CN1194690C - Composition for treating bronchial asthma and allergic rhinitis - Google Patents
Composition for treating bronchial asthma and allergic rhinitis Download PDFInfo
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- CN1194690C CN1194690C CNB021001936A CN02100193A CN1194690C CN 1194690 C CN1194690 C CN 1194690C CN B021001936 A CNB021001936 A CN B021001936A CN 02100193 A CN02100193 A CN 02100193A CN 1194690 C CN1194690 C CN 1194690C
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- anisodine
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- procaine hydrochloride
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Abstract
The present invention relates to a compound for treating bronchial asthma and allergic rhinitis, which comprises a cholinergic receptor antagonist and procaine hydrochloride or lidocaine, wherein the weight proportion of the cholinergic receptor antagonist to the procaine hydrochloride or the lidocaine is 1:2 to 500, and the preferred proportion is 1:40 to 100; the preferred cholinergic receptor antagonist is anisodine and salts thereof or anisodamine. The compound performs the strong function of relieving asthma, and can reduce side effects such as dry mouth, etc.
Description
Invention field
The present invention relates to a kind of medicine for the treatment of bronchial asthma and allergic rhinitis, is a kind of complex that contains cholinoceptor antagonist such as Anisodine and local anaesthetics thing such as procaine for the treatment of bronchial asthma and allergic rhinitis specifically.
Background technology
The cholinoceptor antagonist also claims anticholinergic agent, is used for the treatment of the history of the existing last 100 years of bronchial asthma clinically, after 1930's, because aminophylline and β
2The appearance in succession of-receptor stimulating agent has replaced the treatment status of cholinoceptor antagonist in bronchial asthma gradually.Over nearly 20 years,, recognize that gradually cholinergic nerve system may have important function in regulating the airway pressure function along with to the attention of cholinergic nerve system in the asthma pathogenesis.Ward etc. (1981) use atomizing to suck the critical type asthma patient of ipratropium bromide (Atem) treatment and obtain after the better curative effect, and many researchs have confirmed in succession that further Atem has comparatively unique curative effect in critical type asthma of treatment and chronic obstructive pulmonary disease.Particularly, make the cholinoceptor antagonist in the evaluation of clinical curative effect of improving asthma patient airway pressure obstacle, obtain again certainly along with the exploitation of compound formulations such as Combivent aerosol.(globalinitiative for asthma spells out in GINA), when asthma in acute attack, is using glucocorticoid and fugitive β in GINA
2Also can use the cholinoceptor antagonist in the time of-receptor stimulating agent (consults the Kai Shengzhu of the Li Minghua Yin Dynasty and fastens upright chief editor, asthma, Beijing: People's Health Publisher, 1998.11; Wang Shan pool leaf sunlight a kind of reed mentioned in ancient books, the status of cholinergic m receptor antagonist in treating asthma, new drug and clinical, 1995,14 (3): 161-4).
The traditional cholinoceptor antagonist (comprising scopolamine, 654-2, Flos Daturae and stramonium etc.) that with the atropine is representative has certain diastole effect to bronchial smooth muscle, illustrates that this class medicine has certain curative effect to bronchial asthma.The seventies, once there was the report of widely applying cholinergic nerve receptor antagonist treatment bronchial asthma in China, had all obtained sure curative effect, particularly to using theophylline class or β
2The patient of-receptor stimulating agent class poor effect often still can obtain better curative effect.What used at that time mainly is preparation based on scopolamine.Because these medicines often have certain side effect, particularly because its inhibition respiratory tract glandular secretion makes thick sputum increase the weight of that respiratory tract obstruction, dosage are excessive also can to produce platycoria, xerostomia, urine retention and to M
2The blocking-up of receptor suppressed side effect such as negative feedback adjusting make its application be restricted (Qian Yongwei, cholinergic nerve blocker be in the clinical practice of bronchial asthma, hyoscyami class medicine Clinical advances seminar compilation of data, 1979.6, p92-4).
