium selenite which is used separately.
Description
Technical field
The invention belongs to medical technical field, relate to a kind of for preventing and treating the compositions of ischemical reperfusion injury.
Background technology
In recent years, along with the progress of shock treatment and artery bypass art, thrombolytic therapy, percutaneous intracavity Coronary angioplasty, department of cardiac surgery extracorporeal circulation, cardio-pulmonary-cerebral resuscitation, the foundation of the method such as the replantation of amputated limb and organ transplantation and applying, make again to obtain blood reperfusion after many histoorgan ischemias.In most cases, postischemic reperfusion can make tissue organ function be restored, and the structure of damage is repaired, conditions of patients improvement rehabilitation; But postischemic reperfusion sometimes. not only can not make tissue, organ dysfunction recover, add on the contrary dysfunction and the structural damage of re-organized, organ.This recover blood flow on the ischemia basis after tissue injury increase the weight of on the contrary, the phenomenon that irreversible damage even occurs is called ischemia reperfusion injury (ischemia reperfusion injury, IRI).How to alleviate or to avoid IRI to become the problem in recent years received much attention.By setting up experimental model, drugs and ischemia pretreatment are intervened to alleviate or are prevented that dirty ischemical reperfusion injury has very important clinical practice meaning.
Erythropoietin (hemopoietin, EPO) is by a kind of hormonelike material of kidney and hepatic secretion, can promote erythropoiesis.Scholars find that EPO has inhibited apoptosis, inflammation-inhibiting to react, induce the functions such as Ischemic Tolerance, all has protective effect to the ischemical reperfusion injury of respectively organizing internal organs (as brain, heart, kidney, lung, intestinal etc.) in recent years.In the ischemia-reperfusion tissue, EPO and its receptors bind are regulated apoptotic effect by path performance in the cells such as mitogen activated protein kinase (MAPK), JAK2/NF κ B and phosphatidylinositol 3-kinase (PI3K/Akt).
Selenium (Selenium, Se) be the trace element of needed by human, its biological function is mainly to bring into play its anti-oxidation function as active center or the necessary composition of the enzyme such as glutathione peroxidase, thioredoxin reductase, de-iodine enzyme, Selenoprotein P and W or albumen.
Summary of the invention
The problem that the present invention solves is to provide a kind of compositions and application thereof for preventing and treating ischemical reperfusion injury, and said composition is brought into play good coordinating protection effect to ischemical reperfusion injury.
The present invention is achieved through the following technical solutions:
A kind of for preventing and treating the compositions of ischemical reperfusion injury, the ratio combination by EPO and selenium according to EPO ︰ selenium=10,000 IU ︰ 28.5 ~ 7310.6 μ g.
Further, EPO and selenium are according to the ratio combination of EPO ︰ selenium=10,000 IU ︰ 456 μ g.
Described selenium is that form and the EPO with selenite or seleno sulfate combined.
Described selenite is sodium selenite or sodium hydroselenite, and described seleno sulfate is sodium thiosulfate.
Described selenium is combined with the form of sodium selenite and EPO, and the portfolio ratio of EPO and sodium selenite is EPO ︰ sodium selenite=10,000 IU ︰ 1000 μ g.
A kind of for preventing and treating the injection of ischemical reperfusion injury, comprise sodium selenite, 0.5 ~ 2g human albumin, 0.2 ~ 0.6g sodium chloride and the 10 ~ 50mmol/L citrate buffer of EPO, the 30 ~ 100mg of 30 ~ 1,000,000 IU at the 100mL injection; PH is 6.0 ~ 7.0.
The injection of described control ischemical reperfusion injury, comprise sodium selenite, 1g human albumin, 0.4g sodium chloride, the 10 ~ 50mmol/L citrate buffer of EPO, the 100mg of 1,000,000 IU at the 100mL injection.
