CN100389792C - Pharmaceutical composition for treating nose disease and its preparation method - Google Patents
Pharmaceutical composition for treating nose disease and its preparation method Download PDFInfo
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- CN100389792C CN100389792C CNB200510001994XA CN200510001994A CN100389792C CN 100389792 C CN100389792 C CN 100389792C CN B200510001994X A CNB200510001994X A CN B200510001994XA CN 200510001994 A CN200510001994 A CN 200510001994A CN 100389792 C CN100389792 C CN 100389792C
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Abstract
The present invention discloses a novel Chinese and Western medicine composition for treating nose diseases. The medicine composition is prepared from the following crude drugs of ephedrine hydrochloride, baicalin, magnolia flower oil, borneol and honeysuckle flower. The medicine composition of the present invention can be made into any optimized formulation acceptable clinically according to conventional method in the technical field, and preferably used as nasal drops, aerosols and sprays. As verified by clinical curative effect observation, the medicine composition of the present invention has notable curative effects on acute and chronic rhinitis and clinical symptoms, such as common cold, nasal obstruction, nose discharge, headache, nasal cavity burning feeling, thirst, throat pain, alternating nasal obstruction, instable symptoms, baryodmia, etc., caused by wind heating accumulated at lung. In addition, the present invention is safe and has no toxic or side effect on clinical medication.
Description
Technical field
The present invention relates to a kind of new pharmaceutical composition of Rhinological disease and preparation method thereof that is used for the treatment of, relate in particular to a kind of main be the pharmaceutical composition that is used for the treatment of acute or chronic rhinitis that raw material is made with the Chinese herbal medicine.
Background technology
Rhinological disease is a common clinical, frequently-occurring disease.Theory of Chinese medical science thinks that nose is the door of gas discrepancy, and department's olfactory sensation helps pronunciation, under lung system.Nose is a key outside the lung, and " element asks YIN YANG classification of natural phenomena big opinion " said: " lung controlling nose ... is nose at key ", point out the relation of lung and nose." element is asked a vessles length piece of writing " said: " lung-QI connecting with the nose, lung and then nose can know good and foul smells "." a Ling Shu Miraculous Pivot or Divine Axis Benshen piece of writing " said: " insufficiency of lung-QI is nasal obstruction then ".As seen lung and nose are in close relations.The two is coordinated on physiological function mutually, cooperatively interacts, and then lung qi is advocated, and breathes gentlely, and nose key tonneau can be known good and foul smells.If insufficiency of lung-QI, or exopathogen criminal lung then can cause nose key generation pathological changes.
Clinical common traditional Chinese medical science Rhinological disease mainly contains the cold nasal obstruction, stuffy nose, allergic rhinitis (or claiming nose to sneeze), nasal sinusitis etc.
The cold nasal obstruction is because the diseases caused by exogenous pathogenic factor ailment said due to cold or exposure causes that cardinal symptom is rhinocleisis, watery nasal discharge, sneeze, even anosmia.The primary disease four seasons all can take place, and the course of disease is shorter, and the general a few days can heal, and is equivalent to the acute rhinitis of modern medicine indication.
Stuffy nose is meant when when nasal obstruction is light heavy, or bilateral nose key alternately stops up, and takes place repeatedly, prolongedly do not heal, even the hyposmia person.The chronic rhinitis that is equivalent to the modern medicine indication.
Allergic rhinitis is meant that with rhinocnesmus, sneeze, snivel, nasal obstruction unexpected and outbreak repeatedly be the cacorhinia of feature.The primary disease of repeatedly touching upon in " interior warp ".Say as " element ask arteries and veins separate a piece of writing ": " last person then its grandson's network is also lunar for the then headache of so-called objective grandson's arteries and veins, allergic rhinitis, abdominal distention person, Yang Ming and in last, so headache, allergic rhinitis, abdominal distention are also ".Primary disease is equivalent to the allergic rhinitis of modern medicine indication.
The medicine of the common treatment Rhinological disease in market mainly contains rhinitis tablet up to now, bidouyan mixture, bidouyan koufuye, HUODAN WAN, leaves of pulse plants gallbladder sheet, QIANBAI BIYAN PIAN, DITONG BIYAN SHUI, BIYUANSHU KOUFUYE, tens kinds of BIYAN QINGDU KELI etc., the contained main component of these medicines has: the Herba Pogostemonis leaf, Pulvis Fellis Suis, Flos Chrysanthemi Indici, Fructus Xanthii, Rhizoma Paridis She Pao le, Radix Zanthoxyli, Spica Prunellae, Radix Gentianae, Radix Codonopsis, Flos Magnoliae, Herba Menthae, the Radix Angelicae Dahuricae, Radix Scutellariae, Fructus Gardeniae, Radix Bupleuri, Herba Asari, the Radix Astragali, Radix Platycodonis, Herba Taraxaci, Rhizoma Acori Graminei, Herba Senecionis Scandentis, Herba Selaginellae, Rhizoma Et Radix Notopterygii, Semen Cassiae, Herba Ephedrae, Rhizoma Chuanxiong, Herba Schizonepetae, Poria, Caulis Clematidis Armandii, Radix Saposhnikoviae, Fructus Forsythiae, Fructus Schisandrae Chinensis, the Rhizoma Anemarrhenae, Radix Glycyrrhizae, Cortex Phellodendri etc.They are mainly used in treatment wind and cold heat-transformation, pyretic toxicity, or the nasal obstruction that causes of other exopathogenic factors, and nasosinusitis headache, nasopharyngeal sore pain, nasopharynx inflam mation, sinusitis, nasal sinusitis, diseases such as acute and chronic rhinitis, indivedual medicines relate to allergic rhinitis.They all in various degree exist the defective of curing the symptoms, not the disease.
Summary of the invention
Technical problem to be solved by this invention provides a kind of new pharmaceutical composition that can effectively treat all kinds of acute or chronic rhinitis.
Technical problem to be solved by this invention realizes by following technological approaches:
A kind of pharmaceutical composition for the treatment of Rhinological disease of the present invention, make by following raw medicaments in portion by weight:
7 parts～60 parts of 1.7 parts～15 parts baicalins of ephedrine hydrochloride
0.7 part～6 parts of 0.3 part～3 parts Flos Magnoliae oil of Borneolum Syntheticum
100 parts～900 parts of Flos Loniceraes;
The weight portion proportion optimization of each component of pharmaceutical composition of the present invention is:
10 parts～40 parts of 2.5 parts～10 parts baicalins of ephedrine hydrochloride
1 part～4 parts of 0.5 part～2 parts Flos Magnoliae oil of Borneolum Syntheticum
150 parts～600 parts of Flos Loniceraes;
More preferably:
20 parts of 5 parts of baicalins of ephedrine hydrochloride
2 parts of 1 part of Flos Magnoliae oil of Borneolum Syntheticum
300 parts of Flos Loniceraes.
The used raw material of the present invention all can be bought from common pharmacy and obtain, and specification all meets national medical standard.
Pharmaceutical composition of the present invention based on Chinese medicine and pharmacy to pathogenetic research of Rhinological disease deep layer and Therapeutic Principle thereof, simultaneously according to the pharmaceutical research achievement, filter out that heat-clearing and toxic substances removing, lung qi dispersing are sensible, the crude drug of reducing swelling and alleviating pain, according to the theory of Chinese medical science prescription, be prepared from according to certain weight proportion.
The compatibility of pharmaceutical composition of the present invention is according to being:
Theory of Chinese medical science is thought, no matter the outer excessive heat of nasal obstruction, or interior fire of making, mostly be the burning hot institute of lung meridian and cause, control and should use the wind that looses, heat clearing away, sensible method.Select Flos Magnoliae in this product side for use, it goes into lung meridian, is apt to diffusing pulmonary's ailment said due to cold or exposure and clearing the nasal passage, for controlling rhinitis medicine commonly used.Radix Scutellariae is clinical antipyretic commonly used, with the fire of its lung heat clearing warp with large intestine channel.Modern study shows that Radix Scutellariae has antiinflammatory, anti-allergy action, and than the antibacterial action of wide range.Flos Lonicerae is evacuated the lung meridian pathogenic heat, and the merit of detoxifcation is arranged, for heat-clearing and toxic substances removing and control the good medicine of affection due to external wind and heat.Modern study shows that Flos Lonicerae has inhibitory action to various bacteria, and virus is also had inhibitory action.The Herba Ephedrae effect is opened lung qi dispersing gas, inducing diuresis to remove edema.Modern study proves that Herba Ephedrae epheday intermedia alkali composition has the vasoconstrictive effect, and effect is lasting, also is clinical nose key disease medicament commonly used.It is hot and suffocating that the Borneolum Syntheticum effect is loose, the refreshment of having one's ideas straightened out, and external also has the merit of heat clearing away.In sum, this product compound basis Chinese herb decoction opinion, improvement are discussed and are got in conjunction with the modern medicine and pharmacology result of study cooperates, and play diffusing wind altogether, heat clearing away, and sensible effect, thus can effectively treat all kinds of acute or chronic rhinitis.
Pharmaceutical composition of the present invention can be prepared into any acceptable clinically suitable formulations by this area conventional method, for example can be tablet, capsule, granule, powder, pill, oral liquid, syrup, drop pill, liquid nasal formulations, ointment, emplastrum.Being preferably the liquid nasal formulations, especially is the liquid nasal formulations of nasal drop, aerosol, spray.
Another technical problem to be solved by this invention provides a kind of preparation method of this pharmaceutical composition.