Chen Baojian is in " clinical practice of Anisodine ", hyoscyami class Clinical advances seminar compilation of data, 1979.6, reported PLA's the 38th hospital application Anisodine treatment chronic tracheitis among the p140-6, article is pointed out, clinical observation, and the more patient's effect of type expectoration amount is remarkable to pant.Anisodine is an alkaloid that is separated to from Tang Gute Radix Anisodi Tangutici plant, is the medicine that China at first separates experimentize research and recommendation clinical practice.Its toxic and side effects significantly is lower than scopolamine, Anisodamine and atropine.The inventor is by the therapeutic test to Cavia porcellus medicine bronchospasm model, find that Anisodine is injected, oral medication all can be obtained the effect of well relievining asthma, so carried out clinic trial, the result is satisfactory, but, the patient's reflection that has occurs because the xerostomia discomfort that the glandular secretion inhibition causes when dosage is bigger than normal.Song Chen is in " compound anisodine is in the application of clinical ophthalmology ", medical officer's people magazine, and 1978, reported among the 12:44.6 that PLA General Hospital uses the problem that has solved xerostomia in the compound anisodine treatment ophthalmic diseases.The present invention adopts the complex of Anisodine or Anisodamine and procaine hydrochloride to carry out zoopery, and the treatment of asthma effect is had enhanced effect, has solved the side effect of xerostomia simultaneously.
Summary of the invention
Therefore, the purpose of this invention is to provide the medicine of a kind of effective treatment bronchial asthma and allergic rhinitis, it comprises cholinoceptor antagonist and procaine hydrochloride, and the weight ratio of the two is 1: 2～500, preferred 1: 40～100.
Wherein the cholinoceptor antagonist comprises Anisodine and salt thereof such as Anisodine hydrobromide, Anisodamine (comprising 654-2), scopolamine etc.Wherein Anisodine hydrobromide is preferred.Medicinal composition of the present invention can also contain other composition, as carrier, diluent, common additives, pH regulator agent etc.
In addition, procaine hydrochloride also can replace with lignocaine.
According to conventional method, complex of the present invention can be made the dosage form that is suitable for clinical use, as tablet, capsule, slow releasing tablet, injection etc.
The dosage range of medicine of the present invention can be this two classes medicine dosage range commonly used clinically, for example the daily dose scope of Anisodine hydrobromide is 1～10mg/60kg, about preferred 3mg/60kg, the daily dose scope of procaine hydrochloride is-1000mg/60kg in.
Below in conjunction with embodiment the present invention is described, but these embodiment only are used for illustrative purposes, do not limit the scope of the invention.
Embodiment
Embodiment 1
Anisodine hydrobromide 100mg, procaine hydrochloride 7800mg, cellulose 63500mg and lactose 26200mg uniform mixing, magnesium stearate 2400mg adds in the above mixture, mixes granulate and make 100 tablet by the conventional film-making technology of this area.
Embodiment 2
According to embodiment 1 identical operation sequence, just replace Anisodine hydrobromide with the 100mg Anisodamine.
Embodiment 3
Anisodine hydrobromide 10mg, procaine hydrochloride 1000mg, lactose 1450mg, 40mg magnesium stearate mix homogeneously incapsulates, and makes 10 capsules.
Embodiment 4
With embodiment 3, just replace Anisodine hydrobromide with Anisodamine.
Embodiment 5
Anisodine hydrobromide 10mg and procaine hydrochloride 500mg mix, and add normal saline to 1000ml, make injection.
Embodiment 6
With embodiment 5, just replace Anisodine hydrobromide with Anisodamine.
Pharmacology and clinical trial
Compound anisodine (Anisodine+procaine hydrochloride, down together) is to the therapeutic test of Cavia porcellus drug-induced asthma
1, test objective: observe the compound anisodine oral administration and whether can prolong the incubation period that histamine-acetylcholine brings out Cavia porcellus asthma, thereby judge whether said preparation has (bronchiectasis) effect of relievining asthma.
