CN1293863C - Ibolite fumarate nasal cavity administration preparation - Google Patents
Ibolite fumarate nasal cavity administration preparation Download PDFInfo
- Publication number
- CN1293863C CN1293863C CN 200410098645 CN200410098645A CN1293863C CN 1293863 C CN1293863 C CN 1293863C CN 200410098645 CN200410098645 CN 200410098645 CN 200410098645 A CN200410098645 A CN 200410098645A CN 1293863 C CN1293863 C CN 1293863C
- Authority
- CN
- China
- Prior art keywords
- ibutilide
- preparation
- ibolite
- nasal
- nasal cavity
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 238000002360 preparation method Methods 0.000 title claims abstract description 33
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 title claims description 39
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 title claims description 34
- 210000003928 nasal cavity Anatomy 0.000 title abstract description 19
- 238000010521 absorption reaction Methods 0.000 claims abstract description 9
- 239000003623 enhancer Substances 0.000 claims abstract description 7
- 229960001617 ethyl hydroxybenzoate Drugs 0.000 claims description 12
- NUVBSKCKDOMJSU-UHFFFAOYSA-N ethylparaben Chemical compound CCOC(=O)C1=CC=C(O)C=C1 NUVBSKCKDOMJSU-UHFFFAOYSA-N 0.000 claims description 12
- GYCKQBWUSACYIF-UHFFFAOYSA-N o-hydroxybenzoic acid ethyl ester Natural products CCOC(=O)C1=CC=CC=C1O GYCKQBWUSACYIF-UHFFFAOYSA-N 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- 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 claims description 8
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- VZCYOOQTPOCHFL-OWOJBTEDSA-L fumarate(2-) Chemical class [O-]C(=O)\C=C\C([O-])=O VZCYOOQTPOCHFL-OWOJBTEDSA-L 0.000 claims description 5
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- ALOBUEHUHMBRLE-UHFFFAOYSA-N Ibutilide Chemical compound CCCCCCCN(CC)CCCC(O)C1=CC=C(NS(C)(=O)=O)C=C1 ALOBUEHUHMBRLE-UHFFFAOYSA-N 0.000 abstract description 24
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- PCIOHQNIRPWFMV-WXXKFALUSA-N Ibutilide fumarate Chemical compound OC(=O)\C=C\C(O)=O.CCCCCCCN(CC)CCCC(O)C1=CC=C(NS(C)(=O)=O)C=C1.CCCCCCCN(CC)CCCC(O)C1=CC=C(NS(C)(=O)=O)C=C1 PCIOHQNIRPWFMV-WXXKFALUSA-N 0.000 abstract description 3
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- 239000000463 material Substances 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- ODLHGICHYURWBS-FOSILIAISA-N molport-023-220-444 Chemical compound CC(O)COC[C@@H]([C@@H]([C@H]([C@@H]1O)O)O[C@@H]2O[C@H]([C@H](O[C@@H]3O[C@@H](COCC(C)O)[C@@H]([C@H]([C@@H]3O)O)O[C@@H]3O[C@@H](COCC(C)O)[C@@H]([C@H]([C@@H]3O)O)O[C@@H]3O[C@@H](COCC(C)O)[C@@H]([C@H]([C@@H]3O)O)O[C@@H]3O[C@@H](COCC(C)O)[C@@H]([C@H]([C@@H]3O)O)O3)[C@@H](O)[C@@H]2O)COCC(O)C)O[C@H]1O[C@@H]1[C@@H](O)[C@H](O)[C@H]3O[C@H]1COCC(C)O ODLHGICHYURWBS-FOSILIAISA-N 0.000 description 1
- BAVYZALUXZFZLV-UHFFFAOYSA-N mono-methylamine Natural products NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 1
- 230000002107 myocardial effect Effects 0.000 description 1
- 239000007923 nasal drop Substances 0.000 description 1
- 239000002736 nonionic surfactant Substances 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 229940055577 oleyl alcohol Drugs 0.000 description 1
- XMLQWXUVTXCDDL-UHFFFAOYSA-N oleyl alcohol Natural products CCCCCCC=CCCCCCCCCCCO XMLQWXUVTXCDDL-UHFFFAOYSA-N 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- 229940068196 placebo Drugs 0.000 description 1
- 239000000902 placebo Substances 0.000 description 1
- 229920000191 poly(N-vinyl pyrrolidone) Polymers 0.000 description 1
- 239000004584 polyacrylic acid Substances 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- 229910001414 potassium ion Inorganic materials 0.000 description 1
- REQCZEXYDRLIBE-UHFFFAOYSA-N procainamide Chemical compound CCN(CC)CCNC(=O)C1=CC=C(N)C=C1 REQCZEXYDRLIBE-UHFFFAOYSA-N 0.000 description 1
- 229960000244 procainamide Drugs 0.000 description 1
- MCSINKKTEDDPNK-UHFFFAOYSA-N propyl propionate Chemical compound CCCOC(=O)CC MCSINKKTEDDPNK-UHFFFAOYSA-N 0.000 description 1
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 1
- 150000003856 quaternary ammonium compounds Chemical class 0.000 description 1
