CN117045654A - Application of flunarizine hydrochloride in preparation of extreme environment hypoxia medicament - Google Patents
Application of flunarizine hydrochloride in preparation of extreme environment hypoxia medicament Download PDFInfo
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- CN117045654A CN117045654A CN202310581337.5A CN202310581337A CN117045654A CN 117045654 A CN117045654 A CN 117045654A CN 202310581337 A CN202310581337 A CN 202310581337A CN 117045654 A CN117045654 A CN 117045654A
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- Prior art keywords
- hypoxia
- flunarizine hydrochloride
- medicament
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- 206010021143 Hypoxia Diseases 0.000 title claims abstract description 54
- RXKMOPXNWTYEHI-RDRKJGRWSA-N Flunarizine hydrochloride Chemical compound Cl.Cl.C1=CC(F)=CC=C1C(C=1C=CC(F)=CC=1)N1CCN(C\C=C\C=2C=CC=CC=2)CC1 RXKMOPXNWTYEHI-RDRKJGRWSA-N 0.000 title claims abstract description 41
- 229960002807 flunarizine hydrochloride Drugs 0.000 title claims abstract description 41
- 239000003814 drug Substances 0.000 title claims abstract description 37
- 230000007954 hypoxia Effects 0.000 title claims abstract description 32
- 238000002360 preparation method Methods 0.000 title description 5
- 229940079593 drug Drugs 0.000 claims abstract description 18
- 230000004083 survival effect Effects 0.000 claims abstract description 14
- 238000004519 manufacturing process Methods 0.000 claims description 9
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- 238000002347 injection Methods 0.000 claims description 5
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- 230000007613 environmental effect Effects 0.000 claims description 4
- 239000006186 oral dosage form Substances 0.000 claims description 4
- 239000000843 powder Substances 0.000 claims description 4
- 206010002660 Anoxia Diseases 0.000 claims description 2
- 241000976983 Anoxia Species 0.000 claims description 2
- 239000004480 active ingredient Substances 0.000 claims description 2
- 230000007953 anoxia Effects 0.000 claims description 2
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- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 229920000881 Modified starch Polymers 0.000 description 1
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 1
- 208000037273 Pathologic Processes Diseases 0.000 description 1
- 206010038669 Respiratory arrest Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- BZKPWHYZMXOIDC-UHFFFAOYSA-N acetazolamide Chemical compound CC(=O)NC1=NN=C(S(N)(=O)=O)S1 BZKPWHYZMXOIDC-UHFFFAOYSA-N 0.000 description 1
- 229960000571 acetazolamide Drugs 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
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- 238000003556 assay Methods 0.000 description 1
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- 229960004436 budesonide Drugs 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
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- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229940045110 chitosan Drugs 0.000 description 1
- 229940075614 colloidal silicon dioxide Drugs 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 229960001681 croscarmellose sodium Drugs 0.000 description 1
- 229960000913 crospovidone Drugs 0.000 description 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
- 230000002354 daily effect Effects 0.000 description 1
- 229960003957 dexamethasone Drugs 0.000 description 1
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 235000019700 dicalcium phosphate Nutrition 0.000 description 1
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 239000004088 foaming agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 229940075507 glyceryl monostearate Drugs 0.000 description 1
- 239000008172 hydrogenated vegetable oil Substances 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 229960001375 lactose Drugs 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 229960001021 lactose monohydrate Drugs 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 229960002900 methylcellulose Drugs 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
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- 229940057838 polyethylene glycol 4000 Drugs 0.000 description 1
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- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 1
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- 238000002203 pretreatment Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229940083542 sodium Drugs 0.000 description 1
- 229940083575 sodium dodecyl sulfate Drugs 0.000 description 1
- 229940045902 sodium stearyl fumarate Drugs 0.000 description 1
- HUAUNKAZQWMVFY-UHFFFAOYSA-M sodium;oxocalcium;hydroxide Chemical compound [OH-].[Na+].[Ca]=O HUAUNKAZQWMVFY-UHFFFAOYSA-M 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 238000012353 t test Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 229940099259 vaseline Drugs 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
Abstract
The invention relates to a new pharmaceutical application of flunarizine hydrochloride, and in particular provides an application of flunarizine hydrochloride in preparing anti-hypoxia drugs. Under the condition of intraperitoneal injection administration, the survival time of mice in the hypoxia closed environment can be obviously prolonged, so that the damage to organisms caused by hypoxia is relieved or improved when the mice are operated in the environment with extremely low hypoxia or hypoxia such as high altitude, tunnels, mine holes, diving and the like. The application of the flunarizine hydrochloride in preparing the anti-hypoxia medicament can improve the capability of animals such as mice to resist closed hypoxia injury by adopting the common medicament with proper dosage in adaptation time, is used for preventing and treating hypoxia injury or treating various hypoxia pathological states caused by the reduction of the oxygen content of the external environment, and can create better economic benefit and social benefit.