A kind of preparation method of preventing and treating the injection of ischemical reperfusion injury comprises the following steps:
The EPO of 30 ~ 1,000,000 IU is dissolved with 10 ~ 50mmol/L citrate buffer, add again 30 ~ 100mg sodium selenite, stirring and dissolving, then add 0.5 ~ 2g human albumin and 0.2 ~ 0.6g sodium chloride, fully stirring and evenly mixing, adjust volume to 100mL, and regulate pH to 6.0 ~ 7.0, filtration sterilization, last embedding.
The compositions of described control ischemical reperfusion injury is for the application of the preparation of the medicine of prevention or treatment ischemical reperfusion injury.
Compared with prior art, the present invention has following useful technique effect:
Provided by the invention for preventing and treating the compositions of ischemical reperfusion injury; EPO and selenium are combined; after combining, injected in the preoperative; can reduce the level of the BUN in blood plasma; demonstrate the renal function improved due to renal ischemic reperfusion injury; alleviate injury of renal tubular; and can improve renal function due to renal ischemic reperfusion injury and the pathological change of kidney; illustrate that Papillary has protective effect to ischemical reperfusion injury, for new approach is opened up in the control of ischemical reperfusion injury.
Provided by the invention for preventing and treating the compositions of ischemical reperfusion injury; but the blood sugar reducing function of this compound recipe combination EPO and sodium selenite is mutually collaborative; the organism protective effect of EPO and sodium selenite is strengthened mutually, and ischemical reperfusion injury is had to the coordinating protection effect.Wherein the protective effect of EPO is more obvious, is principal agent; Sodium selenite is accessory drugs, and the curative effect of Papillary obviously is better than EPO or sodium selenite is alone.
The accompanying drawing explanation
Fig. 1 is EPO and sodium selenite on the impact of rat plasma blood urea nitrogen (BUN) level due to ischemia-reperfusion.
Fig. 2 be EPO and sodium selenite to the protective effect of rat kidney cortex damage due to ischemia-reperfusion (HE dyeing, X400).A, sham operated rats; B, ischemia-reperfusion group; C, the EPO group; D, the sodium selenite group; E, EPO+ sodium selenite small dose group; F, dosage group in the EPO+ sodium selenite; G, the heavy dose of group of EPO+ sodium selenite.
The specific embodiment
The invention provides a kind of pharmaceutical composition of preventing and treating ischemical reperfusion injury, be that EPO and selenium are carried out to the compound recipe combination, and further make injection, the organ protection of EPO and the antioxidation of selenium are the bases of EPO and the two rationality of combination prescription of selenium.The combination of this compound recipe can improve the renal function due to renal ischemic reperfusion injury, and the blood sugar reducing function of EPO and sodium selenite is mutually collaborative, and the protecting renal function effect of compound recipe EPO selenium injection is better than that the two is alone.Below in conjunction with specific embodiment, the present invention is described in further detail, and the explanation of the invention is not limited.
1, the combination matching of EPO and selenium compositions and to the protective effect of ischemical reperfusion injury
1.1EPO the combination foundation with selenium
EPO promotes hemopoietic because of it, is mainly used in clinically serious anemia.Scholars find that EPO also has non-promoting erythrocyte nucleus formation in recent years; react, induce the functions such as Ischemic Tolerance as inhibited apoptosis, inflammation-inhibiting, the ischemical reperfusion injury of respectively organizing internal organs (as brain, heart, kidney, lung, intestinal etc.) is all had to protective effect.
Selenium is the trace element of needed by human, and its anti-oxidation function makes selenium may become the alternative medicine of ischemical reperfusion injury drug combination.Sodium selenite is the medicine for selenium deficiency and daily selenium supplement.
EPO and selenium are carried out to the compound recipe combination, likely can play the effect of better ischemical reperfusion injury control, wherein the antioxidation of the organ protection of EPO and selenium is the basis of EPO and the two rationality of combination prescription of selenium.