2, materials and methods:
Test sample: compound anisodine capsule, content are white particle, and the main pharmacodynamics composition is an Anisodine hydrobromide, lot number: 20010102, and the people tries out dosage 3.4mg/kg.Face with preceding and grind to form suspension with 0.5% sodium carboxymethyl cellulose.
Reagent and equipment: histamine phosphate, the beautiful pearl east wind in Shanghai Bioisystech Co., Ltd produces, lot number: 0006058.Acecoline, Military Medical Science Institute medical supply station produces, lot number: 980908.Yadu YC-Y800 type medical vaporizer.26.4L exsiccator.
Laboratory animal and raising: regular grade Hartley Cavia porcellus, body weight 150～200g, male and female half and half.Available from Haidian District Beijing laboratory animal plant.The zoopery environment is a secondary, the quality certification: D98006.
Test method: Cavia porcellus is put into exsiccator, spray into 2% acecoline and the 0.1% isometric(al) mixed liquor 20s of histamine phosphate with nebulizer.After spraying stops, observing the number of animals that drawing of Cavia porcellus breathe heavily incubation period (beginning to dyspnea, time of twitching and falling from spraying) and tic takes place.Cavia porcellus is drawn and breathes heavily before experiment, 1h draws once more and breathes heavily after administration next day, draw the number of animals of breathing heavily incubation period and taking place to twitch before and after observing medication, drawing of asthma animal do not take place more than the 6min after the medication breathes heavily incubation period and calculates by 6min, the result draws after with each experimental group medication and breathes heavily prolongation of latency value and blank group relatively, statistical method: T check.
Grouping and administration: 40 of Cavia porcelluss, body weight: 198.1 ± 20.1g divides 5 groups at random, and 8 every group, male and female half and half.Be made as large, medium and small three the dosage groups of blank group, positive controls and compound anisodine respectively, wherein:
Blank: 0.5% sodium carboxymethyl cellulose, administration volume: 0.2ml/100g.
Positive control: aminophylline, 0.1g/kg, administration volume: 0.2ml/100g.
30.6,20.4,10.2mg/kg dosage is provided with: the large, medium and small dosage of compound anisodine is respectively:, isoconcentration does not wait the capacity administration, and heavy dose of to organize the administration volume be 0.2ml/100g, drug level 0.153%.
Route of administration: irritate stomach.
3, result of the test:
By table 1 as seen, the asthma attack incubation period of the equal significant prolongation Cavia porcellus of aminophylline and compound anisodine.Compound anisodine has certain dose-effect relationship in the test dose scope, when dosage is 10.2mg/kg, draw the trend that prolongation is arranged incubation period of breathing heavily, still do not reach degree as yet with blank group significant difference, dosage be 20.4 and the effect of relievining asthma during 30.6mg/kg remarkable, but individual variation is bigger.
Table 1 compound anisodine draws the Cavia porcellus medicine breathes heavily preclinical influence (n=8)
| Group | Dosage (mg/kg) | Draw and breathe heavily incubation period (s) | Prolongation value (s) | |
| Before the administration | After the administration | |||
| Dosage compound anisodine heavy dose in the low dose of compound anisodine of blank group aminophylline compound anisodine | - 100 10.2 20.4 30.6 | 41.86±7.93 46.92±5.19 46.37±9.16 46.86±8.46 48.29±6.41 | 44.85±8.70 162.52±37.25 67.92±30.33 168.56±91.23 311.46±158.43 | 2.99±7.12 115.56±36.33 ** 21.55±28.59 121.68±95.98 * 263.17±159.12 ** |
Annotate: * * p＜0.01.