Description
Technical Field
The invention belongs to the technical field of medicines, and relates to application of flunarizine hydrochloride in preparation of a medicament for treating hypoxia in extreme environments.
Background
Hypoxia is a pathological process of oxygen deficiency or oxygen consumption disorder of an organism, which leads to dysfunction of tissues and organs, and the reduction of the external oxygen content is one of the important reasons for hypoxia of the organism. With the continuous expansion of the width and depth of human production and life, the operation activities in extremely low-oxygen environments such as high altitude, tunnels, mine holes, diving and the like are more and more, and the low-oxygen content in the environments is one of the important factors of body damage in the extremely environments. It is therefore important how to improve the body's ability to withstand extremely low oxygen environments, and drug assistance is highly desirable to accommodate extreme environmental hypoxia.
The existing clinically effective anti-hypoxia drugs are seriously insufficient, and the drugs with anti-hypoxia effect mainly comprise acetazolamide, dexamethasone, budesonide and the like, but have various degrees of shortages. In recent years, the potential of new use of old drugs in the treatment of new indications is of interest, and the new drugs have the advantages of clear safety and tolerability, short development period and clear clinical application.
Disclosure of Invention
In view of the above, the invention aims to provide a new application of flunarizine hydrochloride in preparing anti-hypoxia drugs.
In order to achieve the above purpose, the present invention provides the following technical solutions:
1. the application of flunarizine hydrochloride in preparing anti-hypoxia drugs.
The flunarizine hydrochloride is further applied to the preparation of anti-hypoxia drugs, wherein the anti-hypoxia drugs are drugs for improving or preventing extreme environmental hypoxia or hypoxia.
The flunarizine hydrochloride can be used for improving or preventing hypoxia or anoxia in extreme environment to improve living time of organism.
Further, in the application of the flunarizine hydrochloride in preparing the anti-hypoxia medicament, the purity of the flunarizine hydrochloride is more than 95 percent.
Further, the purity of the flunarizine hydrochloride in the application of the flunarizine hydrochloride in the preparation of the anti-hypoxia medicament is more than 99 percent.
The application of the flunarizine hydrochloride in preparing the anti-hypoxia medicament is further disclosed, wherein the anti-hypoxia medicament is prepared from the flunarizine hydrochloride serving as an active ingredient and pharmaceutical excipients, and is prepared into oral dosage forms and/or injection dosage forms.
The pharmaceutical auxiliary materials comprise at least one of a filling agent, a disintegrating agent, a lubricant, a wetting agent, auxiliary lipid, a glidant, a flavoring agent, a solvent, a dissolution auxiliary agent, a suspending agent, an isotonic agent, a buffer solution, a preservative, an antioxidant, a colorant and a foaming agent.
The filler is at least one selected from starch, lactose monohydrate, cellulose lactose, pregelatinized starch, sucrose, mannitol, sorbitol, calcium phosphate, dextrin, calcium hydrogen phosphate and mannitol-starch complex;
the disintegrating agent is at least one selected from the group consisting of croscarmellose sodium, carboxymethylcellulose calcium, sodium carboxymethyl starch, methylcellulose, low-substituted hydroxypropyl cellulose, crospovidone and chitosan.
