CN104188998A - Naringin and fexofenadine hydrochloride drug composition and preparation thereof - Google Patents
Naringin and fexofenadine hydrochloride drug composition and preparation thereof Download PDFInfo
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- CN104188998A CN104188998A CN201410479695.6A CN201410479695A CN104188998A CN 104188998 A CN104188998 A CN 104188998A CN 201410479695 A CN201410479695 A CN 201410479695A CN 104188998 A CN104188998 A CN 104188998A
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- Prior art keywords
- naringin
- fexofenadine hydrochloride
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- preparation
- cough
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- DFPMSGMNTNDNHN-ZPHOTFPESA-N naringin Chemical compound O[C@@H]1[C@H](O)[C@@H](O)[C@H](C)O[C@H]1O[C@H]1[C@H](OC=2C=C3O[C@@H](CC(=O)C3=C(O)C=2)C=2C=CC(O)=CC=2)O[C@H](CO)[C@@H](O)[C@@H]1O DFPMSGMNTNDNHN-ZPHOTFPESA-N 0.000 title claims abstract description 78
- 239000001606 7-[(2S,3R,4S,5S,6R)-4,5-dihydroxy-6-(hydroxymethyl)-3-[(2S,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyloxan-2-yl]oxyoxan-2-yl]oxy-5-hydroxy-2-(4-hydroxyphenyl)chroman-4-one Substances 0.000 title claims abstract description 70
- 229940052490 naringin Drugs 0.000 title claims abstract description 70
- 229930019673 naringin Natural products 0.000 title claims abstract description 70
- RRJFVPUCXDGFJB-UHFFFAOYSA-N Fexofenadine hydrochloride Chemical compound Cl.C1=CC(C(C)(C(O)=O)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 RRJFVPUCXDGFJB-UHFFFAOYSA-N 0.000 title claims abstract description 68
- 229960000354 fexofenadine hydrochloride Drugs 0.000 title claims abstract description 68
- 238000002360 preparation method Methods 0.000 title claims abstract description 36
- 239000000203 mixture Substances 0.000 title abstract description 42
- 239000003814 drug Substances 0.000 title abstract description 33
- 229940079593 drug Drugs 0.000 title abstract description 17
- 239000008194 pharmaceutical composition Substances 0.000 claims description 17
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- 229920002472 Starch Polymers 0.000 claims description 6
- 239000008107 starch Substances 0.000 claims description 6
- 235000019698 starch Nutrition 0.000 claims description 6
- 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 claims description 3
- 239000008101 lactose Substances 0.000 claims description 3
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- 235000019425 dextrin Nutrition 0.000 claims description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims 1
- 229920001661 Chitosan Polymers 0.000 claims 1
- 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 1
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- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 claims 1
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 claims 1
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- 125000001424 substituent group Chemical group 0.000 claims 1
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- 206010011224 Cough Diseases 0.000 abstract description 34
- 208000006673 asthma Diseases 0.000 abstract description 12
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- 238000007796 conventional method Methods 0.000 abstract description 2
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- 241000700199 Cavia porcellus Species 0.000 description 16
- BELBBZDIHDAJOR-UHFFFAOYSA-N Phenolsulfonephthalein Chemical compound C1=CC(O)=CC=C1C1(C=2C=CC(O)=CC=2)C2=CC=CC=C2S(=O)(=O)O1 BELBBZDIHDAJOR-UHFFFAOYSA-N 0.000 description 11
- 229960003531 phenolsulfonphthalein Drugs 0.000 description 11
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 9
- 230000000694 effects Effects 0.000 description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- NZWOPGCLSHLLPA-UHFFFAOYSA-N methacholine Chemical compound C[N+](C)(C)CC(C)OC(C)=O NZWOPGCLSHLLPA-UHFFFAOYSA-N 0.000 description 8
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- 230000029142 excretion Effects 0.000 description 6
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- MKXZASYAUGDDCJ-SZMVWBNQSA-N LSM-2525 Chemical compound C1CCC[C@H]2[C@@]3([H])N(C)CC[C@]21C1=CC(OC)=CC=C1C3 MKXZASYAUGDDCJ-SZMVWBNQSA-N 0.000 description 4