A kind of preparation method of pharmaceutical composition of the present invention, step is as follows:
(1) take by weighing each component by following weight portion:
7 parts～60 parts of 1.7 parts～15 parts baicalins of ephedrine hydrochloride
0.7 part～6 parts of 0.3 part～3 parts Flos Magnoliae oil of Borneolum Syntheticum
100 parts～900 parts of Flos Loniceraes;
(2) add the hydro-oxidation sodium solution again after baicalin is added water stirring evenly and make its dissolving, it is standby to regulate pH value to 6.5～8.5 backs with dilute hydrochloric acid;
(3) Flos Lonicerae is used water extraction, extracting solution is purified, refinement treatment gets refined solution or dry extract is standby;
(4) it is standby after ephedrine hydrochloride is dissolved in water;
(5) with Borneolum Syntheticum, Flos Magnoliae oil dissolve with ethanol, add again after Tween-80 stirs evenly, mix with above-mentioned baicalin solution, Flos Lonicerae refined solution or Getrocknete Blumen extract powder and ephedrine hydrochloride solution, stir evenly, add adjuvant and mixing, make the preparation intermediate, make preparation through preparations shaping technology again, promptly.
Usage and consumption: dosage of the present invention depends on factors such as concrete dosage form, patient's age, health status.As guidance: for spray, its effective dose is 0.16ml every day, about 0.05g crude drug; Usage: spray into nasal cavity, press (every side) one time 1～2, every day 2～4 times, continuous 5 days.
Further describe the present invention by the following examples, it should be understood that these embodiment only are used for the purpose of illustration, never limit the scope of the invention.
The specific embodiment
The preparation of [embodiment 1] spray
One, takes by weighing each raw material
Ephedrine hydrochloride 5g baicalin 20g
Borneolum Syntheticum 1g Flos Magnoliae oil 2g
Flos Lonicerae 300g;
Two, baicalin adds water, stirs evenly, and after the hydro-oxidation sodium solution makes dissolving in right amount, regulates pH value to 6.5～8.5, and is standby;
Three, the preparation of Flos Lonicerae refined solution
Flos Lonicerae chooses decontamination, cleans medical material.Extracting honeysuckle 300g decocts with water twice, filters, and it is about 1.0～1.2 that filtrate is concentrated into relative density, adds 1kg ethanol, carries out purification, and refined solution concentrates, and filters, and is standby;
Four, ephedrine hydrochloride add water make the dissolving standby;
Five, the preparation of spray
Borneolum Syntheticum, Flos Magnoliae oil add dissolve with ethanol, add after Tween-80 stirs evenly again, and mix with above-mentioned baicalin solution, Flos Lonicerae refined solution and ephedrine hydrochloride solution, stir evenly, add water in right amount, stir evenly, regulate pH value to 6.0～7.0, filter, add water to 1000ml, packing, promptly.
The preparation of [embodiment 2] pill
One, takes by weighing each raw material
Ephedrine hydrochloride 2g baicalin 7g
Borneolum Syntheticum 0.4g Flos Magnoliae oil 0.8g
Flos Lonicerae 100g
Two, the arrangement of medical material
Flos Lonicerae: choose decontamination, clean medical material.
Three, the preparation of Flos Lonicerae extractive solution or Getrocknete Blumen extract powder
Extracting honeysuckle 100g decocts with water twice, filters, and it is about 1.0～1.2 that filtrate is concentrated into relative density, adds the about 1kg of ethanol, purification, and refined solution is concentrated or carry out spray drying promptly again.
Four, general ball
The Flos Lonicerae extractive solution thin up filters filtrate for later use.Ephedrine hydrochloride, baicalin and 3.75g carboxymethylstach sodium are mixed and made into fine powder.A small amount of fine powder is put into cylinder, start the pill cylinder, begin spray and add a small amount of Flos Lonicerae extractive solution, constantly be stirred to and make fine powder be moistening graininess, add an amount of fine powder again, continuing to stir makes fine powder evenly overlay on the granule, spray adds Flos Lonicerae extractive solution or Getrocknete Blumen extract powder lysate successively again, spreads and adds fine powder, makes powder slowly add the tiny pill of great achievement with the method, cross the sieve in 1mm～1.5mm aperture, get the piller that sieves and make the ball kind.
Add the ball kind in the pill cylinder, start the pill cylinder, spray adds an amount of Flos Lonicerae extractive solution, adds an amount of fine powder again after stirring makes the piller moistening, is the piller of 3.0mm～3.5mm size with the general ball of the method to diameter, takes out.
Five, drying
To wet ball stand dish, drying, the ball embryo.
Six, coating
Borneolum Syntheticum, Flos Magnoliae oil add dissolve with ethanol, add an amount of corn gastral cavity, get volatile oil.Place the pill cylinder to roll every cylinder ball embryo, and spray into volatile oil, stir evenly, take out, promptly with Sprayable.
The preparation of [embodiment 3] tablet
One, takes by weighing each raw material
Ephedrine hydrochloride 15g baicalin 60g
Borneolum Syntheticum 3g Flos Magnoliae oil 5.5g
Flos Lonicerae 900g
Two, the arrangement of medical material
Flos Lonicerae: choose decontamination, clean medical material.
Three, the preparation of Getrocknete Blumen extract powder
Extracting honeysuckle 900g decocts with water twice, filters, and it is about 1.0～1.2 that filtrate is concentrated into relative density, spray drying, the Getrocknete Blumen extract powder.
Four, the preparation of tablet
With Getrocknete Blumen extract powder, ephedrine hydrochloride, Borneolum Syntheticum, Flos Magnoliae oil, baicalin and an amount of pregelatinized Starch, make granule, tabletting, the bag film-coat is promptly.
The preparation of [embodiment 4] granule
One, takes by weighing each raw material
Ephedrine hydrochloride 2.5g baicalin 10g
Borneolum Syntheticum 0.5g Flos Magnoliae oil 1g
Flos Lonicerae 150g;
Two, baicalin adds water, stirs evenly, and after the hydro-oxidation sodium solution makes dissolving in right amount, regulates pH value to 6.5～8.5, and is standby;
Three, the preparation of Getrocknete Blumen extract powder
Flos Lonicerae chooses decontamination, cleans medical material.Extracting honeysuckle 150g decocts with water twice, filters, and it is about 1.0～1.2 that filtrate is concentrated into relative density, spray drying, the Getrocknete Blumen extract powder, standby.
Four, ephedrine hydrochloride adds water and makes dissolving, and is standby;
Five, the preparation of granule
Borneolum Syntheticum, Flos Magnoliae oil add dissolve with ethanol, add after Tween-80 stirs evenly again, and mix with Getrocknete Blumen extract powder, ephedrine hydrochloride solution, baicalin solution and an amount of pregelatinized Starch, stir evenly, and make granule, promptly.
The preparation of [embodiment 5] capsule
One, takes by weighing each raw material
Ephedrine hydrochloride 10g baicalin 40g
Borneolum Syntheticum 2g Flos Magnoliae oil 4g
Flos Lonicerae 600g;
Two, baicalin adds water, stirs evenly, and after the hydro-oxidation sodium solution makes dissolving in right amount, regulates pH value to 6.5～8.5, and is standby;
Three, the preparation of Getrocknete Blumen extract powder
Flos Lonicerae chooses decontamination, cleans medical material.Extracting honeysuckle 600g decocts with water twice, filters, and it is about 1.0～1.2 that filtrate is concentrated into relative density, spray drying, the Getrocknete Blumen extract powder, standby.
Four, ephedrine hydrochloride adds water and makes dissolving, and is standby;
Five, the preparation of capsule
Borneolum Syntheticum, Flos Magnoliae oil add dissolve with ethanol, add after Tween-80 stirs evenly again, and mix with Getrocknete Blumen extract powder, ephedrine hydrochloride solution, baicalin solution and an amount of pregelatinized Starch, stir evenly, and make granule, filled capsules, promptly.
The acute toxicity test of [test example 1] pharmaceutical composition of the present invention
1, test material
(1), for the reagent thing: the spray that the embodiment of the invention 1 is prepared.
(2), laboratory animal and raising condition: NIH be the regular grade mice, body weight 18～22 grams, male and female half and half.Provide the laboratory animal certification of fitness number by Guangdong Medical Lab Animal Center: 99A032 (the Guangdong Province State Scientific and Technological Commission is sent out).Tried the preceding fasting of mice administration 12 hours, freely drunk water.
Experiment is carried out at the regular grade Animal Lab. that air-conditioning and ventilation equipment are housed.
2, method for preparation of drug
(1) LD
50Prediction: test with following 4 clinical concentrations (clinical concentration is the prepared spray concentration of the embodiment of the invention 1, and wherein every milliliter contains 20 milligrams of baicalins) for the reagent thing: 4 times, 2 times, 1 times and 0.5 times of clinical concentration of using; 2 times, 1 times and 0.5 times of clinical concentration form with 4 times of clinical concentration adding distil waters dilution configurations.
(2) maximum tolerance determination: as can not survey LD
50, then survey the intranasal administration maximum tolerated dose, medicine is pressed Cmax (4 times of concentration of clinical usefulness) and maximum volume (5 μ l/10g) administration.
3, dosage and route of administration
(1) prediction LD
50: for the reagent thing with following 4 dosage intranasal administrations (representing) with concentration: 4 times, 2 times, 1 times and 0.5 times of clinical concentration once give.
(2) maximum tolerance determination: can not survey LD
50The time, survey maximum tolerated dose, medicine is pressed Cmax (4 times of concentration of clinical usefulness) and maximum volume (5 μ l/10g) administration.Every animal intranasal administration volume is 5 μ l/10g, intranasal administration, 2 times/day, 8 hours at interval.