1.2EPO with the combination of the selenium checking to the protection of ischemical reperfusion injury
1.2.1 using the ischemia-reperfusion of kidney as concrete ischemia-reperfusion injury model, copying of animal model is as follows:
Healthy male mice in kunming, body weight 18 ~ 22g,, provided by Xi'an Jiaotong University Medical College's Experimental Animal Center by 10 every group.Lumbar injection 20% urethane solution is anaesthetized, and the row abdominal operation: dorsal position is fixed, sterilization.Do abdominal incision, expose bilateral renal, excision right side kidney, blunt separation left side perirenal tissue, close the left side kidney base of a fruit with not damaged bulldog clamp folder, causes left renal ischaemia.After 60min, unclamp the bulldog clamp implementation and pour into again (the visible kidney of naked eyes is become scarlet by kermesinus, show to pour into successfully) again.Pour into again 4h and get blood execution by plucking eyeball.
1.2.2EPO divide into groups with the combination of selenium and the animal of processing:
Relate to the combination of EPO and selenium, concrete EPO adopts recombinant human erythropoietin (rhEPO, recombinant human erythropoietin), and being form and EPO with selenite or seleno sulfate, combined on selenium, usually selenite is sodium selenite or sodium hydroselenite, and described seleno sulfate is sodium thiosulfate.Described selenite or seleno sulfate are all for the combination of selenium and EPO can be provided, not the difference of other essence.Concrete employing sodium selenite is combined, and further adopts the research of weight proportioning prescription, determines the best proportioning ratio of EPO and sodium selenite.
Utilize uniform designs table, choose EPO dosage and sodium selenite (selenium: 78.96; Sodium selenite: 172.94) two factors of dosage are respectively established 6 levels, select U
6(6
4) uniform designs table tested (specifically as shown in table 1).
Administering mode: preoperative 3 days lumbar injections, 1 time/d, 3d, carry out the ischemia-reperfusion surgical procedure subsequently continuously.Observation index: pluck eyeball and get blood, get blood plasma after centrifugal, detect plasma urea nitrogen (BUN) level.
Table 1. uniform Design prescription testing program
| Group | EPO(IU/kg) | Sodium selenite (μ g/kg) |
| EPO+Se① | 125 | 50 |
| EPO+Se② | 250 | 400 |
| EPO+Se③ | 500 | 25 |
| EPO+Se④ | 1000 | 200 |
| EPO+Se⑤ | 2000 | 12.5 |
| EPO+Se⑥ | 4000 | 100 |
3) compound recipe of EPO and sodium selenite injection combination and preparation method thereof
According to the prescription proportioning of EPO and selenium compositions in the prescription of Chinese Pharmacopoeia 2010 two middle Recombinant Human Erythropoietin injection of version (Chinese hamster ovary celI) and table 1, compound recipe combination of design compound recipe EPO and sodium selenite injection and preparation method thereof.Concrete design is as shown in table 2:
The compound recipe combination of table 2 compound recipe EPO and sodium selenite injection
The preparation method of compound recipe EPO and sodium selenite injection comprises the following steps:
The EPO of recipe quantity is dissolved with 10 ~ 50mmol/L citrate buffer;
The sodium selenite that adds again recipe quantity, stirring and dissolving;
Then the human albumin and the sodium chloride that add recipe quantity, fully stirring and evenly mixing, adjust volume to 100mL, and regulate pH to 6.0 ~ 7.0, filtration sterilization, last embedding, obtain.
4) impact of the compound recipe of EPO and sodium selenite injection combination on renal ischemic reperfusion injury blood plasma BUN level
BUN is the main dead end product of protein metabolism.In carbamide, nitrogen content is 28/60, almost reaches half.Kidney is the major organs of excretion carbamide, and blood plasma BUN is one of main detection index of reflection renal function.Early stage when renal function injury, blood plasma BUN can be in normal range.Filter and to drop to normal 50% when following when the glomerule rate, the concentration of blood plasma BUN is rising rapidly.Renal ischemic reperfusion injury can cause acute renal insufficiency, and the degree that blood plasma BUN raises is general consistent with coincident with severity degree of condition, and blood plasma BUN is higher, and renal dysfunction is heavier.Therefore can adopt and detect blood plasma BUN level as reflecting that ischemia-reperfusion causes the index of renal dysfunction.