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- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 238000000034 method Methods 0.000 description 4
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- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
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- YQSHYGCCYVPRDI-UHFFFAOYSA-N (4-propan-2-ylphenyl)methanamine Chemical compound CC(C)C1=CC=C(CN)C=C1 YQSHYGCCYVPRDI-UHFFFAOYSA-N 0.000 description 2
- DKSZLDSPXIWGFO-BLOJGBSASA-N (4r,4ar,7s,7ar,12bs)-9-methoxy-3-methyl-2,4,4a,7,7a,13-hexahydro-1h-4,12-methanobenzofuro[3,2-e]isoquinoline-7-ol;phosphoric acid;hydrate Chemical compound O.OP(O)(O)=O.OP(O)(O)=O.C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC.C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC DKSZLDSPXIWGFO-BLOJGBSASA-N 0.000 description 2
- 206010067484 Adverse reaction Diseases 0.000 description 2
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 2
- 238000012449 Kunming mouse Methods 0.000 description 2
- 206010036790 Productive cough Diseases 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 206010041349 Somnolence Diseases 0.000 description 2
- 206010047700 Vomiting Diseases 0.000 description 2
- 230000006838 adverse reaction Effects 0.000 description 2
- WNROFYMDJYEPJX-UHFFFAOYSA-K aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 description 2
- 229910021502 aluminium hydroxide Inorganic materials 0.000 description 2
- JBDGDEWWOUBZPM-XYPYZODXSA-N ambroxol Chemical compound NC1=C(Br)C=C(Br)C=C1CN[C@@H]1CC[C@@H](O)CC1 JBDGDEWWOUBZPM-XYPYZODXSA-N 0.000 description 2
- 230000001088 anti-asthma Effects 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 229960004415 codeine phosphate Drugs 0.000 description 2
- 229960004397 cyclophosphamide Drugs 0.000 description 2
- 229960003782 dextromethorphan hydrobromide Drugs 0.000 description 2
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- 235000019359 magnesium stearate Nutrition 0.000 description 2
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- DBAKFASWICGISY-BTJKTKAUSA-N Chlorpheniramine maleate Chemical compound OC(=O)\C=C/C(O)=O.C=1C=CC=NC=1C(CCN(C)C)C1=CC=C(Cl)C=C1 DBAKFASWICGISY-BTJKTKAUSA-N 0.000 description 1
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- 208000008454 Hyperhidrosis Diseases 0.000 description 1
- 206010021079 Hypopnoea Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- PVLJETXTTWAYEW-UHFFFAOYSA-N Mizolastine Chemical compound N=1C=CC(=O)NC=1N(C)C(CC1)CCN1C1=NC2=CC=CC=C2N1CC1=CC=C(F)C=C1 PVLJETXTTWAYEW-UHFFFAOYSA-N 0.000 description 1
- 208000002740 Muscle Rigidity Diseases 0.000 description 1
- JAUOIFJMECXRGI-UHFFFAOYSA-N Neoclaritin Chemical compound C=1C(Cl)=CC=C2C=1CCC1=CC=CN=C1C2=C1CCNCC1 JAUOIFJMECXRGI-UHFFFAOYSA-N 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
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- YEJAJYAHJQIWNU-UHFFFAOYSA-N azelastine hydrochloride Chemical compound Cl.C1CN(C)CCCC1N1C(=O)C2=CC=CC=C2C(CC=2C=CC(Cl)=CC=2)=N1 YEJAJYAHJQIWNU-UHFFFAOYSA-N 0.000 description 1
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- 208000013116 chronic cough Diseases 0.000 description 1
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- 229960001271 desloratadine Drugs 0.000 description 1
- MZDOIJOUFRQXHC-UHFFFAOYSA-N dimenhydrinate Chemical compound O=C1N(C)C(=O)N(C)C2=NC(Cl)=N[C]21.C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 MZDOIJOUFRQXHC-UHFFFAOYSA-N 0.000 description 1
- 229960004993 dimenhydrinate Drugs 0.000 description 1
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical compound C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 description 1
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- WHWZLSFABNNENI-UHFFFAOYSA-N epinastine Chemical compound C1C2=CC=CC=C2C2CN=C(N)N2C2=CC=CC=C21 WHWZLSFABNNENI-UHFFFAOYSA-N 0.000 description 1
- 229960002548 epinastine hydrochloride Drugs 0.000 description 1
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- 229960003088 loratadine Drugs 0.000 description 1