The lubricant is at least one selected from magnesium stearate, colloidal silicon dioxide, talcum powder, sodium dodecyl sulfate, calcium stearate, polyethylene glycol 4000, polyethylene glycol 6000, sodium stearyl fumarate, glyceryl monostearate and hydrogenated vegetable oil.
Further, the flunarizine hydrochloride can be applied to preparing anti-hypoxia drugs, and the oral dosage forms comprise tablets, capsules, dripping pills, dispersible tablets, dispersible powders or granules.
The further application of the flunarizine hydrochloride in preparing the anti-hypoxia medicament comprises injection or freeze-dried powder injection for injection.
The invention has the beneficial effects that: the invention verifies and provides the new medical application of the flunarizine hydrochloride, and under the condition of intraperitoneal injection administration, the survival time of mice in an anoxic closed environment can be obviously prolonged, so that the injury to organisms caused by hypoxia is relieved or improved when the mice are operated in the environment with extremely low oxygen or hypoxia such as high altitude, tunnels, mine holes, diving and the like. The application of the flunarizine hydrochloride in preparing the anti-hypoxia medicament can improve the capability of animals such as mice to resist closed hypoxia injury by adopting the common medicament with proper dosage in adaptation time, is used for preventing and treating hypoxia injury or treating various hypoxia pathological states caused by the reduction of the oxygen content of the external environment, and can create better economic benefit and social benefit.
Drawings
In order to make the objects, technical solutions and advantageous effects of the present invention more clear, the present invention provides the following drawings for description:
FIG. 1 shows the mean survival time of mice, with the mean survival time (min) on the ordinate and the group on the abscissa.
FIG. 2 is a graph of small mouse quasi-hypoxia tolerance time, with the ordinate being standard hypoxia tolerance time (min/ml) and the abscissa being the group.
FIG. 3 is a graph of survival of mice with survival on the ordinate and experimental run time on the abscissa.
Detailed Description
The following description of the preferred embodiments of the present invention will be made clearly and fully with reference to the accompanying drawings, in which it is evident that the embodiments described are only some, but not all embodiments of the invention. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention. The experimental methods for which specific conditions are not specified in the examples are generally conducted under conventional conditions or under conditions recommended by the manufacturer.
Example 1
The mice were qualified laboratory animals and were male C57BL/6N, purchased from Experimental animal technologies Inc., beijing, uighur. Animal feeding and constant temperature (23+ -2deg.C), constant humidity animal room, and daily 12/12 hr circulation, and can feed water freely.
The experimental reagent is flunarizine hydrochloride: selleck company, cat No. S2030, molecular weight 477.42, purity 99.92%, was dissolved in 50% PEG400 solution for each use, ready-to-use.
Dosing and hypoxia closed injury:
flunarizine hydrochloride was administered intraperitoneally based on mouse body weight. And (3) performing anoxic sealing treatment after the flunarizine hydrochloride is given for two weeks.
The specific experimental steps are as follows:
(1) After 3 days of acclimation, the mice were randomized into experimental and control groups of 10 mice each. Mice in the experimental group were intraperitoneally injected with flunarizine hydrochloride solution (50% peg400 formulation) at a dose of 30mg/kg,/day,200 μl/mouse, and the control group was intraperitoneally injected with the same volume of 50% peg400 solution every day for two consecutive weeks.
(2) On the day of the experiment, mice were taken, groups were recorded, weighed and weights were recorded, and then placed in glass vials containing 5g soda lime, the glass vials having a volume of 150ml. The glass bottle is quickly plugged by a rubber plug coated with vaseline, the bottle mouth is sleeved by a preservative film, and the bottle mouth is tightly hooped by a rubber rope, so that the glass bottle is in a closed state.