4, administration and observation:
(1) LD
50Measure: the death toll and the behavior performance of writing down each dosage group day by day.The variation of nasal mucosa and respiratory tract local mucous membrane is paid special attention in the timely postmortem of dead animal.Find the organ and respiratory tract (nose, larynx, trachea, the bronchus) mucosa of pathological changes, do the pathology histological examination.
(2) intranasal administration maximum tolerance determination: tightly observe the animal subject response situation, and the outward appearance sign, behavioral activity, the mental status, appetite of record animal, just large and small and character, had or not abnormal secretion thing, body weight change by hair, the colour of skin, breathing, nose (particularly mucosa), eye, oral cavity.Write out animal dead reason and pathological change.
5, result of the test
(1) LD
50Measure: 16 of mices are divided into 4 groups, and male and female half and half will give mice with four concentration (4 times, 2 times, 1 times, 0.5 times clinical concentration) collunarium for the reagent thing, consumption 5 μ l/10g body weight, prediction LD
50, mice all survives, and can not measure LD
50, transform maximum tolerance determination into.
(2) maximum tolerance determination: 20 of body weight 18～22 gram mices, male and female half and half, mice is clinical in concentration intranasal administration (5 μ l/10g) twice with 4 times, 8 hours at interval.Mice did not see death in 7 days, the diet of mice, general activity, Excreta are normal, weight increase (seeing Table 1).Dissection each main organs of mice and the perusal of respiratory tract local mucous membrane show no obvious abnormalities after 7 days.
Table 1 is for the variation (n=20) of mice body weight before and after the administration of reagent thing
| Before the administration | After the administration (7 days) |
| 21.1±1.2 | 24.6±2.5 |
For the clinical recommended drug amount of reagent thing is 0.4ml/60kg/ day, is equivalent to 0.007ml/kg/ day.The maximum dosage of every mice intranasal administration (4 times of clinical concentrations) is 5 μ l/10g/ time, and promptly dosage is 0.5 * 4/kg/ time, 4.0ml/kg/ day.Calculate as follows, the tolerance dose of mice is equivalent to 572 times of clinical application amount.
Toxicity is judged and conclusion: will can not survey LD by the mice intranasal administration for the reagent thing
50, its maximum tolerated dose is 4.0ml/kg; This dosage is equivalent to 572 times of people's clinical application amount, and route of administration illustrates that pharmaceutical composition toxicity of the present invention is less, clinical drug safety with clinical consistent.
The correlational study test of [test example 2] long-term toxicity of pharmaceutical composition of the present invention
One, test material
(1), for reagent thing and compound method
For the reagent thing: 1) the prepared spray of the embodiment of the invention 1; 2) other is diluted to embodiment 1 prepared spray with distilled water the suspension of 2 times and 1 times concentration of clinical usefulness.Altogether the suspension of three kinds of unequal concentration of equal volume, make each dosage treated animal reach requirement by 45 μ l/100g body weight intranasal administrations, keep in Dark Place in refrigerator (4 ℃) abundant mixing during administration.
(2), excipient: the applicant oneself produces.
(3), laboratory animal and feeding environment
Laboratory animal: regular grade SD rat is provided the laboratory animal certification of fitness number by Guangdong Medical Lab Animal Center: Guangdong Province State Scientific and Technological Commission 99A032 number, 8～9 ages in week, body weight 119.0 ± 7.2 grams.
100 of rats are in indoor one week of breeding observing of regular grade zoopery, no abnormality seen, get 20 do hematology before the medicine, blood biochemical learn routine urianlysis qualified after, be divided into 5 groups (high dose group, middle dosage group, low dose group, excipient group and matched groups) at random, every group 20, male and female half and half, male and female divide cage to feed, 5 in every cage, the active area of average every Mus are 0.03m
2
Laboratory is the constant toxicity of condition chamber, and room temperature is 25 ± 2 ℃, and relative temperature 70～80%, experimental period are year July in April, 2000 to 2000.Experimental session regularly sterilize ground, rearging cage and drinking-water bottle.
Two, dosage setting
For the clinical recommended drug amount of reagent thing is 0.4ml/60kg/ day, is equivalent to 0.007ml/kg/ day.The maximum tolerated dose of acute toxicity test in mice intranasal administration is 4ml/kg, is 572 times of clinical application amount.This experimental evidence is provided with following 3 dosage groups for the characteristics of reagent thing:
High dose 1.8ml/kg; Be equivalent to the clinical recommended drug amount of people and be converted into 50 times of rat dose,equivalent.
Middle dosage 0.9ml/kg; Be equivalent to clinical recommended drug amount and be converted into 25 times of rat dose,equivalent.
Low dosage 0.45ml/kg; Be equivalent to clinical recommended drug amount and be converted into 12.5 times of rat equivalent.
Three, the administration phase
The administration phase is 8 weeks (clinical applications the course of treatment be 4 weeks).
Four, convalescent period
Recovering the observation period is 2 weeks after the drug withdrawal.
Five, route of administration
Intranasal administration, consistent with the clinical application approach.
Six, test method and observation index
By above-mentioned grouping and route of administration, every morning regularly intranasal administration once, matched group gives the isometric(al) distilled water, weighs in weekly, and accurately gives dose by every Mus body weight with adjustable micro sample adding appliance, continuous 8 weeks.After the 8th all last administrations and drug withdrawal 2 week the back get 10 rats (male and female half and half) eye socket rear vein beard (the 10th week) every group respectively and get blood and carry out hematology and blood biochemical and learn and check, get half rat sacrificed by decapitation the 8th week, carry out the becoming celestial substantially of system, organ coefficient and histopathological examination.Live extremely after remaining rat continuation observed for 2 weeks, carry out inspection same as described above.
General symptom: sign, behavioral activity, urine and feces character etc., before and after the administration every day observed and recorded once, and recording exceptional situation at any time.Weigh weekly once and write down food-intake and amount of drinking water once.
Hematology: 2 weekly checks before the administration, after 8 weeks and the drug withdrawal: red blood cell count(RBC), hemoglobinometry, platelet count (measuring) numeration of leukocyte and classification with the moving blood analyser of the U.S. CELL-DYN of Abbott 3500 type whole bloods.
Blood biochemical is learned: 2 weekly checks before the administration, after 8 weeks and the drug withdrawal:
AST, ALT, Crea, BUN, U.S. CIBA-CORNING 550 automatic clinical chemistry analyzers, Japanese OLYMPUS AU 600 automatic clinical chemistry analyzers are measured.
System's postmortem, organ coefficient (heart, liver, spleen, lung, kidney, adrenal gland, brain, prostate, ovary, uterus, testis), histopathological examination comprise the heart, liver, spleen, lung, kidney, adrenal gland, thymus, thyroid, brain, stomach, uterus, testis (attached testis), prostate, ovary, nose, larynx, trachea, bronchus and esophagus.
Convalescent period observes: comprise general state and body weight, hematology, blood biochemical, organ coefficient and histopathological examination, method and index are the same.
Seven, statistical method:
New drug statistical software (NDST, 5.1 versions), Sun Ruiyuan etc., Wuhu three happy institute of Pharmaceutical Research.Statistical method is variance analysis and T check.
Eight, result of the test
General state and body weight:
During the administration, each dosage group rat physically well develops, and behavioral activity is normal, and hair color is smooth, tight, and diet is normal, and the feces character is no abnormal.Each is organized the rat body weight growth and all is directly proportional with the time, and the body weight gain of male rat is faster than female, meets the rule of its growth promoter; The body weight gain of each administration treated animal and matched group relatively there are no significant difference (table 3, table 4).The amount of drinking water of each administration group and food-intake and matched group be there was no significant difference (table 5) relatively.
In the process of the test, matched group has 1 animal after the 1st administration, and vehicle group has 4, and high dose group has 2 runny noses; Low dose group had 2 nostril mild hyperaemias on the 2nd day, and 1 nostril mild hyperaemia was arranged on the 6th day.High dose group respectively had 1 rat runny nose in 24 days, 33 days, 34 days behind medicine.Asthma, cough all do not appear in each dosage group and matched group, vehicle group, untoward reaction such as vomit, suffocate.
The hematology:
In 2 weeks after 8 weeks of administration and the drug withdrawal, three dosage groups of pharmaceutical composition of the present invention are to RBC number, and hemoglobin, platelet number average do not have obvious influence (seeing Table 6,7,10), and 8 all high dose group WBC are more lower slightly than matched group behind the medicine, but in normal range (table 8).Drug withdrawal 2 week, high and low dose group mononuclear cells in back were slightly higher than matched group, but with medicine after close during 8 weeks, all fluctuations (table 9) in normal range.
Haemobiochemistry:
In 2 weeks after 8 weeks of administration and the drug withdrawal, the Serum ALT of each dosage group, creatinine, blood urea nitrogen all fluctuate in normal range, relatively show no obvious abnormalities (seeing Table 12,13,14) with matched group.
Serum AST: behind the medicine 8 when week each dosage group with matched group than no significant difference; Each dosage group obviously descends after 2 weeks of drug withdrawal, but matched group also descends serum AST value (table 11) in normal range.
Organ coefficient:
The organ coefficient of the heart of each dosage group, liver, spleen, lung, kidney, adrenal gland, prostate, brain, ovary, uterus or testis 8 weeks behind medicine all do not have obvious change, with matched group there was no significant difference (P＞0.05).Convalescent period observes: each dosage group organ coefficient is not seen change (seeing Table 15).