- JCCNYMKQOSZNPW-UHFFFAOYSA-N loratadine Chemical compound C1CN(C(=O)OCC)CCC1=C1C2=NC=CC=C2CCC2=CC(Cl)=CC=C21 JCCNYMKQOSZNPW-UHFFFAOYSA-N 0.000 description 1
- 208000019017 loss of appetite Diseases 0.000 description 1
- 235000021266 loss of appetite Nutrition 0.000 description 1
- 229960001144 mizolastine Drugs 0.000 description 1
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical class O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 1
- 230000003387 muscular Effects 0.000 description 1
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- 230000007935 neutral effect Effects 0.000 description 1
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- 229940011964 pentobarbital sodium 30 mg Drugs 0.000 description 1
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- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
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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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
-
- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Medicinal Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention relates to a naringin drug composition for relieving cough, eliminating phlegm and relieving asthma and a preparation thereof. The naringin drug composition is characterized in that the naringin drug composition contains naringin and fexofenadine hydrochloride, the content per unit of the naringin in each compounding agent (preparation) is 27.5-275 mg, and the content per unit of the fexofenadine hydrochloride is 30-300 mg; in the composition, the preferred mass ratio of the naringin to the fexofenadine hydrochloride is 1 to 1, and the preferred dosage of the naringin and the fexofenadine hydrochloride in each compounding agent (preparation) are 40 mg and 40 mg respectively. The naringin drug composition and the preparation thereof have the benefits that with the adoption of the drug composition, the cough and the phlegm caused by various reasons as well as the cough variant asthma can be treated; the drug composition can be added with conventional excipients and then can be prepared into a drug for relieving cough, eliminating phlegm and relieving asthma by adopting any conventional methods; the drug effect generated by the composition is better than that generated when the naringin or the fexofenadine hydrochloride is independently used.
Description
Technical field
The present invention relates to a kind of for cough-relieving, the naringin pharmaceutical composition and the preparation thereof that reduce phlegm and relieving asthma.
Background technology
Cough, coughing up phlegm is two common large symptoms of respiratory system disease, closely related on pathology, and general cough presss from both sides expectorant, and abundant expectoration also often causes cough, more may not cause emphysema, bronchiectasis, pulmonary heart disease etc. for a long time.Cough variant asthma, refers to and take a kind of specific type asthma that chronic cough is main or unique clinical manifestation.
At present, in pharmacy medicine, most widely used cough suppressing medicine has codeine phosphate and dextromethorphan hydrobromide etc.
Codeine phosphate is the nervus centralis class chemical drugs that is widely used in cough-relieving or flu, but in recent years because its serious adverse reaction is improved its supervisory level by state food pharmaceuticals administration again and again.Common untoward reaction has: psychopathology or illusion; Shallow breathing, slow or irregular; Heart rate is fast or slow, abnormal.Rare untoward reaction: convulsions, tinnitus, tremble or muscular movement that can not automatic control etc.; Urticaria; The anaphylaxiss such as rash is itched, erythra or face are swollen; Spirit depressing and muscle rigidity etc.Prolonged application can cause dependency.A little less than usual amounts causes that dependent tendency compared with other morphine class medicines is.Typical symptom is: goose pimples, loss of appetite, diarrhoea, toothache, nausea and vomiting, watery nasal discharge, shiver, sneeze, yawn, sleep disorder, stomach spasm, hyperhidrosis, languishment, heart rate speedup, excited or agnogenic heating.