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- 238000011160 research Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 150000004671 saturated fatty acids Chemical class 0.000 description 1
- 229910001415 sodium ion Inorganic materials 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
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- 235000010199 sorbic acid Nutrition 0.000 description 1
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- 235000011067 sorbitan monolaureate Nutrition 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- ZBMZVLHSJCTVON-UHFFFAOYSA-N sotalol Chemical compound CC(C)NCC(O)C1=CC=C(NS(C)(=O)=O)C=C1 ZBMZVLHSJCTVON-UHFFFAOYSA-N 0.000 description 1
- 229960002370 sotalol Drugs 0.000 description 1
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- 239000004094 surface-active agent Substances 0.000 description 1
- WBWWGRHZICKQGZ-HZAMXZRMSA-N taurocholic acid Chemical class C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(=O)NCCS(O)(=O)=O)C)[C@@]2(C)[C@@H](O)C1 WBWWGRHZICKQGZ-HZAMXZRMSA-N 0.000 description 1
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- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicinal Preparation (AREA)
Abstract
The present invention provides an ibutilide preparation whose administration mode adopts a nasal cavity administration mode. The preparation contains ibutilide fumarate, ibutilide free alkali, or other medical salts of ibutilide, which are acceptable on medicine, a stereo isomer which has the pharmacological activity, and an absorption enhancer. The preparation medicine which adopts the nasal cavity administration mode and is provided by the present invention is absorbed by the nasal mucous membrane, the medicine enters blood circulation to exert the function, and the present invention has the advantages of stable performance, controllable quality and no stimulation on the nasal mucous membrane. The preparation which adopts the nasal cavity administration mode and is provided by the present invention is used for treating arrhythmia.
Description
Invention field
The present invention relates to a kind of nasal cavity administrated preparation, specifically relate to Ibolite fumarate nasal cavity administration preparation.
Background technology
Arrhythmia is very common, and numerous disease and medicine all can cause or bring out arrhythmia.According to interrelated data various arrhythmia sickness rate are compared and to show, wherein the arrhythmia sickness rate is the highest, be 25%～27%, sinus tachycardia is taken second place, and is 20%～22%, sinus bradycardia is 13%～15%, ventricular presystole is 14%～16%, and atrial premature beats is 5%～7%, and atrial fibrillation is 11%～15%, atrioventricular block is 5%～7%, other various arrhythmia about 5%～8%.Therefore, people are devoted to out a kind ofly can give antiarrhythmic drug administration, easy to use, that therapeutic effect is good in patient's very first time always.
Ibolite fumarate (Ibutilide fumarate) is the novel anti antiarrhythmic medicament, has quick-acting, safe antiarrhythmic drug, especially to quick termination room pounce on, the atrial fibrillation curative effect is better.Ibolite fumarate in nineteen ninety-five December by drugs approved by FDA, in 96 years first the intravenous applications treatment room in the 1st approval of U.S. listing pounce on, the medicine of atrial fibrillation.Its molecular formula is:
Ibutilide (IbutIlIde) belongs to the derivant of sulfonyloxy methyl amine, is a kind of III class antiarrhythmic drug of novel ion channel activity.This product is developed by U.S. Pharmacia S.P.A., nineteen ninety-five, December obtained FDA approval, went on the market in the U.S. in 1996, in the listing of American-European 11 states, be used for acute Atrial Fibrillation and atrial flutter disease, this medicine is to adopt the intravenously administrable mode, and therapeutic effect is more remarkable, and pouncing on to change again for treatment atrial fibrillation, room provides novel good medicine for sinus rhythm.