Histopathology changes:
The heart of matched group and each dosage group, liver, spleen, lung, kidney, adrenal gland, thyroid, thymus, brain, stomach, uterus, testis (attached testis), ovary, nose, larynx, trachea, bronchus and esophagus become celestial normally substantially, and each organs and tissues of rat is learned inspection and do not seen pathological change (referring to pathological replacement and section photo).
Conclusion (of pressure testing):
Pharmaceutical composition of the present invention gives rat 0.45ml/kg/day, 0.9ml/kg/day, three 8 weeks of dosage successive administration of 1.8ml/kg/day, does not see that animal general state, body weight, hematology, blood biochemical, organ coefficient and histopathologic toxicity occur and changes.Minority animal runny nose that occurs in the process of the test and mild hyperaemia phenomenon because vehicle group and matched group all occur, consideration be in the administration process sample injector to due to the mechanical stimulus of animal, but not medicine factor.Asthma, cough all do not appear in each dosage group of duration of test and matched group, vehicle group, untoward reaction such as vomit, suffocate.Above-mentioned three dosage are not found the toxicity target organ and the sensitive indicator of pharmaceutical composition of the present invention, do not see the slowness toxicity of pharmaceutical composition of the present invention after 2 weeks of drug withdrawal yet.
Table 3 pharmaceutical composition of the present invention is to the influence of rat body weight
Each dosage group and matched group be P＞0.05 relatively
Table 4 pharmaceutical composition of the present invention is to the influence of different sexes rat body weight
Each dosage group and matched group be P＞0.05 relatively
Table 5 pharmaceutical composition of the present invention is to the influence of rats eating amount, amount of drinking water
Each dosage group and matched group be P＞0.05 relatively
Rat RBC number after the table 6 pharmaceutical composition administration of the present invention
Each dosage group and matched group be P＞0.05 relatively
Rat hemoglobin after the table 7 pharmaceutical composition administration of the present invention
Each dosage group and matched group be P＞0.05 relatively
Rat cell number after the table 8 pharmaceutical composition administration of the present invention
Each dosage group and matched group be P＞0.05 relatively
Rat leukocyte differential counting after the table 9 pharmaceutical composition administration of the present invention (X ± SD)
Each dosage group and matched group be P＜0.05 relatively
Rat serum plate number after the table 10 pharmaceutical composition administration of the present invention
Each dosage group and matched group be P＞0.05 relatively
Table 11 pharmaceutical composition administration of the present invention descendant Mus serum AST
Each dosage group and matched group be P＜0.05 relatively
Rat blood serum ALT after the table 12 pharmaceutical composition administration of the present invention
Each dosage group and matched group be P＞0.05 relatively
Rat blood serum creatinine (Cr) after the table 13 pharmaceutical composition administration of the present invention
Each dosage group and matched group be P＞0.05 relatively
Rat blood serum blood urea nitrogen (BUN) after the table 14 pharmaceutical composition administration of the present invention
Each dosage group and matched group be P＞0.05 relatively
Rats Organs and Tissues coefficient after the table 15 pharmaceutical composition administration of the present invention (%X ± SD)
| Group | Matched group | The excipient group | Low dose group 0.45ml/kg | Middle dosage group 0.9ml/kg | High dose group 1.8ml/kg |
| The heart | 8 all 10 weeks | 0.3108± 0.0272 0.3122± 0.0245 | 0.3182± 0.0246 0.2968± 0.0258 | 0.3015±0.0352 0.3027±0.0188 | 0.3022± 0.0202 0.2971± 0.0295 | 0.2995± 0.0205 0.2908± 0.0233 |
| Liver | 8 all 10 weeks | 2.6378± 0.2433 2.6651± 0.3484 | 2.6170± 0.2218 2.4211± 0.1305 | 2.5464±0.1835 2.4271±0.0525 | 2.5706± 0.1863 2.3392± 0.1463 | 2.4669± 0.1658 2.4269± 0.2039 |
| Spleen | 8 all 10 weeks | 0.2366± 0.0537 0.2312± 0.0687 | 0.2625± 0.0652 0.2356± 0.0471 | 0.2393±0.0711 0.2013±0.0365 | 0.2173± 0.0455 0.2107± 0.0519 | 0.2366± 0.0450 0.2072± 0.0322 |
| Lung | 8 all 10 weeks | 0.5616± 0.1861 0.4647± 0.0656 | 0.5293± 0.1425 0.5358± 0.1351 | 0.6758±0.2168 0.4523±0.0605 | 0.4857± 0.0558 0.5025± 0.0796 | 0.4713± 0.1154 0.5256± 0.1067 |
| Kidney | 8 all 10 weeks | 0.5826± 0.0413 0.5822± 0.0414 | 0.5919± 0.0435 0.5499± 0.0556 | 0.5885±0.0810 0.5575±0.0506 | 0.5737± 0.0265 0.5467± 0.0550 | 0.5672± 0.0445 0.5474± 0.0479 |
| The adrenal gland | 8 all 10 weeks | 0.0189± 0.0049 0.0186± 0.0076 | 0.0207± 0.0067 0.0206± 0.0068 | 0.0195±0.0044 0.0168±0.0062 | 0.0165± 0.0046 0.171±0.0056 | 0.0167± 0.0051 0.0158± 0.0058 |
| Prostate | 8 all 10 weeks | 0.4666± 0.1799 0.5384± 0.0556 | 0.6636± 0.0526 0.4333± 0.1368 | 0.5901±0.1095 0.5114±0.2108 | 0.5392± 0.0674 0.4242± 0.1500 | 0.6279± 0.0733 0.4550± 0.1415 |
| Testis | 8 all 10 weeks | 1.3570± 0.0945 1.2810± 0.1554 | 1.3747± 0.1844 1.2830± 0.1882 | 1.4943±0.2304 1.1725±0.0603 | 1.3786± 0.1378 1.3169± 0.1143 | 1.3312± 0.1884 1.1772± 0.1038 |
| The uterus | 8 all 10 weeks | 0.1794± 0.0473 0.2335± 0.0614 | 0.2052± 0.0577 0.2208± 0.0616 | 0.2176±0.0708 0.1956±0.0385 | 0.1593± 0.0544 0.2037± 0.0497 | 0.2112± 0.0510 0.2147± 0.0621 |
| Ovary | 8 all 10 weeks | 0.0501± 0.0036 0.0600± 0.0046 | 0.0606± 0.0238 0.0599± 0.0092 | 0.0600±0.0133 0.0658±0.0140 | 0.0557± 0.0077 0.0551± 0.0073 | 0.0587± 0.0127 0.0592± 0.0085 |
| Brain | 8 all 10 weeks | 0.6069± 0.0837 0.5316± 0.0958 | 0.6267± 0.1024 0.5707± 0.0988 | 0.6152±0.1208 0.5679±0.1122 | 0.6479± 0.1010 0.5891± 0.0964 | 0.6183± 0.1050 0.5686± 0.1021 |
Annotate: 1,2 weeks 2, uterus, ovary, testis, prostate: n=5 after 10 weeks=drug withdrawal
Conclusion (of pressure testing): pharmaceutical composition of the present invention is established 0.45ml/kg/day, 0.9ml/kg/day, 3 administration groups of 1.8ml/kg/day, establishes vehicle group and matched group simultaneously, 8 weeks of successive administration.As a result, during administration, each treated animal all movable normal, behavior is active, weight increase, feces no abnormality seen, none death of administration group rat, untoward reaction such as do not see asthma, cough, vomit, suffocate.After 8 weeks and 2 weeks of drug withdrawal hematology and blood biochemical are learned obviously influence of nothing behind each dosage group medicine; The internal organs of each dosage treated animal become celestial substantially, change is not seen by organ coefficient and histopathologic examination.The result shows that high, medium and low three dosage continuous 8 all administrations of medicine of the present invention do not have obvious influence to rat, no clear and definite toxicity target organ and sensitive indicator; Recover to observe and also do not see slowness toxicity.
[test example 3] pharmaceutical composition of the present invention is to Cavia porcellus toxicity and irritation test
One, test material
1, for the reagent thing: the spray that the embodiment of the invention 1 is prepared.
2, laboratory animal and raising condition:
40 of healthy adult Cavia porcelluss, male and female half and half are about body weight 250g.Provide the laboratory animal certification of fitness number by No.1 Military Medical Univ.'s Experimental Animal Center: Guangdong probatio inspectionem pecuoarem word 99A047 number.Tried preceding free diet of Cavia porcellus medicine and drinking-water.
Experiment is carried out at the regular grade Animal Lab. that air-conditioning and ventilation equipment are housed.
Two, method for preparation of drug
Will for the reagent thing join be 4 times clinical clinical in two kinds of concentration (2 times clinical clinically form by 4 times) with the dilution of concentration adding distil water with concentration with concentration and 2 times
Three, test grouping, dosage and route of administration:
1, test grouping: Cavia porcellus is divided into 4 groups, for reagent object height, low dose group, normal control group, vehicle group.
2, dosage: give 4 times and 2 times of clinical concentration medicines of using respectively for reagent object height, low dose group, normal control group and vehicle group then give isopyknic distilled water and excipient.
3, route of administration: select intranasal administration, consistent with the clinical application approach, every animal intranasal administration volume is 50 μ l/100g, an intranasal administration.