Dextromethorphan hydrobromide is also conventional nervus centralis class chemistry antitussive, and consumer can buy in pharmacy.But along with the increase of its consumption, also there is serious adverse reaction, particularly abuse condition, abroad repeatedly reported that patient causes death because of the capsule that excessive use powdery dextromethorphan is packaged into.U.S. food Drug Administration pays close attention to the abuse condition of dextromethorphan constantly, and sends the warning of not abusing dextromethorphan.U.S. food Drug Administration represents, low dose of correct use of dextromethorphan, can suppress cold symptoms safely and effectively, but abuse can cause death and other serious untoward reaction, as brain injury, epilepsy, loss of consciousness and irregular heartbeats.
Naringin has good relieving cough and resolving phlegm antiasthmatic effect, and there is no addiction, and side effect is minimum.Therefore, the naringin compound preparation of exploitation better efficacy is the fine approach of developing naringin clinical practice.
Summary of the invention
The invention provides a kind of for cough-relieving, the naringin pharmaceutical composition and the preparation thereof that eliminate the phlegm and relieving asthma.
This pharmaceutical composition is comprised of naringin and fexofenadine hydrochloride fourth, and said composition preferred mass proportioning is: naringin: fexofenadine hydrochloride fourth=1:1.It is that 27.5～275mg, fexofenadine hydrochloride fourth content are 30～300mg that consumption per day is recommended naringin content.Its preferred dose is that each ingredients (preparation) unit is containing naringin 40mg, fexofenadine hydrochloride fourth 40mg.
The medicine tool test data that two kinds of pharmaceutical compositions of the present invention are made shows that naringin and fexofenadine hydrochloride fourth have synergism by proportioning use of the present invention, compound effect is obviously better than the effect of one pack system, the effect of better having brought into play cough-relieving, reduce phlegm and having relievingd asthma.Adopt of the present invention and pharmaceutical composition can treat cough, cough up phlegm and cough variant asthma causes pants, and take Shi Buhui cause drowsiness, drowsiness, nauseating, vomiting side effect, this pharmaceutical composition can add conventional adjuvant, the medicine that is prepared into cough-relieving, eliminates the phlegm and relievings asthma according to any conventional method.
We are also studied the effect of naringin combination other drug under study for action, result table amount naringin is during respectively with hydrochloric acid Cha Hai Lamine, hydrochloric acid dimenhydrinate chlorphenamine maleate, loratadine, Desloratadine, A-5610, mizolastine, epinastine hydrochloride use in conjunction, between without collaborative.
The specific embodiment
Below in conjunction with embodiment, the present invention is described further.
Embodiment 1: the inhibition to guinea pig cough due to citric acid
1. material
The qualified Hartley Cavia porcellus of 1.1 laboratory animal, body weight 250～300g, male and female half and half, are provided by Guangdong Medical Lab Animal Center.
1.2 medicines and reagent Hui Feining; Naringin is by people's consumption per day 120mg preparation; Fexofenadine hydrochloride fourth is by people's consumption per day 6mg preparation; Compositions (1) group is by people's consumption per day naringin 27.5mg, fexofenadine hydrochloride fourth 30mg preparation; Compositions (2) group is by people's consumption per day naringin 27.5mg, fexofenadine hydrochloride fourth 300mg preparation; Compositions (3) group is by people's consumption per day naringin 275mg, fexofenadine hydrochloride fourth 30mg preparation; Compositions (4) group is by people's consumption per day naringin 275mg, fexofenadine hydrochloride fourth 300mg preparation; Compositions (5) group is by people's consumption per day naringin 120mg, fexofenadine hydrochloride fourth 120mg preparation.
1.3 instrument YLS-8A lure to cough to draw and breathe heavily instrument (medical science equipment station, Shandong Province product).