(3) Mouse survival time assay: immediately after sealing the vial, the survival time of each mouse was recorded. The sign of death of mice was judged to be respiratory arrest, plotted against various mice survival times. Mice in each experimental group were compared for hypoxia tolerance time. The specific experimental results are shown in table 1.
Table 2 shows the effect of flunarizine hydrochloride on the quasi-hypoxia tolerance time (min/ml) of a small mouse, the formula of which is STT=t/(V-BW/0.94), where t is the recorded survival time, V is the container volume, V is 150ml, and BW is the body weight of the mouse.
TABLE 1 Effect of flunarizine hydrochloride on survival time of mice under confined hypoxia
As shown in FIG. 1, the survival time of the two groups is statistically tested by Shapiro-Wilk test, the two groups of data conform to a normal distribution, and p is 0.2578<0.05 and 0.8993<0.05 respectively. The two sets of data were statistically different, p=0.0249 <0.05, by t test.
TABLE 2 influence of Flunarizine hydrochloride on the quasi-hypoxia tolerance time of mice
As shown in fig. 2, the standard hypoxia tolerance time of both groups was statistically checked by Shapiro-Wilktest, and both groups of data were in conformity with the normal distribution, with p being 0.1813<0.05, and 0.9779<0.05, respectively. The two sets of data were statistically tested for differences, p=0.0307 <0.05.
As shown in fig. 3, the survival curves of the two groups were statistically checked by Mantel-Cox test, and the two groups were different, p=0.0089 <0.01.
These results suggest that the pre-treatment of flunarizine hydrochloride can enhance the tolerance of mice to hypoxia, and can be applied to new intended uses of hypoxia and hypoxia in extreme environments.
Finally, it is noted that the above-mentioned preferred embodiments are only intended to illustrate rather than limit the invention, and that, although the invention has been described in detail by means of the above-mentioned preferred embodiments, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the invention as defined by the appended claims.
Claims (9)
1. The application of flunarizine hydrochloride in preparing anti-hypoxia drugs.
2. The use of flunarizine hydrochloride according to claim 1 for the manufacture of an anti-hypoxic drug, wherein the anti-hypoxic drug is a drug that ameliorates or prevents extreme environmental hypoxia or hypoxia.
3. The use of flunarizine hydrochloride according to claim 2 in the manufacture of an anti-hypoxic medicament, wherein said improvement or prevention of extreme environmental hypoxia or anoxia is an increase in survival time of the body.
4. The use of flunarizine hydrochloride according to claim 1 for the manufacture of an anti-hypoxic medicament, wherein the purity of flunarizine hydrochloride is greater than 95%.
5. The use of flunarizine hydrochloride according to claim 1 for the manufacture of an anti-hypoxic medicament, wherein the purity of the flunarizine hydrochloride is greater than 99%.
6. The use of flunarizine hydrochloride according to claim 1 for the manufacture of an anti-hypoxic drug, wherein the drug is flunarizine hydrochloride dissolved in 50% PEG400 solution.
7. The use of flunarizine hydrochloride according to any one of claims 1-6 for the manufacture of an anti-hypoxic medicament, wherein the anti-hypoxic medicament is prepared from flunarizine hydrochloride as an active ingredient and pharmaceutical excipients into oral dosage forms and/or injection dosage forms.
8. The use of flunarizine hydrochloride as claimed in claim 7 in the manufacture of an anti-hypoxic medicament, wherein the oral dosage form comprises a tablet, capsule, drop pill, dispersible tablet, dispersible powder or granule.
9. The use of flunarizine hydrochloride as claimed in claim 7 in the manufacture of an anti-hypoxic medicament, wherein the injectable formulation comprises an injectable solution or a lyophilized injectable powder.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310581337.5A CN117045654A (en) | 2023-05-23 | 2023-05-23 | Application of flunarizine hydrochloride in preparation of extreme environment hypoxia medicament |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310581337.5A CN117045654A (en) | 2023-05-23 | 2023-05-23 | Application of flunarizine hydrochloride in preparation of extreme environment hypoxia medicament |
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