Table 2 medicine draws the back Cavia porcellus situation (n=8) of falling of twitching of breathing heavily
| Group | Dosage (mg/kg) | The number of animals of falling (only) | |
| Before the administration | After the administration | ||
| Dosage compound anisodine heavy dose in the low dose of compound anisodine of blank group aminophylline compound anisodine | - 100 10.2 20.4 30.6 | 8 8 8 8 8 | 8 7 8 6 2 |
4, brief summary
Compound anisodine has relieving asthma (bronchiectasis) to act on to Cavia porcellus in 10.2～30.6mg/kg dosage range, and is certain dose-effect relationship.Dosage be 20.4 and the effect of relievining asthma during 30.6mg/kg obvious, still, certain individual variation is arranged.
The compound anisodine side of tearing open pharmacodynamics test
One Anisodine hydrobromide, procaine hydrochloride and compound anisodine are to the synchronous therapeutic test of Cavia porcellus drug-induced asthma
1, test objective: observe Anisodine hydrobromide, procaine hydrochloride and compound anisodine oral administration and whether can prolong the incubation period that histamine-acetylcholine brings out Cavia porcellus asthma, the therapeutic effect of three kinds of medicines relatively, thus judge that Anisodine hydrobromide, procaine hydrochloride form the pharmacodynamic change behind the compound anisodine.
2, materials and methods:
Test sample: Anisodine hydrobromide (AN), Chengdu, Sichuan pharmaceutical factory produces, lot number: 891001.Procaine hydrochloride (PR), Nanjing Pharmaceutical Plant produces, lot number: 970701.Compound anisodine (CA) is formed in 1: 50 ratio with AN and PR.All test samples are facing with before being mixed with normal saline solution.
Reagent and equipment: histamine phosphate, the beautiful pearl east wind in Shanghai Bioisystech Co., Ltd produces, lot number: 0006058.Acecoline, Military Medical Science Institute medical supply station produces, lot number: 980908.Yadu YC-Y800 type medical vaporizer.26.4L exsiccator.
Laboratory animal and raising: regular grade Hartley Cavia porcellus, available from Haidian District Beijing laboratory animal plant.The zoopery environment is a secondary, the quality certification: D98006.
Test method: Cavia porcellus is put into exsiccator, spray into 2% acecoline and the 0.1% isometric(al) mixed liquor 20s of histamine phosphate with nebulizer.After spraying stops, observing the number of animals that drawing of Cavia porcellus breathe heavily incubation period (beginning to dyspnea, time of twitching and falling from spraying) and tic takes place.Cavia porcellus is drawn and breathes heavily before experiment, 1h draws once more and breathes heavily after administration next day, draw the number of animals of breathing heavily incubation period and taking place to twitch before and after observing medication, drawing of asthma animal do not take place more than the 6min after the medication breathes heavily incubation period and calculates by 6min, the result draws after with the medication of AN and PR group and breathes heavily prolongation of latency value and CA group relatively, and statistical method: T checks.
Grouping and administration: 24 of Cavia porcelluss, body weight: 154.5 ± 19.9g divides 3 groups at random, and 8 every group, male and female half and half.Be made as AN, PR and CA group respectively.Dosage:
AN: calculate that with human dosage 3mg/60kg dose,equivalent is 0.36mg/kg.Computed path-build Y-factor method Y: d
B=d
A* R
B/ R
A* (W
A/ W
B)
1/3=3/60 * 99/100 * (60/0.1545)
1/3=0.36mg/kg, administration volume: 0.9ml/kg.
PR: in PR: AN=50: 1 ratio is 18mg/kg, administration volume: 0.9ml/kg.
CA:AN+PR=0.36mg/kg+18mg/kg=18.36mg/kg, administration volume: 1.8ml/kg.
Route of administration: irritate stomach.
3, result of the test:
Animal is drawn to breathe heavily and dyspnea all occurs, fall before and after the administration, by table 3 as seen, but AN and CA equal asthma attack incubation period of prolonged guinea pig, and PR does not show therapeutic effect.The drawing of CA group breathes heavily prolongation of latency value and AN group and PR and organizes and compare that all there were significant differences, and this shows that AN and CA all have therapeutical effect to Cavia porcellus medicine bronchospasm, and CA is better than AN and PR uses separately.