Clinical research shows: this medical instrument has high selectivity, interior slowly by activating to sodium ion stream, the outflow of blocking-up cardiac muscle cell potassium ion, increase the repolarization effect, effective over reach current potential time-histories prolongs the effective refractory period (ERP) of myocardial cell simultaneously, and it is more more effective than chamber property that medicine stops atrial arrhythmia, to atrium ERP effect obvious 10 times, and make the defibrillation threshold reduction than ventricle.
Bibliographical information: ibutilide is evident in efficacy, is effectively nearly antiarrhythmic effect medicine at a specified future date of a class.The average arrhythmia time weak point that stops, in 30 minutes, can take a turn for the better after 80% patient's administration comprehensively, comprehensive assessment for acute attack effectiveness, safety shows, it is 48%～70% that the multiple success rate of commentaries on classics is pounced in the room, atrial fibrillation is 22%～43%, being better than sotalol and procainamide changes multiple success rate several times, the atrial fibrillation of heart pass postoperative and room is pounced on safe and effective, and the rhythm of the heart changes multiple rate and reaches 57%.30 days persistent period that atrial fibrillation and room are pounced on, 42% patient to change multiple after with this product, secondary administration patient pounces in the room, atrial fibrillation changes multiple rate and can improve 75% and 45% respectively, and hematodinamics is not had obvious influence, even the patient that left ventricular function lowers influence is also very little.
Oral ibutilide, for example the preparation of Ibolite fumarate has stronger first-pass metabolism, and bioavailability is low, thus adopt intravenous administration, and, must have the professional health care personnel to operate again through intravenously administrable.For requiring under the very first time in time, make things convenient for the morbidity patient of administration, and the patient of the morbidity of being in, provide a kind of drug-delivery preparation except that injection very necessary.
Summary of the invention
The objective of the invention is to overcome the inconvenience that on route of administration, exists of known Ibolite fumarate preparation, overcome the defective at the bottom of the oral administration bioavailability, develop a kind of new, non-injection administration, anti-arrhythmia, have interests doctor and patient easily, medication Ibolite fumarate nasal cavity administration preparation fast.Inventor's further investigation, discovery comprises other pharmaceutical salts of Ibolite fumarate, ibutilide free alkali or pharmaceutically acceptable ibutilide and has the ibutilide stereoisomer of pharmacologically active and the nasal cavity administrated preparation of absorption enhancer, especially comprising osmotic pressure regulator, thickening agent, antiseptic, pH regulator agent or other pharmaceutic adjuvant are made into the via intranasal application drug-delivery preparation, can avoid the Ibolite fumarate oral administration biaavailability low effectively, avoid the characteristics of the not compliance of drug administration by injection simultaneously again.
A large amount of experiments show,,, play a role and enter blood circulation drug absorption by the nasal mucosa approach according to nasal cavity administrated preparation of the present invention, have stable performance, quality controllable, non-stimulated to nasal mucosa advantage.
The present invention has absorption rapidly, bioavailability height, determined curative effect, characteristics easy to use.Each dosage is to adjust in the 0.01mg-2.0mg scope.Press weighing machine, each administration is 0.005～0.035mg/kg.
The ibutilide preparation of via intranasal application administration provided by the invention comprises other pharmaceutical salts of Ibolite fumarate, ibutilide free alkali or pharmaceutically acceptable ibutilide and has the stereoisomer of pharmacologically active, absorption enhancer.
Comprise osmotic pressure regulator, surfactant in provided by the invention second the ibutilide preparation.
The invention provides in the 3rd the nasal-cavity administration ibutilide preparation and comprise antiseptic and PH regulator.
The invention provides the 4th nasal-cavity administration ibutilide preparation, wherein:
Described absorption enhancer is selected from any material in following (1)-(8):
(1) cyclodextrin of the cyclodextrin of α, β or gamma-cyclodextrin and alkyl replacement is as methyl-beta-schardinger dextrin-, DM-or HP-;
(2) cholic acid salt: as glycocholate, cholate, deoxycholate, cholyltaurine salt, glucose cholate, CDC or ursol deoxycholate;
(3) saturated and unsaturated fatty acid and esters thereof: as lauric acid, oleic acid, myristic acid, capric acid, laurate, monooctyl ester acid, certain herbaceous plants with big flowers acid esters, cetylate or ethyl lactate:
(4) alcohols: as glycol, isopropyl alcohol, hexadecanol, lauryl alcohol or oleyl alcohol etc.;
(5) ethers: polyoxyethylene laurel ether or polyoxyethylene octyl ether;
(6) sulfoxide class: as dodecyl methyl sulfoxide or dimethyl sulfoxide;
(7) lactams: as the tall and erect ketone of dodecyl nitrogen or hold together the tall and erect ketone of cattle base nitrogen;
(8) ion-type nonionic surfactant: as sodium lauryl sulphate, sad monoglyceride, Tween 80 or span 20;
Above absorption enhancer comprises their two or more mixture;
Described osmotic pressure regulator is for being selected from lactose, glucose, dextran, sorbitol, mannitol or its pharmaceutically acceptable inorganic salt;
Described thickening agent is for being selected from macromolecular compound, carboxymethyl cellulose, hydroxypropyl cellulose, Polyethylene Glycol, polyacrylic acid, acid polyethylene or carbopol;
Described antiseptic is the cationic surfactant that is selected from ethyl hydroxybenzoate, p-Hydroxybenzoate, benzoic acid and pharmaceutically acceptable salt thereof, sorbic acid, chlorobutanol, benzyl alcohol, phenethanol, thimerosal, chlorhexidine acetate or quaternary ammonium compound.