Preoperative 3 days, the above-mentioned compound recipe EPO of lumbar injection every day and sodium selenite injection, observation is on its impact on blood plasma BUN level due to the Mouse Kidney ischemical reperfusion injury (adopting urease method BUN test kit to be detected), found that various prescriptions all can reduce blood plasma BUN level, wherein ceiling effect is the 5th kind of prescription, refers to table 3.
The impact on mice plasma BUN of table 3 compound recipe EPO and sodium selenite prescription
| Group | BUN(mmol/L) | 1/BUN |
| EPO+Se① | 15.13±1.48 | 0.067±0.006 |
| EPO+Se② | 14.16±3.13 | 0.074±0.018 |
| EPO+Se③ | 16.29±1.71 | 0.062±0.007 |
| EPO+Se④ | 10.74±1.65 | 0.098±0.017 |
| EPO+Se⑤ | 9.09±2.35 | 0.117±0.031 |
| EPO+Se⑥ | 9.76±1.66 | 0.112±0.020 |
The result of table 3 shows, carries out in the preoperative the injection of EPO and sodium selenite combination, can reduce renal ischemic reperfusion injury blood plasma BUN effect, and wherein the proportioning of EPO and selenium is scaled:
EPO ︰ selenium=1IU ︰ 0.0114～0.0731 μ g(1 ten thousand IU ︰ 114～731 μ g), the proportioning of wherein optimizing is: EPO 10,000 IU ︰ selenium 456 μ g.
And further result is carried out to statistical procedures: adopt DAS1.0 software to carry out weight proportioning prescription analysis (table 4) to the proportioning of EPO and selenium, the best prescription ratio that obtains EPO and selenium is:
EPO ︰ sodium selenite=10 ︰ 1=1 ︰ 0.1(1IU ︰ 0.1 μ g).
Table 4EPO and effect and the interaction qualitative analysis thereof of sodium selenite in prescription
EPO and the combination of sodium selenite compound recipe are carried out to weight proportioning prescription analysis to the effect of renal ischemic reperfusion injury blood plasma BUN; result shows; the best proportioning ratio of EPO and sodium selenite is 10 ︰ 1; wherein EPO is principal agent; sodium selenite is accessory drugs, and the two has the coordinating protection effect to renal ischemia-reperfusion injury.The theoretical optimization prescription is EPO(4000IU/kg) and sodium selenite (400 μ g/kg), best prescription ratio is: 1 ︰ 0.1.
2, EPO and the selenium compositions coordinating protection effect to Ischemia-reperfusion Injury
At EPO, be principal agent, on the basis that sodium selenite is accessory drugs, to the two further torn open side research, to EPO and selenium compositions and alone comparing separately.The animal model preparation: rats by intraperitoneal injection 20% urethane solution is anaesthetized, and the row abdominal operation: dorsal position is fixed, sterilization.Do abdominal incision, expose bilateral renal, excision right side kidney, blunt separation left side perirenal tissue, close the left side kidney base of a fruit with not damaged bulldog clamp folder, causes left renal ischaemia.After 60min, unclamp the bulldog clamp implementation and pour into again (the visible kidney of naked eyes is become scarlet by kermesinus, show to pour into successfully) again.Pouring into 4h puts to death by abdominal aortic blood again.Observation index: abdominal aortic blood, get blood plasma after centrifugal, detect blood plasma BUN; Excise left kidney, after top is placed in 10% formalin fixative paraffin embedding, routine is cut into slices, and HE dyeing, observe the nephridial tissue pathological change under light microscopic.
Animal grouping and processing: healthy male SD rat, body weight 180 ~ 220g,, provided by Xi'an Jiaotong University Medical College's Experimental Animal Center by 10 every group.Be grouped as follows: 1. (Sham group: excise the right side kidney, blunt separation left side perirenal tissue, do not press from both sides and close sham operated rats; Normal saline 0.5ml/100g body weight, preoperative 3 days lumbar injections, 1 time/d, continuous 3d); 2. ischemia-reperfusion group (be also model group, I/R group: normal saline 0.5ml/100g body weight); 3. EPO group (EPO group:1500U/kg); 4. sodium selenite group (Se group:150 μ g/kg); 5. EPO+ sodium selenite small dose group (EPO+Se small dose group:EPO 750U/kg+Na
2seO
375 μ g/kg); 6. dosage group (EPO+Se middle dose group:EPO 1500U/kg+Na in the EPO+ sodium selenite
2seO
3150 μ g/kg); 7. heavy dose of group (the EPO+Se large dose group:EPO 3000U/kg+Na of EPO+ sodium selenite
2seO
3300 μ g/kg).Be preoperative 3 days lumbar injections, 1 time/d, continuous 3d.