Four, test method
Animal via 1 week observe qualified back and is divided into 4 groups at random by body weight, sex, collunarium gives the thing that tried of variable concentrations respectively, takes suitable protective measure during administration, guarantees to be tried contacting of thing and nasal mucosa.Tight observe outward appearance sign after the animal subject administration, behavioral activity, the mental status, appetite, just large and small and character, by the variation of hair, the colour of skin, breathing, body weight change and local mucous membrane, put to death half Cavia porcellus behind the medicine in 24 hours and take out respiratory tract local mucous membrane structure observation, remainder is left to the 7th day, puts to death and does same the inspection.
Five, result of the test
Result of the test shows that outward appearance sign, the behavioral activity of respectively organizing Cavia porcellus during the administration are normal, the mental status, appetite and large and small just normal, do not seen variation by hair, the colour of skin etc., no asthma, cough, symptom such as vomit, suffocate, body weight do not have and alleviate (seeing Table 16), and nasal mucosa does not have hyperemia, red and swollen phenomenon.Put to death half Cavia porcellus after 24 hours, respectively tried respiratory tract local mucous membrane such as treated animal nose, larynx, trachea, bronchus and organize all normal.Remaining animal all survived in 7 days, and Cavia porcellus is respectively tried treated animal respiratory tract local mucous membrane and organizes naked eyes also to show no obvious abnormalities (table 17) through anatomic observation after 7 days.
The variation of Cavia porcellus body weight before and after the table 16 pharmaceutical composition administration of the present invention (X ± SD, N=10*)
| Dosage (ml/kg) | Before the administration | 24 hours | After the administration (7 days) | |
| The normal control group | The equal-volume distilled water | 258.4±15.9 | 257.0±16.1 | 259.4±18.9 |
| Vehicle group | The equal-volume excipient | 257.1±18.5 | 256.5±19.3 | 269.0±27.6 |
| High dose group | 2 | 253.2±11.9 | 249.6±16.2 | 260.8±22.0 |
| Low dose group | 1 | 254.9±20.3 | 254.2±20.0 | 257.8±34.0 |
Annotate: compare P＞0.05, * 7 days: N=5 with matched group.
Table 17 pharmaceutical composition toxicity of the present invention and irritation test result
Conclusion (of pressure testing):
After pharmaceutical composition of the present invention once gives (intranasal administration) Cavia porcellus, respectively tried the no abnormal reaction of treated animal, healthy survival, animal appearance sign, behavioral activity are normal, and the mental status, appetite are good, large and small just normal, do not seen variation by hair, the colour of skin etc., body weight no change, nasal mucosa do not have significant change, no asthma, cough, symptom such as vomit, suffocate are respectively tried respiratory tract local mucous membrane such as treated animal nose, larynx, trachea, bronchus and are organized perusal all normal.
For the clinical recommended drug amount of reagent thing is 0.4ml/60kg/ day, is equivalent to 0.007ml/kg/ day.The high and low dose of Cavia porcellus medication is respectively 2ml/kg, 1ml/kg in this test, then is equivalent to 286 times, 143 times of clinical application amount according to the weight.
Result of the test shows, pharmaceutical composition avirulence of the present invention, has no stimulation.
The pharmacodynamics test of [test example 5] pharmaceutical composition of the present invention
Supply the reagent thing:
The spray that the embodiment of the invention 1 is prepared is formulated as clinical practice concentration, 2 times of clinical practice concentration and three groups of 4 times of clinical practice concentration respectively, is numbered respectively for reagent thing I, II and III group.
Control drug:
Prescription removes the pharmaceutical composition of the present invention for preparing behind the ephedrine, lot number: 9904040, and Foshan Dezhong Pharmaceutical Co., Ltd. produces.
Ephedrine hydrochloride, Wenquan County, Xinjiang ephedrine factory product, lot number: 981109.
DITONG BIYAN SHUI, 10mL/ bottle, Guangdong Sanitary Material Factory product, lot number: 980801.
Chlorpheniramine maleate tablets, 4mg/ sheet, bridge pharmaceutical factory, city product, lot number: 930805.
Aspirin Enteric-coated Tablets, 50mg/ sheet, guilin pharmacy factory product, lot number: 990101.
Hydrocortisone, Yangzhou, Jiangsu pharmaceutical factory product, lot number: 990103.
Laboratory animal:
1) Kunming mouse, the quality certification number: 98A011; 2) SD rat, the quality certification number: 98A033 is provided by Department of Health of Guangdong Province's Experimental Animal Center.
Main agents:
Azo-Blue, Fluka import packing, lot number: 92-11-0
Dimethylbenzene, Guangzhou Chemical Reagent Factory product, lot number: 971001-22.
Carrageenin, U.S. Sigma company product, lot number: 127H1227.
Be dry yeast (bakery yeast), Chinese-foreign joint venture Mei Shan-Ma Li yeast company limited product, lot number: 005A, produce in January, 1999.
Key instrument
753BI microcomputer type ultraviolet-uisible spectrophotometer, the optical instrument factory, Shanghai makes.
AL-300 type electronic balance, U.S. Denver Instrument Company produces.
Electronic clinical thermometer, the DT-1TB type is produced by Shanghai Medical Instrument and Meter Factory.
One, the influence of histamine rhinitis rat nasal mucosa capillary permeability is tested
Get body weight and be the S.D rat about 250 grams, the male and female dual-purpose.Be divided into 9 groups by the randomly assigne under the equilibrium, 8～13/group.Test and respectively organized rat intranasal administration secondary (the chlorphenamine group is administered once) respectively the same day, 0.08mL/ (being equivalent to clinical once amount), 30min at interval.Blank and model control group are dripped the equivalent normal saline.30min behind the last intranasal administration, and usefulness pentobarbital sodium anesthetized rat (39mg/kg, ip), through vena femoralis injection 1.5% Azo-Blue 5mL/kg.Use 3 * 10 immediately then
-3Mol/L histamine collunarium, every side 50 μ L, the blank group is dripped the equivalent normal saline.Open breast behind the 5min, cut off right atrium, through left ventricle puncture aorta, with the normal saline perfusion, till the right atrium effluent changes clearly.Cut nasal cavity open through median sagittal plane, take off the whole nasal mucosas in respiratory region, be cut into small pieces, put into the test tube that covers that is added with the 5mL Methanamide after weighing, put 37 ℃ of incubators.The 48h after-filtration uses ultraviolet-uisible spectrophotometer in 620nm wavelength place colorimetric.Reference literature (Yang Pingchang etc., Chinese ear,nose ﹠ throat magazine, 1989,24 (6): 324) make the Azo-Blue working curve, and obtain regression equation.According to measured light density value (OD), can try to achieve Azo-Blue content in the nasal mucosa.The results are shown in Table 18.
Table 18 pair histamine rhinitis rat nasal mucosa capillary permeability influence test
Annotate: compare with model control group
*P＜0.01; Compare with 0.5% ephedrine hydrochloride group
☆P＜0.05,
☆ ☆P＜0.01.
#: be equivalent to content for reagent thing clinical practice concentration.
By table 18 as seen, each administration group all can obviously suppress the rhinitis that histamine causes oozes out, and the Azo-Blue amount that the rat nasal mucosa is oozed out obviously reduces, with model control group relatively, difference highly significant (P＜0.01).
The result shows, removing the pharmaceutical composition of the present invention (B) for preparing behind the ephedrine all has obvious inhibitory action for each group of reagent thing, ephedrine hydrochloride (A) and prescription to nasal mucosa capillary permeability increase due to the histamine.
Two, xylol causes the influence of mice auricle swelling
Get male mice in kunming, body weight: 20～24g is divided into 8 groups by the randomly assigne under the equilibrium, 10～13/group.Test and respectively organized the wide coating secondary (the aspirin group is administered once) of mouse right ear, 0.05mL/ time, interval 30min the same day.The blank group is coated with the equivalent normal saline.Behind the last coating 30min, each group is dried with dry cotton ball with distilled water flush away medicinal liquid.With dimethylbenzene 0.02mL/ only be coated with for the mouse right ear exterior feature, left ear compares.Putting to death animal after 15 minutes, with the card punch of diameter 8mm ears are downcut with the position homalographic, weigh with the electronic balance precision, is the swelling degree with the difference of left and right auricle weight.The results are shown in Table 19.
Table 19. xylol causes the influence of mice auricle swelling
Annotate: compare with the blank group
*P＜0.05,
*P＜0.01
By table 19 as seen, for reagent thing II group, for reagent thing III group, aspirin, DITONG BIYAN SHUI, xylol causes mice auricle swelling obvious inhibitory action, suppression ratio is respectively 42%, 48%, 51% and 66%, with blank group comparing difference highly significant, P＜0.05 or 0.01.All the other each groups also have certain inhibitory action to auricle edema, and suppression ratio is respectively 22%, 28% and 33%, but compare there was no significant difference with the blank group.
Three, on Carrageenan causes the influence of rat paw edema
Get male S.D rat, body weight: 180～220g is divided into 8 groups by the randomly assigne under the equilibrium, 10/group.(in June, 1991, P299 P304) measures and respectively to organize the right back sufficient normal volume of rat (mL) for Li Yikui, " herbal pharmacology experimental methodology " to press capillary tube measurement by magnification method before the experiment.The experiment same day, aspirin group gastric infusion, all the other each administration groups in the right back sufficient coating of rat once, the blank group is coated with the equivalent distilled water.After the administration 1 hour, in each group rat right back sufficient plantar subcutaneous injection 1% carrageenin 0.1mL, coating is once more simultaneously.Mensuration causes the right back sufficient volume of inflammation back 2h, 4h, 6h.So that sufficient volume difference is the swelling degree before and after scorching.The results are shown in Table 20.