2. method
Get 72 of qualified Hartley Cavia porcelluss, body weight 250～300g, is divided into blank group, naringin group, Hui Feining group, fexofenadine hydrochloride fourth, compositions (1)～compositions (5) group at random, and totally 9 groups, 8 every group.Each organizes Cavia porcellus by 0.5ml/100g body weight gastric infusion, wherein blank group is to equal-volume normal saline, after gastric infusion 1h, start to accept citric acid spraying 7min, spraying finishes, observe and record while starting from spraying, in ten minutes, cough number of times (typical case's cough for cough clear loud, the Chang Youqian work of fluttering).
3. result
From table 1, naringin and fexofenadine hydrochloride fourth medicine are individually dosed, all have remarkable antitussive effect (with the comparison of blank group, P<0.05 or 0.01); Each naringin and fexofenadine hydrochloride fourth drug regimen also all have good antitussive effect, and antitussive effect is significantly better than individually dosed group of individually dosed group of naringin or fexofenadine hydrochloride fourth, difference has statistical significance (with individually dosed group of comparison, P<0.05 or 0.01).Result proves: this pharmaceutical composition has good antitussive effect, and is significantly better than separately individually dosed group.
The inhibition situation (n=8) of the tested medicine of table 1 to the cough of citric acid induction
Note:
1, with the comparison of blank group,
*p < 0.05,
*p < 0.01;
2, with the comparison of naringin group,
※p < 0.05,
※ ※p < 0.01;
3, with the comparison of fexofenadine hydrochloride fourth group,
□p < 0.05,
?p < 0.01.
Embodiment 2: the impact on the phenol red excretion experiment of mice
1. material
1.1 laboratory animal kunming mices, male and female half and half, body weight 30～40g, is provided by Guangdong Medical Lab Animal Center.
1.2 medicines and reagent ambroxol; Naringin is by people's consumption per day 120mg preparation; Fexofenadine hydrochloride fourth is by people's consumption per day 120mg preparation; Compositions (1) group is by people's consumption per day naringin 27.5mg, fexofenadine hydrochloride fourth 30mg preparation; Compositions (2) group is by people's consumption per day naringin 27.5mg, fexofenadine hydrochloride fourth 300mg preparation; Compositions (3) group is by people's consumption per day naringin 275mg, fexofenadine hydrochloride fourth 30mg preparation; Compositions (4) group is by people's consumption per day naringin 275mg, fexofenadine hydrochloride fourth 300mg preparation; Compositions (5) group is by people's consumption per day naringin 120mg, fexofenadine hydrochloride fourth 120mg preparation.
1.3 instrument Hitachi 3010 ultraviolet-uisible spectrophotometers.
2. method
Get kunming mice, male and female half and half, are divided into blank group, ambroxol group, naringin group, fexofenadine hydrochloride fourth, compositions (1)～compositions (5) group, 10 every group at random.The continuous gastric infusion 2d of 0.2ml/10g, the phenol red normal saline 0.2ml/10g of 30min lumbar injection 5% after last administration, after 30min, put to death mice separated trachea, cut one section of trachea to trachea bifurcation from thyroid cartilage, put into the test tube that fills 3ml normal saline, the sodium bicarbonate solution that adds again 0.1ml15%. after centrifugal, get supernatant, in 546nln place, survey OD value.According to phenol red standard curve, convert out phenol red content.Standard curve: the phenolsulfonphthalein standards of preparing respectively 0.1 μ g/ml, 0.3 μ g/ml, 0.5 μ g/ml, 0.7 μ g/ml, l μ g/ml, 3 μ g/ml, 5 μ g/ml, 10 μ g/ml.If medicine can increase the secretory function of respiratory tract, can increase phenol red excretion amount, so record the height of phenol red content, can compare the difference of medicine expectoration effect.