Each processed group to the rectangular histogram of the testing result of rat plasma blood urea nitrogen (BUN) content as shown in Figure 1.Model group rat plasma BUN content obviously raises (compare with sham operated rats P<0.05), and hints model is successfully prepared, give separately EPO and sodium selenite on the impact of blood plasma BUN not obvious (P > 0.05, with model group, compare), and after the two coupling, be that compound recipe EPO and each dosage group of sodium selenite injection all can make rat plasma BUN content obviously reduce (P<0.05, with model group, compare), and there is certain dose relationship, compound recipe EPO and selenium injection can reduce blood plasma BUN level, its effect is better than alone EPO and sodium selenite (P<0.01), also be better than qdx EPO and sodium selenite alone (P<0.05), be A+B > 2A, A+B > 2B, prompting EPO and sodium selenite coupling have the coordinating protection effect to the acute kidney ischemical reperfusion injury.
The nephridial tissue pathological change
Under light microscopic, visible sham operated rats kidney interstitial is without hyperemia, edema and inflammatory cell infiltration, and the renal tubules marshalling, do not find obvious pathological change.The model group Renal tissues damage obviously increases the weight of, kidney cortical area proximal tubular epithelial cells edema, and part has epithelial cell degeneration, necrosis to come off, and parts of fine karyon chromatin margination, comes off, forms apoptotic body; A large amount of renal cells swelling, visible a large amount of protein casts and downright bad exfoliative cyte in tubule, interstitial is congested, edema, focal inflammatory cell infiltration; Part glomerule, the visible hyaline degeneration of interstitial, the visible thread exudate of glomerular capsule.Alone or the large, medium and small dosage group of the compound recipe Renal tissues damage of EPO and Se obviously alleviates, and take renal tubules swelling as main, is individually downright bad sample and changes, and in tubule, protein cast obviously reduces; The hyperemia of kidney interstitial, edema, inflammatory cell infiltration are not obvious.With model group, compare, each processed group all can obviously alleviate ischemical reperfusion injury, shows as the necrosis that reduces renal cells, alleviates interstitial hyperemia, edema, reduces protein cast, reduces inflammatory cell and invades profit, and concrete result as shown in Figure 2.
3, combination of compound recipe EPO and sodium selenite injection and preparation method thereof
According to above-mentioned experimental result, the combination of optimization is as follows: EPO 1,000,000 IU, and sodium selenite 100mg, human albumin 1g, sodium chloride 0.4g, 10 ~ 50mmol/L citrate buffer adds to 100mL.
In view of the combination of EPO and selenium need to be injected in the preoperative, therefore, a kind of preparation method for the injection of preventing and treating ischemical reperfusion injury is proposed, comprise the following steps:
The EPO of 30 ~ 1,000,000 IU is dissolved with 10 ~ 50mmol/L citrate buffer, add again 30 ~ 100mg sodium selenite, stirring and dissolving, then add 0.5 ~ 2g human albumin and 0.2 ~ 0.6g sodium chloride, fully stirring and evenly mixing, adjust volume to 100mL, and adjusting pH to 6.0 ~ 7.0, filtration sterilization, last embedding, obtain.
Claims (9)
1. one kind for preventing and treating the compositions of ischemical reperfusion injury, it is characterized in that, is the ratio combination according to EPO ︰ selenium=10,000 IU ︰ 28.5～7310.6 μ g by EPO and selenium.
2. as claimed in claim 1ly for preventing and treating the compositions of ischemical reperfusion injury, it is characterized in that, EPO and selenium are according to EPO: the ratio combination of selenium=10,000 IU ︰ 400～500 μ g.