Table 20 on Carrageenan causes the influence of rat paw edema
Annotate: compare with the blank group
*P＜0.05,
*P＜0.01.In " () " is suppression ratio (%)
By table 20 as seen, each administration group is to causing scorching back 2h, 4h, and the rat paw edema of 6h all has obvious inhibitory action, with blank group comparing difference highly significant (P＜0.01).It is the strongest to cause scorching back 4h for acting on of three dosage groups inhibition of reagent thing rat paw edema, and suppression ratio is respectively 52%, 58% and 65%.
Four, to the swollen influence that forms of rat granuloma
Get male S.D rat, body weight 145 ± 10g is divided into 8 groups at random, 9～12/group.
Under the anesthesia of 1% pentobarbital sodium, an osculum is cut at the place in rat hypogastric region ventrimeson, expands subcutaneous tissue with vascular forceps, respectively buries a sterilization cotton balls (weight is 10 ± 1mg, adds ampicillin 1mg/0.1mL, in case infect) at left and right sides groin, sews up then.Performing the operation began intraperitoneal injection the same day, and dosage is the 1mL/100g body weight.Blank group injection equivalent water for injection.Administration every day 1 time, continuous 7 days.Animal is put to death in dislocation in the 8th day, takes out the cotton balls granulation tissue, and rejects fatty tissue,, weighs after 1 hour in 80 ℃ of oven dryings, deducts cotton balls weight, is granuloma weight.Granuloma weight is represented with the mg/100g body weight, be the results are shown in Table 21.
The bullate influence of table 21. pair rat granuloma (X ± SD)
Annotate: compare with the blank group:
*P＜0.05, P＜0.01
*
#: be equivalent to the content in the pharmaceutical composition 2.6mL/kg dosage of the present invention.
By table 21 as seen, hydrocortisone group, confession reagent thing III group (5.2mL/kg) and DITONG BIYAN SHUI group swell to rat granuloma obvious inhibitory action, compare P＜0.01 or P＜0.05 with the blank group, its suppression ratio is respectively 37.09%, 22.62% and 13.98%.For reagent thing I group, for reagent thing II group (1.3mL/kg, 2.6mL/kg), prescription removes the pharmaceutical composition group of the present invention for preparing behind the ephedrine, the trend that the swollen effect of certain inhibition rat granuloma is also arranged, but compare there was no significant difference with the blank group, its suppression ratio is respectively 10.84%, 10.61% and 8.13%.The ephedrine hydrochloride group is to the swollen unrestraint effect of rat granuloma.Comprehensive above-mentioned experimental result shows that pharmaceutical composition of the present invention has effect and resist inflammation on repercussive function that obvious suppression histamine rhinitis rat nasal mucosa capillary permeability increases.
The choice criteria of clinical observation on the therapeutic effect of [test example 5] pharmaceutical composition of the present invention and safety testing one thereof, study subject
(1) acute rhinitis
1, diagnostic criteria
According to " the clinical research guideline of new Chinese medicine treatment cold nasal obstruction ", the diagnostic criteria of establishing this research is as follows:
1) local symptom (indispensability): nasal obstruction, watery nasal discharge (clear rare or thickness), sneeze, hyposmia.
2) General Symptoms: general malaises such as heating, headache, pharyngalgia, cough can be arranged.
3) check: nasal mucosa hyperemia, swelling, secretions increase.
4) course of disease is in 1 week.
2, Chinese medical discrimination standard
According to " the clinical research guideline of new Chinese medicine treatment cold nasal obstruction ", the dialectical standard that establishment acute rhinitis wind heat is accumulate pulmonary type is as follows:
1. rhinocnesmus, burning sensation, sneeze, nasal obstruction, nasal mucus is sticking yellow:
2. nasal cavity inspection: nasal mucosa hyperemia, swelling, the thick Huang of nasal secretion:
3. heating, micro evil wind, headache;
4. xerostomia is coughed, pharyngalgia, and expectorant is sticking;
5. red tongue, white and thin fur or BOHUANG;
6. floating and rapid pulse.
Below 1., 2. two indispensabilities, all the other four possess plural Sx and get final product.
3, include standard in
Meet above diagnostic criteria and Chinese medical discrimination standard, the morbidity 72 hours with interior person, include the test case in.
4, exclusion standard
1) age is below 10 years old or the over-65s person;
2) gestation or women breast-feeding their children, allergic constitution or to this medicine allergy sufferers;
3) specificity inflammation causers such as influenza, measles, scarlet fever, chickenpox;
4) merge patients such as tracheitis, bronchitis, sinusitis;
5) be associated with serious primary disease such as cardiovascular, cerebrovascular, liver, kidney and hemopoietic system and psychotic;
6) do not meet the standard of including in, not medication in accordance with regulations can't be judged curative effect, or data is not congruent affects the treatment or safety judgement person.
(2) chronic rhinitis
1, diagnostic criteria
According to the high medical college teaching material in the whole nation " otolaryngology " (the 4th edition), the disconnected standard of judgement of establishing this research is as follows:
1) regular nasal obstruction is intermittent, alternately property outbreak, night, flat when crouching or sitting quietly nasal obstruction increase the weight of, its downside nasal obstruction increases the weight of when lying on one's side.
2) often with symptoms such as watery nasal discharge, distending pain in the heads, or hyposmia.
3) check: the hyperemia of bilateral concha nasalis inferior, swelling, smooth surface, mucosa is soft and flexible, and is good to vasoconstrictor response.
4) course of disease is more than 1 month.
2, Chinese medical discrimination standard
Teach by correspondence teaching material " otorhinolaryngology of Chinese medicine " according to the high Chinese medicine in whole nation universities and colleges, the dialectical standard that establishment chronic rhinitis wind heat is accumulate pulmonary type is as follows:
1) with the passing of time nasal obstruction is intermittent or alternately property, outbreak repeatedly;
2) nasal cavity inspection: two concha nasalis inferior hyperemia, swelling, smooth surface, good to vasoconstrictor response;
3) nose Qiao Gan inflammation burning sensation, nasal mucus is sticking yellow;
4) xerostomia, cough expectorant Huang, pharyngalgia;
5) red tongue, white and thin fur or BOHUANG;
6) rapid pulse.
More than 1), 2) two indispensabilities, all the other four possess plural Sx and get final product.
3, include standard in
Meet above diagnostic criteria and Chinese medical discrimination standard person simultaneously, include the test case in.
4, exclusion standard
1) age is below 10 years old or the over-65s person;
2) gestation or women breast-feeding their children, allergic constitution or to this medicine allergy sufferers;
3) chronic hypertrophic rhinitis, hypertrophic inferior turbinate is to ephedrine poor response person;
4) merge patients such as tracheitis, bronchitis, sinusitis;
5) be associated with serious primary disease such as cardiovascular, cerebrovascular, liver, kidney and hemopoietic system and psychotic;
6) do not meet the standard of including in, not medication in accordance with regulations can't be judged curative effect, or data is not congruent affects the treatment or safety judgement person.
Two, test method
(1) random packet
Produce the random assortment card in advance, the proportion control that makes treatment group and matched group (respectively called after 1 group with 2 groups) was at 3: 1, and treatment is organized total routine number and is no less than 300 examples.Random card numbering back is sealed the envelope of packing into.The clinical research personnel press the simple randomization method and extract envelope by the sequencing that enters test, and the Kaifeng card taking is pressed the grouping of card regulation and carried out testing program.
(2) blind method contrast
To be repacked respectively for reagent thing (medicinal composition spray of the present invention) and positive control drug DITONG BIYAN SHUI by the pharmaceutical factory, and make its external form similar substantially, compiling respectively is I number and II number, and study subject is not known actual medicine content, and single blind method is implemented.
(3) Therapeutic Method
1, acute rhinitis
Treatment group (1 group): for the reagent thing: the spray that the embodiment of the invention 1 is prepared, compile and be I number;
Usage and consumption: spray into nasal cavity, press (every side) one time 1～2, every day 2～4 times, continuous 5 days.
Matched group (2 groups): positive control medicine: DITONG BIYAN SHUI (commercially available, Guangzhou Sanitary Materials Factory produce), compile and be II number; Usage and consumption: spray into nasal cavity, press (every side) one time 1～2, every day 2～4 times, continuous 5 days.
Viewing duration all no longer adds with other medicine or treatment means for two groups.
2, chronic rhinitis
Treatment group (1 group): for the reagent thing: the spray that the embodiment of the invention 1 is prepared, compile and be I number; Usage and consumption: spray into nasal cavity, press (every side) one time 1～2, every day 2～4 times, continuous 5 days.
Matched group (2 groups): positive control medicine: DITONG BIYAN SHUI, compile and be II number; Usage and consumption: spray into nasal cavity, press (every side) one time 1～2, every day 2～4 times, continuous 5 days.
Viewing duration all no longer adds with other medicine or treatment means for two groups.
(4) observation item and recording method
1, general data: name, sex, age, address, the course of disease etc.
2, cardinal symptom and sign: the record wind heat is accumulate the cardinal symptom and the sign of pulmonary type acute or chronic rhinitis, give blood, nasal mucosa swelling, nasal secretion etc. as nasal obstruction, watery nasal discharge, closed rhinolalia, hyposmia, rhinocnesmus, sneeze, heating, headache, xerostomia, nose burning sensation, pharyngalgia, cough, nasal mucosa, wherein the cardinal symptom of acute or chronic rhinitis such as nasal obstruction, watery nasal discharge, nasal mucosa hyperemia, nasal mucosa swelling, nasal secretion and sign adopt scoring method (standard of keeping the score sees Table 18～19), and whether all the other Sxs only write down appearance.