3. result
From table 2, naringin and fexofenadine hydrochloride fourth medicine are individually dosed, all can significantly improve the effect of the phenol red excretion amount of mice (with the comparison of blank group, P<0.05 or 0.01), have remarkable phlegm-dispelling functions; Each naringin and fexofenadine hydrochloride fourth drug regimen also all have the phenol red excretion dose-effect fruit of good raising mice, and improve the phenol red excretion dose-effect of mice and be really significantly better than individually dosed group of individually dosed group of naringin or fexofenadine hydrochloride fourth, difference has statistical significance (with individually dosed group of comparison, P<0.05 or 0.01).Result
Proof: naringin and fexofenadine hydrochloride fourth drug regimen have good expectorant effect, and expectorant effect is better than individually dosed group of individually dosed group of naringin and fexofenadine hydrochloride fourth.
The impact (n=10) of the tested medicine of table 2 on the phenol red excretion experiment of mice
Note:
With the comparison of blank group,
*p < 0.05,
*p < 0.01;
With the comparison of naringin group,
※p < 0.05,
※ ※p < 0.01;
With the comparison of fexofenadine hydrochloride fourth group,
□p < 0.05,
?p < 0.01.
Embodiment 3: allergic cough's's (Asthma) impact due to ovalbumin is induced
1. material
1.1 laboratory animals: Hartley Cavia porcellus, male, body weight 250～300g, SPF level, is provided by Guangdong Medical Lab Animal Center.
1.2 medicines and reagent cyclophosphamide; Ovalbumin; Capsaicin; Methacholine; Booth pectoral syrup (FUFANG LINSUANKEDAIYIN RONGYE) difficult to understand; Naringin is by people's consumption per day 120mg preparation; Fexofenadine hydrochloride fourth is by people's consumption per day 120mg preparation; Compositions (1) group is by people's consumption per day naringin 27.5mg, fexofenadine hydrochloride fourth 30mg preparation; Compositions (2) group is by people's consumption per day naringin 27.5mg, fexofenadine hydrochloride fourth 300mg preparation; Compositions (3) group is by people's consumption per day naringin 275mg, fexofenadine hydrochloride fourth 30mg preparation; Compositions (4) group is by people's consumption per day naringin 275mg, fexofenadine hydrochloride fourth 300mg preparation; Compositions (5) group is by people's consumption per day naringin 120mg, fexofenadine hydrochloride fourth 120mg
Preparation.
1.3 instrument and equipments: BUXCO cough system and whole body plethysmography system (U.S. BUXCO company).
2. method
2.1 groupings: male Hartley Cavia porcellus, body weight 250～300g, is divided into Normal group, model control group, booth group difficult to understand, naringin group, fexofenadine hydrochloride fourth group, compositions (1)～compositions (5) group, 10 every group at random.
2.2 modelings: except Normal group, all the other respectively organize Cavia porcellus sensitization as follows: 1d is with 30mg/kg dosage intraperitoneal injection of cyclophosphamide; 3d lumbar injection is containing the suspension 1mL of egg protein 2mg and aluminium hydroxide 100mg; After 3 weeks, re-inject the suspension 1mL containing ovum protein 10.01 mg and aluminium hydroxide 100mg, normal group guinea pig intraperitoneal injection normal saline 1mL; Rear all modeling animals atomization in 3 weeks sucks 1% egg protein solution 90s and excites, and Normal group atomization sucks normal saline 90s.
2.3 administrations: excite rear 24h, each group is according to dosed administration shown in table 1, successive administration 7 days.The mensuration of guinea pig cough's number of times: after last administration 1h, Cavia porcellus is placed in to Buxco cough monitor, the capsaicin of employing 50 μ mol/L draws to be coughed, total amount 1ml records the cough number of times in 10min (containing nebulisation time).
The mensuration of 2.4 Guinea Pig Airways reactivities (AR): rear 24h is measured in cough, exhales intermittence (Enhanced Pause, Penh) with the enhancing that detects Cavia porcellus in Buxco whole body plethysmography system.Measure the variation that methacholine (MeCh) atomization excites rear Penh, MeCh excites concentration from low to high, is followed successively by 100mg/L, 200mg/L, and 400mg/L, 800mg/L, 1600mg/L, records the Penh meansigma methods of each concentration level MeCh under exciting.When each MeCh is excited Penh value under concentration to be converted to excite with normal saline (NS), the percentage ratio of Penh value, represents with Penh%, as the evaluation index of AR.