Described pH regulator agent is for being selected from hydrochloric acid, citric acid, fumaric acid or acetic acid.
The invention provides the 5th nasal-cavity administration ibutilide preparation, by percent by weight, said preparation contains other salt of Ibolite fumarate, its free alkali or the pharmaceutically acceptable ibutilide of 0.2-50%.
The invention provides in 100 milliliters of said preparations of the 6th nasal-cavity administration and contain 50 milligrams of Ibolite fumarates, polyvinylpyrrolidone 0.3 gram, 0.5 milliliter of laurocapram, propylene glycol 1.0 grams, ethyl hydroxybenzoate 0.1 gram, hydrochloric acid PH.
The invention provides in 100 milliliters of said preparations of the 7th nasal-cavity administration ibutilide and comprise 50 milligrams of Ibolite fumarates, hydroxypropyl B-cyclodextrin 2.5 grams, ethyl hydroxybenzoate 0.1 gram, mannitol 0.5 gram, 1.0 milliliters of Polyethylene Glycol, purified water to 100 milliliter.Hydrochloric acid is transferred pH.
The invention provides in 100 milliliters of said preparations of the 8th nasal-cavity administration ibutilide and comprise 150 milligrams of Ibolite fumarates, methyl B-cyclodextrin 5 grams, ethyl hydroxybenzoate 0.1 gram, polyvinyl alcohol 0.5 gram, mannitol 2-4 gram, purified water to 100 milliliter.Hydrochloric acid is transferred pH.
The administration ibutilide preparation of nasal-cavity administration provided by the invention is nasal mist or nasal cavity nasal drop.
Nasal cavity administrated preparation available treatment atrial fibrillation provided by the invention and room are pounced on and are made it to change rapidly to be the pernasal preparation of sinus rhythm again.
According to the present invention, the content of other pharmaceutical salts of Ibolite fumarate or ibutilide in the unit pernasal preparation is 0.1-150% (weight %), preferred 0.2-50% (weight %).
The present invention will be further described below by embodiment, but and do not mean that restriction to protection scope of the present invention.
Embodiment 1: the preparation of Ibolite fumarate spray
Become deal
Ibolite fumarate 50mg
Kollidon 0.3g
Laurocapram 0.5ml
Propylene glycol 1.0g
Ethyl hydroxybenzoate 0.1g
Distilled water is to 100ml
Method for making: above-mentioned weight northylen ketopyrrolidine, Ibolite fumarate, propylene glycol, Laurel nitrogen statistics ethyl hydroxybenzoate are fully stirred evenly and make whole dissolvings, add distilled water at last to 100ml.Hydrochloric acid is transferred pH.Gained solution is sub-packed in atomizing pump or quantitatively drips in the pump.
Embodiment 2: the preparation of Ibolite fumarate spray
Become deal
Ibolite fumarate 50mg
HP-2.5g
Ethyl hydroxybenzoate 0.1g
Mannitol 0.5g
PEG400 1.0ml
Distilled water is to 100ml
Method for making: after above-mentioned amount Ibolite fumarate, HP-, ethyl hydroxybenzoate, the jolting of mannitol adding distil water made dissolving, add above-mentioned PEG400, add distilled water at last to 100ml.Hydrochloric acid is transferred pH.