3, picture of the tongue and pulse condition: as practical writing record.
4, untoward reaction: record faithfully untoward reaction and treatment measures after the medication.
5, recording method:, respectively write down 1 time in 3 days, 5 days before medication and after the medication to acute rhinitis; To chronic rhinitis, before medication and medication after 2 weeks, respectively write down in 4 weeks 1 time.
Table 22 acute rhinitis cardinal symptom and the sign standard of keeping the score
Table 23 chronic rhinitis cardinal symptom and the sign standard of keeping the score
(5) curative effect judging standard
1, acute rhinitis
According to " the clinical research guideline of new Chinese medicine treatment cold nasal obstruction ", curative effect determinate standard is as follows:
Recovery from illness: sx in the medication 3 days, symptom and sign disappear in 5 days.
Produce effects: sx in the medication 3 days, 2/3 symptom and sign disappear in 5 days.
Effectively: sx in the medication 3 days, 1/3 symptom and sign disappear in 5 days.
Invalid: as not reach effective standard.
Chronic rhinitis
The ratio of the difference of 4 cardinal symptom integrations such as nasal obstruction, nasal mucosa hyperemia, nasal mucosa swelling, nasal secretion and the preceding total mark of treatment before and after the medication, and judge curative effect in conjunction with the disappearance situation of other symptom and sign, that is:
Produce effects: score value 〉=51%, all the other transference cures are more than 2/3;
Effectively: score value is 21～50%, and all the other transference cures are more than 1/3;
Invalid: score value≤20% whether (no matter all the other transference cures).
(6), statistical analysis
After observing end, all case histories input computers carry out data analysis with the SPSS statistical package and handle, and enumeration data adopts chi-square analysis, and two means relatively adopt the t check.
Overall merit is made in clinical efficacy and the safety thereof that pharmaceutical composition of the present invention (spray) is accumulate the pulmonary type acute or chronic rhinitis to wind heat at last.
(7), result of the test
One, physical data
This group case is respectively from three tame hals,Nasen und Ohrenheilkunde outpatients of hospital such as The First Affiliated Hospital of Guangzhou University of Traditional Chinese Med, first Affiliated Hospital of Zhongshan Medical Univ., Guangzhou institutes of traditional Chinese medicine, qualified acute rhinitis 130 examples, wherein 100 examples are organized in treatment, matched group 30 examples; Chronic rhinitis 260 examples, wherein 200 examples are organized in treatment, matched group 60 examples.
Two, comparability detects between the group
(1) acute rhinitis
1, age ratio
11～64 years old treatment group age, average 29.82 ± 11.09 years old (x ± s, down together); 14～60 years old matched group age, average 31.53 ± 12.12 years old.Two groups relatively, there was no significant difference (t=0.72, P＞0.2).Two groups of age distribution see Table 24.
Two groups of age distribution of table 24 acute rhinitis are (example) relatively
| Group | Total routine number | 10～20 years old | 21～30 years old | 31～40 years old | 41～50 years old | ＞50 years old | x 2 | The P value |
| Treatment group matched group | 100 30 | 17 3 | 45 15 | 21 6 | 11 2 | 6 4 | 2.92 | ＞0.2 |
2, sex ratio
Treatment is organized in 100 examples, and male's 61 examples account for 61%, and women's 39 examples account for 39%; In matched group 30 examples, male's 13 examples account for 43.3%, women's 17 examples, 56.7%.Two groups relatively, there was no significant difference (x
2=2.94, P＞0.05).
3, the course of disease relatively
Average 2.08 ± 0.75 days of the treatment group course of disease (x ± s, down together); Average 2.28 ± 0.78 days of the matched group course of disease, two groups relatively, there was no significant difference (t=1.27, P＞0.2).
4, severity extent relatively
1) cardinal symptom and sign integrated value are relatively
Treatment is organized in 100 examples, and the total mark value of 5 cardinal symptoms such as nasal obstruction, watery nasal discharge, nasal mucosa hyperemia, nasal mucosa swelling, nasal secretion and sign is 11.73 ± 2.76 (x ± s, down together); In matched group 30 examples, the total mark value of above-mentioned symptom and sign is 11.27 ± 2.83.Two groups relatively, there was no significant difference (t=0.8, P＞0.2).
2) symptom and sign number are relatively
Add up two groups and the number that symptom situation signs such as nasal obstruction, watery nasal discharge, hyposmia, closed rhinolalia, rhinocnesmus, sneeze, heating, headache, xerostomia, nose burning sensation, pharyngalgia, cough, nasal mucosa hyperemia, nasal mucosa swelling, nasal secretion occur occurs, the treatment group is 11.06 ± 2.5 (x ± s, down together); Matched group is 10.9 ± 2.78.Two groups relatively, there was no significant difference (t=0.3, P＞0.2).
5, the tongue pulse condition relatively
1) body of the tongue (seeing Table 25)
Two groups of body of the tongues of table 25 acute rhinitis are (example) relatively
2) tongue fur (seeing Table 26)
Two groups of tongue furs of table 26 acute rhinitis are (example) relatively
3) pulse condition (seeing Table 27)
Two groups of pulse conditions of table 27 acute rhinitis are (example) relatively
In sum, treatment group and matched group there are no significant at aspects such as age, sex, the course of disease, severity extent, tongue pulse conditions difference points out two groups to have comparability.
(2) chronic rhinitis
1, age ratio
15～65 years old treatment group age, average 34.99 ± 13.22 years old (x ± s, down together); 15～63 years old matched group age, average 35.13 ± 12.62 years old.Two groups relatively, there was no significant difference (t=0.07, P＞0.2).
Two groups of age distribution of table 28 chronic rhinitis are (example) relatively
2, sex ratio
Treatment is organized in 200 examples, and male's 108 examples account for 54%, and women's 92 examples account for 46%; In matched group 60 examples, male's 26 examples account for 43.3%, and women's 34 examples account for 56.7%.Two groups relatively, there was no significant difference (x
2=2.1, P＞0.1).
3, the course of disease relatively
Average 45.01 ± 48.92 months of the treatment group course of disease (x ± s, down together), average 34.7 ± 30.27 months of the matched group course of disease, two groups are relatively, there was no significant difference (t=1.54, P＞0.1).
4, severity extent relatively
1) cardinal symptom and sign are relatively
The cardinal symptom of chronic rhinitiss such as nasal obstruction, nasal mucosa hyperemia, nasal mucosa swelling, nasal secretion and the integrated value of sign appear in statistics, two groups of there are no significant differences (P＞0.1, table 29).
Preceding two groups of cardinal symptoms of table 29 chronic rhinitis medication and the comparison of sign integrated value (x ± s)
2) minor symptom relatively
Statistics chronic rhinitis wind heat is accumulate symptoms such as nose burning sensation, dizzy headache, hyposmia, xerostomia, cough, dry pharynx pain, expectorant that pulmonary type may occur is sticking, two groups occurrence rate there are no significant difference (P＞0.1, table 30).
The preceding two groups of minor symptom occurrence rates of table 30 chronic rhinitis treatment are (routine number) relatively
5, the tongue pulse condition relatively
In the 260 routine chronic rhinitiss, have 130 examples and write down tongue, pulse condition.
1) body of the tongue (seeing Table 31)
Table 31 130 routine chronic rhinitis body of the tongues are (example) relatively
2) tongue fur (seeing Table 32)
Table 32 130 routine chronic rhinitis tongue furs are (example) relatively
3) pulse condition (seeing Table 33)
Table 33 130 routine chronic rhinitis pulse conditions are (example) relatively
In sum, treatment group and matched group there are no significant at aspects such as age, sex, the course of disease, severity extent, tongue pulse conditions difference points out two groups to have comparability.
Three, curative effect relatively
(1) acute rhinitis
1, total effects relatively
Two groups of total effectses of table 34 acute rhinitis are [example (%)] * relatively
*x
2＝1.41，P＞0.05
Shown in table 34, treatment group obvious effective rate 37%, total effective rate 85%; Matched group obvious effective rate 26.7%, total effective rate 86.7%.Two groups relatively, and obvious effective rate and total effective rate there are no significant difference (P＞0.05) points out two general curative effects similar substantially.
2, cardinal symptom and sign improvement situation are relatively
Shown in table 35～39, before the treatment, the integrated value of treatment cardinal symptom such as nasal obstruction, watery nasal discharge, nasal mucosa hyperemia, nasal mucosa swelling, nasal secretion and sign after 3 days and 5 days, two groups of there are no significant differences (P＞0.05), point out two groups similar substantially to this this symptom to the improvement situation of sign.
Nasal obstruction integrated value comparison before and after the treatment of table 35 acute rhinitis (x ± s)
Watery nasal discharge integrated value comparison before and after the treatment of table 36 acute rhinitis (x ± s)
The congested integrated value comparison of nasal mucosa before and after the treatment of table 37 acute rhinitis (x ± s)
Nasal mucosa swelling integrated value comparison before and after the treatment of table 38 acute rhinitis (x ± s)
Nasal secretion integrated value comparison before and after the treatment of table 39 acute rhinitis (x ± s)
(2) chronic rhinitis
1, two groups of recent total effectses relatively
Two groups of total effectses of table 40 chronic rhinitis are [example (%)] * relatively
*x
2＝17.5，P＜0.005
Shown in table 40, treatment group obvious effective rate 50%, total effective rate 94%; Matched group obvious effective rate 25%, total effective rate 80%.Two groups relatively, and significant difference (P＜0.005) is arranged, and the total curative effect of prompting treatment group is better than matched group.