3. the pharmaceutical composition of control ischemical reperfusion injury as claimed in claim 1, is characterized in that, described selenium is that form and the EPO with selenite or seleno sulfate combined.
4. the pharmaceutical composition of control ischemical reperfusion injury as claimed in claim 3, is characterized in that, described selenite is sodium selenite or sodium hydroselenite, and described seleno sulfate is sodium thiosulfate.
5. the pharmaceutical composition of control ischemical reperfusion injury as claimed in claim 1, is characterized in that, described selenium is combined with the form of sodium selenite and EPO, and the portfolio ratio of EPO and sodium selenite is EPO ︰ sodium selenite=10,000 IU ︰ 1000 μ g.
6. one kind for preventing and treating the injection of ischemical reperfusion injury, it is characterized in that, at the 100mL injection, comprise sodium selenite, 0.5～2g human albumin, 0.2～0.6g sodium chloride, the 10～50mmol/L citrate buffer of EPO, the 30～100mg of 30～1,000,000 IU; PH is 6.0～7.0.
7. the injection of control ischemical reperfusion injury as claimed in claim 6, it is characterized in that, at the 100mL injection, comprise sodium selenite, 1g human albumin, 0.4g sodium chloride, the 10～50mmol/L citrate buffer of EPO, the 100mg of 1,000,000 IU.
8. a preparation method of preventing and treating the injection of ischemical reperfusion injury, it is characterized in that, comprise the following steps: the EPO of 30～1,000,000 IU is dissolved with 10～50mmol/L citrate buffer, then add 30～100mg sodium selenite, stirring and dissolving, then add 0.5～2g human albumin and 0.2～0.6g sodium chloride, fully stirring and evenly mixing, adjust volume to 100mL, and regulate pH to 6.0～7.0, filtration sterilization, last embedding.
9. the compositions of control ischemical reperfusion injury claimed in claim 1 is for the application of the preparation of the medicine of prevention or treatment renal ischemic reperfusion injury.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101015684A (en) * | 2006-02-10 | 2007-08-15 | 华北制药集团新药研究开发有限责任公司 | Recombinant erythropoietin liquor preparation |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101015684A (en) * | 2006-02-10 | 2007-08-15 | 华北制药集团新药研究开发有限责任公司 | Recombinant erythropoietin liquor preparation |
Non-Patent Citations (6)
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| B.A.Zachara等.Seleniumandglutathionelevels and glutathione peroxidase activities in blood components of uremic patients on hemodialysis supplemented with selenium and treated with erythropoietin.《Journal of trace elements in medicine and biology》.2001 |
| Seda Ozbal等.The effects of selenium against cerebral ischemia-reperfusion injury in rats.《Neuroscience Letters》.2008,第438卷(第3期),第265-269页. |
| Selenium and glutathione levels, and glutathione peroxidase activities in blood components of uremic patients on hemodialysis supplemented with selenium and treated with erythropoietin;B. A. Zachara等;《Journal of trace elements in medicine and biology》;20010430;第15卷(第4期);第201-208页 * |
| The effects of selenium against cerebral ischemia-reperfusion injury in rats;Seda Ozbal等;《Neuroscience Letters》;20080627;第438卷(第3期);第265-269页 * |
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Effective date of registration: 20171220 Address after: 511430 1402 room 1402, No. 383 office building, North 383 Panyu Avenue, Panyu District South Village, Panyu District, Guangdong Patentee after: Guangzhou Intellectual Property Service Co., Ltd. Address before: 710049 Xianning West Road, Shaanxi, China, No. 28, No. Patentee before: Xi'an Jiaotong University |
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| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20180116 Address after: 710049 Xianning West Road, Shaanxi, China, No. 28, No. Patentee after: Xi'an Jiaotong University Address before: 511430 1402 room 1402, No. 383 office building, North 383 Panyu Avenue, Panyu District South Village, Panyu District, Guangdong Patentee before: Guangzhou Intellectual Property Service Co., Ltd. |
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Granted publication date: 20131211 Termination date: 20190509 |