Embodiment 3: the preparation of Ibolite fumarate spray
Become deal
Ibolite fumarate 150mg
Methyl-beta-schardinger dextrin-5g
Ethyl hydroxybenzoate 0.1g
Polyvinyl alcohol 0.5g
Mannitol 2-4g
Distilled water is to 100ml
Method for making:, after jolting makes whole dissolvings, add distilled water at last to 100ml with above-mentioned amount Ibolite fumarate, methyl-beta-schardinger dextrin-, ethyl hydroxybenzoate, polyvinyl alcohol adding distil water.Hydrochloric acid is transferred pH.
Pharmacological evaluation
Implement after 1 fumaric acid Yi Yilite nasal spray and the administration of fumaric acid Yi Yilite injection than the intravital medicine of lattice Canis familiaris L. for test, the results are shown in Table 1
After table 1 fumaric acid Yi Yilite nasal spray and the administration of fumaric acid Yi Yilite injection
Plasma protein binding rate and plasma clearance are relatively in than lattice Canis familiaris L. body
| Medicine | Dosage | Plasma clearance | Plasma protein binding rate |
| The nasal spray injection | 0.3mg/kg 5mg/kg 0.3mg/kg 5mg/kg | 5.3L/h/kg 3.7L/h/kg 5.6L/h/kg 4.0L/h/kg | 39％ 40％ 41％ 42％ |
Ibutilide nasal spray and injection medicine are for the explanation of test comparative result, and both show as concordance at metabolism.
Experiment 2, Ibolite fumarate nasal spray and injection treatment dog arrhythmia (room is pounced on) conversion percentage rate
Table 2 Ibolite fumarate nasal spray and injection treatment dog arrhythmia (room is pounced on) conversion percentage rate
| The conversion percentage rate of dog arrhythmia model | ||||||||||
| Placebo | The Ibolite fumarate nasal spray | Ibutilide fumarate injection | ||||||||
| 0.005 mg/kg | 0.035 mg/kg | 0.100 mg/kg | 0.300 mg/kg | 0.005 mg/kg | 0.035 mg/kg | 0.100 mg/kg | 0.300 mg/kg | |||
| Quantity | 15 | 15 | 16 | 15 | 15 | 16 | 16 | 15 | 16 | |
| Atrial flutter | Initial # | 0 | 17 | 30 | 40 | 70 | 17 | 31 | 46 | 68 |
| ## after 24 hours | 0 | 16 | 30 | 58 | 59 | 15 | 33 | 60 | 61 | |
| # begins the dog percentage rate that nose sprays conversion in back 70 minutes | ||||||||||
| The quantitative nose spray of ## back keeps 24 hours dog percentage rate of sinus rhythm | ||||||||||
Ibutilide makes the local delayed conduction of reentrant cycle, pounces on the increase of reentrant cycle length and cause the room, makes the room pounce on termination, and injection is suitable with the nasal spray effect.
Experiment 1 and experiment 2 presentation of results Ibolite fumarate nasal sprays and Ibolite fumarate injection show as concordance in medicine generation and pharmacological action.
The technical staff can carry out all changes and modification after reading the present patent application description, but these changes and modification are all within the claim protection domain that application is awaited the reply.
Claims (2)
1, a kind of Ibolite fumarate spray of via intranasal application administration is characterized in that comprising in 100 milliliters the described preparation:
50 milligrams of Ibolite fumarates,
Absorption enhancer HP-2.5 grams,
Antiseptic ethyl hydroxybenzoate 0.1 gram,
Osmotic pressure regulator mannitol 0.5 gram,
1.0 milliliters of thickening agent PEG400s,
Distilled water to 100 milliliter.
2, a kind of Ibolite fumarate spray of via intranasal application administration is characterized in that comprising in 100 milliliters the described preparation:
150 milligrams of Ibolite fumarates,
Absorption enhancer methyl-beta-schardinger dextrin-5.0 grams,
Antiseptic ethyl hydroxybenzoate 0.1 gram,
Osmotic pressure regulator mannitol 2-4 gram
Thickening agent polyvinyl alcohol 0.5 gram,
Distilled water to 100 milliliter.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200410098645 CN1293863C (en) | 2004-12-15 | 2004-12-15 | Ibolite fumarate nasal cavity administration preparation |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200410098645 CN1293863C (en) | 2004-12-15 | 2004-12-15 | Ibolite fumarate nasal cavity administration preparation |
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| CN1293863C true CN1293863C (en) | 2007-01-10 |
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| CN107753485A (en) * | 2017-11-28 | 2018-03-06 | 赵永宏 | A kind of pharmaceutical composition for having nose congestion and anesthetic effect concurrently and its application |
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