2, cardinal symptom and sign improvement situation are relatively
Integration difference with cardinal symptom or sign before and after the treatment is an index, the improvement that the improvement situation of two groups of cardinal symptoms and sign relatively, discovery treatment group increase nasal obstruction, nasal mucosa hyperemia, nasal mucosa swelling, nasal secretion is all than matched group obvious (P＜0.05 or 0.01=.The results are shown in Table 41.
Cardinal symptoms and the comparison of sign integral difference before and after two groups of treatments of table 41 chronic rhinitis (x ± s)
3, minor symptom improvement situation relatively
Add up the disappearance situation of less important symptoms such as two groups of treatment front and back nose burning sensations, dizzy headache, hyposmia, xerostomia, cough, dry pharynx pain, expectorant glue, find that treatment organizes the improvement of four symptoms such as correct confused pain, hyposmia, dry pharynx pain, expectorant be sticking than matched group obvious (P＜0.01=, two groups of the improvement situations of all the other symptoms similar substantially (table 42).
Two groups of minor symptom improvement of table 42 chronic rhinitis situation relatively
| Symptom | Group | The example number | Routine number disappears | Effective percentage (%) | x 2Value | The P value |
| The nose burning sensation | Treatment group matched group | 96 33 | 74 21 | 77.08％ 63.64％ | 2.29 | ＞0.1 |
| Dizzy, headache | Treatment group matched group | 121 30 | 108 19 | 89.26％ 63.33％ | 12.08 | ＜0.01 |
| Hyposmia | Treatment group matched group | 75 25 | 60 12 | 80.00％ 48.00％ | 9.52 | ＜0.01 |
| Xerostomia | Treatment group matched group | 104 28 | 81 24 | 77.88％ 85.71％ | 0.83 | ＞0.2 |
| Cough | Treatment group matched group | 48 9 | 40 7 | 83.33％ 77.78％ | 0.16 | ＞0.2 |
| The dry pharynx pain | Treatment group matched group | 84 29 | 70 15 | 83.33％ 51.72％ | 11.56 | ＜0.01 |
| Expectorant is sticking | Treatment group matched group | 125 24 | 100 12 | 80.00％ 50.00％ | 28.75 | ＜0.005 |
Four, untoward reaction
Treatment is organized in the 300 routine observation processes, malaise symptoms person 8 examples in various degree appear, incidence rate is 2.7%, all occur in the chronic rhinitis continuous use case in 4 weeks xeromycteria 6 examples wherein, intranasal excitement 1 example, pharyngeal dry 1 example, all after drug withdrawal, disappear, need not do special handling, do not have obvious sequela.In the matched group 90 routine observation processes, malaise symptoms person 3 examples in various degree occur, incidence rate is 3.3%, also all occur in the chronic rhinitis group, and xeromycteria 2 examples wherein, pharyngeal dry 1 example all need not drug withdrawal and processing.Learn by statistics and handle two groups of adverse reaction rate there was no significant difference (x
2=0.29, P＞0.2).
Conclusion (of pressure testing):
1, this research adopts single at random blind controlled trial method to observe 390 routine qualified study subjects altogether, and 300 examples are organized in medicine wherein of the present invention (spray) treatment, positive control medicine DITONG BIYAN SHUI matched group 90 examples.The comparability testing result shows, two groups at aspects such as age, sex, the course of disease, severity extent, tongue pulse conditions there are no significant difference (P＞0.05), point out two groups to have comparability.
2, general curative effect statistical result shows: wind heat is accumulate the pulmonary type acute rhinitis, and medicine of the present invention (spray) treatment group obvious effective rate is 37%, and total effective rate is 85%: DITONG BIYAN SHUI matched group obvious effective rate is 26.7%, and total effective rate is 86.7%.Two groups are relatively, obvious effective rate and total effective rate there are no significant difference (P＞0.5), and the prompting curative is with to contrast the medicine general curative effect similar substantially.Wind heat is accumulate the pulmonary type chronic rhinitis, and medicine of the present invention (spray) treatment group obvious effective rate is 50%, and total effective rate is 94%; DITONG BIYAN SHUI matched group obvious effective rate is 25%, and total effective rate is 80%.Two groups relatively, and significant difference (P＜0.005) is arranged, and the total curative effect of prompting treatment group is better than matched group.
3, the improvement situation of cardinal symptom and sign relatively, to acute rhinitis, treatment group and matched group there are no significant aspect the improving of the cardinal symptom of acute rhinitises such as nasal obstruction, watery nasal discharge, nasal mucosa hyperemia, nasal mucosa swelling, nasal secretion and sign difference (P＞0.05), the prompting curative is roughly the same to the improvement effect of these symptoms and sign with the contrast medicine.To chronic rhinitis, the treatment group to the improvement of less important symptoms such as cardinal symptoms such as nasal obstruction, nasal mucosa hyperemia, nasal mucosa swelling, nasal secretion increase and sign and dizzy headache, hyposmia, dry pharynx pain, expectorant is sticking all than matched group obvious (P＜0.05 or 0.01).
4, untoward reaction is observed and to be shown: medicine of the present invention (spray) treatment group has 2.7% patient in various degree malaise symptoms to occur in the continuous use process, xeromycteria 6 examples wherein, intranasal excitement 1 example, pharyngeal dry 1 example, all after drug withdrawal, disappear, need not do special handling, not have obvious sequela.The DITONG BIYAN SHUI matched group also has 3.3% patient in various degree malaise symptoms to occur in the continuous use process, xeromycteria 2 examples wherein, and pharyngeal dry 1 example all need not drug withdrawal and processing.Learn by statistics and handle, two groups of adverse reaction rate there was no significant differences (P＞0.2) are pointed out this untoward reaction to differ and are decided to be due to the medicine itself.Because this untoward reaction degree is lighter, can disappear after the drug withdrawal, therefore, it generally is safe using this medicine.
Comprehensive above result of the test shows that pharmaceutical composition of the present invention accumulates the pulmonary type acute or chronic rhinitis to wind heat and all has significant clinical efficacy, and clinical drug safety.
Claims (9)
1. pharmaceutical composition that is used for the treatment of acute or chronic rhinitis is characterized in that being made by following raw medicaments in portion by weight:
7 parts～60 parts of 1.7 parts～15 parts baicalins of ephedrine hydrochloride
0.7 part～6 parts of 0.3 part～3 parts Flos Magnoliae oil of Borneolum Syntheticum
100 parts～900 parts of Flos Loniceraes.
2. according to the described pharmaceutical composition of claim 1, it is characterized in that: the weight portion of each crude drug is:
10 parts～40 parts of 2.5 parts～10 parts baicalins of ephedrine hydrochloride
1 part～4 parts of 0.5 part～2 parts Flos Magnoliae oil of Borneolum Syntheticum
150 parts～600 parts of Flos Loniceraes.
3. according to the described pharmaceutical composition of claim 2, it is characterized in that: the weight portion of each crude drug is:
20 parts of 5 parts of baicalins of ephedrine hydrochloride
2 parts of 1 part of Flos Magnoliae oil of Borneolum Syntheticum
300 parts of Flos Loniceraes.
4. prepare the method for arbitrary described pharmaceutical composition of claim 1～3, step is as follows:
(1) takes by weighing each crude drug by weight;
(2) baicalin is added stir evenly behind the water and add sodium hydroxide solution again and make its dissolving, it is standby to regulate pH value to 6.5～8.5 backs;
(3) Flos Lonicerae is used water extraction, extracting solution is purified, refinement treatment gets refined solution or dry extract is standby;
(4) it is standby after ephedrine hydrochloride is dissolved in water;
(5) Borneolum Syntheticum, Flos Magnoliae oil are added after with dissolve with ethanol after Tween-80 stirs evenly, be mixed together, stir evenly with baicalin solution, Flos Lonicerae refined solution or Getrocknete Blumen extract powder and the ephedrine hydrochloride solution of above-mentioned steps gained, add adjuvant and make the preparation intermediate, make preparation through preparations shaping technology again, promptly.
5. according to claim 1,2 or 3 described arbitrary pharmaceutical compositions, it is characterized in that making any acceptable clinically suitable formulations by this area conventional formulation method.
6. according to the described pharmaceutical composition of claim 5, it is characterized in that: described pharmaceutical preparation is tablet, capsule, granule, powder, pill, oral liquid, syrup, liquid nasal formulations, ointment or emplastrum.
7. according to the described pharmaceutical composition of claim 6, it is characterized in that: described pharmaceutical preparation is the liquid nasal formulations.
8. according to the described pharmaceutical composition of claim 7, it is characterized in that: described liquid nasal formulations is nasal drop, aerosol or spray.
9. any one described pharmaceutical composition of claim 1-3 is preparing the purposes for the treatment of in the acute or chronic rhinitis medicine.
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| CN103735496B (en) * | 2014-02-14 | 2015-08-05 | 孙迎东 | Compound collunarium gel for the treatment of of allergic rhinitis disease and preparation method thereof |
| CN105434944A (en) * | 2015-12-22 | 2016-03-30 | 青岛海之源智能技术有限公司 | Ephedrine hydrochloride compound capsule and preparation method thereof |
| CN110917271A (en) * | 2019-11-25 | 2020-03-27 | 垒途智能教科技术研究院江苏有限公司 | Spray for preventing and treating allergic asthma combined allergic rhinitis of children and teenagers |
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