After 2.5 bronchoalveolar lavage and bronchoalveolar lavage fluid (BALF) differential blood count: AR measures and finishes, Cavia porcellus adopts pentobarbital sodium 30mg/kg to anaesthetize, then cut off skin of neck, and cut off osculum in place, trachea center, insert tracheal casing pipe.With the capable bronchoalveolar lavage of normal saline 5mL, rinse back and forth 3 times, collect bronchoalveolar lavage fluid.4 ℃ of whole bronchoalveolar lavage fluid
Centrifugal 1500rpm * 10min, supernatant-80 ℃ save backup.
2.6 lung tissue sections: get right lung portion of tissue row frozen section, conventional fixing, dehydration, row HE dyeing, observation air flue and lung tissue disease are of science to be changed.
3. result
3.1 cough number of times
From table 3, model group and Normal group comparison, cough number of times significantly increases (P<0.01).After administration, each administration group all can reduce cough number of times, with model control group comparison, variant statistically.Each naringin and fexofenadine hydrochloride fourth compositions group and individually dosed group of naringin or the comparison of the only administration group of fexofenadine hydrochloride fourth, cough number of times significantly reduces, difference has statistical significance (with individually dosed group of comparison, P<0.05 or 0.01).Above result proves, pharmaceutical composition has good antitussive effect for the cough of ovalbumin induction, and is all better than separately individually dosed antitussive effect.
The tested medicine of table 3 draws the inhibition (n=10) of coughing to Cavia porcellus capsaicin
Note:
With Normal group comparison,
##p < 0.01;
With model control group comparison,
*p < 0.05,
*p < 0.01;
With the comparison of naringin group,
※p < 0.05,
※ ※p < 0.01;
With the comparison of fexofenadine hydrochloride fourth group,
□p < 0.05,
?p < 0.01.
3.2 airway reactivity
From table 4, with Normal group comparison, model group airway reactivity obviously improves (with Normal group comparison, P<0.01); After administration, each organizes medicine all can reduce airway reactivity; Wherein, each naringin and fexofenadine hydrochloride fourth compositions, due to reduction methacholine (MeCh), the effect of airway hyper-reaction is better than individually dosed group of naringin or individually dosed group of fexofenadine hydrochloride fourth (with individually dosed group of comparison, P<0.05 or 0.01).Result shows, naringin and fexofenadine hydrochloride fourth pharmaceutical composition have significant antiasthmatic effect to the cough variant asthma of ovalbumin induction, and are all better than separately individually dosed group.
The tested medicine of table 4 is on the reactive impact of Guinea Pig Airway (n=10)
Note: 1. with Normal group comparison,
#p < 0.01,
##p < 0.01;
With model control group comparison,
*p < 0.05,
*p < 0.01;
With the comparison of naringin group,
※p < 0.05,
※ ※p < 0.01;
With the comparison of fexofenadine hydrochloride fourth group,
□p < 0.05,
?p < 0.01.
3.3 bronchoalveolar lavage fluid differential blood count results
From table 5, model control group and Normal group comparison, total white blood cells, lymphocyte, neutrophilic granulocyte and eosinophilic granulocyte's sum all obviously raise (with Normal group comparison, P<0.01); Naringin, fexofenadine hydrochloride fourth are individually dosed, also can significantly reduce total white blood cells, lymphocyte, neutrophilic granulocyte and eosinophilic granulocyte's sum (with model group comparison, P<0.05 or 0.01); Each naringin and fexofenadine hydrochloride fourth compositions, all can significantly reduce total white blood cells, lymphocyte, neutral grain
Cell and eosinophilic granulocyte's sum are (with model group comparison, P<0.05 or 0.01), and compare with individually dosed group of individually dosed group of naringin or fexofenadine hydrochloride fourth, the effect of its reduction total white blood cells, neutrophilic granulocyte number, lymphocyte number and eosinophilic granulocyte's number is (with individually dosed group of comparison, P<0.05 or 0.01) significantly.Result proof pharmaceutical composition is at individually dosed group that is all better than aspect inflammation-inhibiting cell separately.
The tested medicine of table 5 is to the result of Cavia porcellus bronchoalveolar lavage fluid differential blood count (n=10)
Note:
With Normal group comparison,
#p < 0.01,
##p < 0.01;
With model control group comparison,
*p < 0.05,
*p < 0.01;
With the comparison of naringin group,
※p < 0.05,
※ ※p < 0.01;
With the comparison of fexofenadine hydrochloride fourth group,
□p < 0.05,
?p < 0.01.
3.4 lung tissue section's results
After administration, from inflammatory cell infiltration degree, alveolar wall edema and congested degree, the aspect overall merits such as alveolar space structure and bronchial lumen integrated degree, naringin obviously improves obviously than booth group difficult to understand, naringin group, fexofenadine hydrochloride fourth group with each compositions group of fexofenadine hydrochloride fourth medicine.
Embodiment 4:
Get naringin 40g, fexofenadine hydrochloride fourth 40g.First fexofenadine hydrochloride fourth and naringin are mixed, then add starch 65g and mix, then add micropowder silica gel 5g, mix, pack in 1000 capsules, obtain capsule.
Embodiment 5:
Get naringin 40g, fexofenadine hydrochloride fourth 40g, then add lactose 65g and mix, then add micropowder silica gel 5g, and mix, pack in 1000 capsules, obtain capsule.
Embodiment 6:
Get naringin 40g, fexofenadine hydrochloride fourth 40g.First fexofenadine hydrochloride fourth and naringin are mixed, then add 120 grams of starch, wet granulation, particle drying, adds magnesium stearate 1g, mixes, and is pressed into 1000, obtains tablet.
Embodiment 7:
Get naringin 40g, fexofenadine hydrochloride fourth 40g.First naringin, fexofenadine hydrochloride fourth are mixed, add 88 grams of dextrin 30g, starch and mix, add micropowder silica gel 2g, mix, pack in 1000 capsules, obtain capsule.
Embodiment 8:
Get naringin 40g, fexofenadine hydrochloride fourth 40g.First fexofenadine hydrochloride fourth is added to lactose 48g and mix, then add 98 grams of naringins, starch to mix, wet granulation, particle drying, adds magnesium stearate 1g, mixes, and is pressed into 1000, obtains tablet.
Claims (6)
1. a naringin pharmaceutical composition, is characterized in that: this kind of pharmaceutical composition is comprised of naringin 27.5～275mg and fexofenadine hydrochloride fourth 30～300mg.
2. pharmaceutical composition according to claim 1, is characterized in that: the quality proportioning of naringin and fexofenadine hydrochloride fourth is 1:1.
3. according to the pharmaceutical composition described in claim 1 and 2, it is characterized in that: this kind of pharmaceutical composition is comprised of naringin 40mg and fexofenadine hydrochloride fourth 40mg.
4. according to the made clinical acceptable preparation of pharmaceutical composition described in claims 1 to 3.
5. preparation according to claim 4, is characterized in that: described preparation is tablet, capsule, water preparation or aerosol.
6. preparation according to claim 5, is characterized in that: described pharmaceutical adjunct is starch, lactose, mannitol, calcium hydrogen phosphate, carboxymethyl starch or its salt and group substituent, dextrin, chitosan, polyvinylpyrrolidone, cellulose and derivant thereof or Polyethylene Glycol.
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| WO2016041438A1 (en) * | 2014-09-18 | 2016-03-24 | 中山大学 | Naringin and fexofenadine hydrochloride pharmaceutical composition and preparation thereof |
| CN107573393A (en) * | 2017-10-23 | 2018-01-12 | 梅州金柚康健康科技有限公司 | The preparation of hypo-glycosylated Pu Luning a kind of and its application in anti-inflammatory suppressing panting calming medicine |
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Application publication date: 20141210 |