Table 3.AN, PR and CA draw the Cavia porcellus medicine and breathe heavily preclinical influence (n=8)
| Group | Dosage (mg/kg) | Draw and breathe heavily incubation period (s) | Prolongation value (s) | |
| Before the administration | After the administration | |||
| AN PR CA | 0.36 18 18.36 | 55.08±10.08 54.07±4.99 55.91±6.78 | 66.67±20.40 54.92±5.74 80.36±20.82 | 11.59±12.73 0.85±6.22 24.45±14.17 *## |
Annotate: * and AN group be p＜0.05 relatively; ## and PR group be p＜0.01 relatively.
4, brief summary
AN, PR and CA dosage be respectively 0.36,18 and synchronous therapeutic test during 18.36mg/kg show that AN and CA have (bronchiectasis) effect of relievining asthma to Cavia porcellus, PR does not show therapeutic effect.The therapeutic effect of the CA that is made up of AN and PR is better than AN and PR uses separately.
The acute toxicity test of mice oral administered compound Anisodine
1, test objective: observe acute toxic reaction and the death condition of an orally give mice of test sample, and calculate LD
50Dosage.
2, materials and methods:
Test sample: compound anisodine capsule, content are white particle, and the main pharmacodynamics composition is an Anisodine hydrobromide, lot number: 20010102, and the people tries out dosage 3.4mg/kg.Face with preceding and grind to form suspension with 0.5% sodium carboxymethyl cellulose.
Laboratory animal and raising: regular grade KM mice, body weight 18～22g, available from Military Medical Science Institute's animal center, the quality certification: BDW95007, zoopery environment are secondary, the quality certification: D98006.
Test method:
Trial test: 20 of mices, male and female half and half, fasting is after 12 hours, and the test sample of orally give variable concentrations tentatively obtains the full dosage 1224mg/kg that lives, complete extremely dosage 2856mg/kg.
Test: according to the trial test result, set agent apart from and 5 dosage groups, behind mice fasting 12h, give the test sample of 0.8ml variable concentrations respectively, observe 7 days continuously after, put to death surviving animals, and carry out the gross anatomy inspection.
Every treated animal number: 10, male and female half and half.
2856.0,2284.8,1827.8,1462.3,1169.8mg/kg dosage is provided with:.
Observation index: general clinical observation, death condition and gross anatomy, and calculate LD
50Dosage.
3, result of the test:
General clinical observation: instability of gait appears in high dose group mice 2～3min after administration, twitches immediately, jumps, very fast death.Depressed, the movable minimizing of slight spirit appears in low dose group animal 2～3min after administration, and recovers normal behind 5～6min.Most of dead animal betides after the administration in the 10min, and only 2 animals are in dead about 10h after the administration.Surviving animals is the clinical manifestation no abnormality seen during to off-test.
Dissect to check: be poisoned to death and the heart, lung, liver,spleen,kidney and the gastrointestinal tract of surviving animals show no obvious abnormalities.
LD
50Dosage: see Table 4.
Table 4 mice oral administered compound Anisodine The acute toxicity tests
Dosage number of animals dead animal is counted mortality rate
(mg/kg) (only) (only) (%)
2856.0 10 9 90
2284.8 10 7 70
1827.8 10 3 30
1462.3 10 1 10
1169.8 10 0 0
LD
50(95% fiducial limit)=2043.38 (1813.32～2273.44) mg/kg.
4, brief summary:
The acute toxic reaction of mice oral administered compound Anisodine mainly shows as depressed, instability of gait of spirit and tic, occurs that poisoning symptom is fast, the persistent period short, the dead or rapid recovery of final result.Because this medicine main pharmacodynamics composition is an Anisodine hydrobromide, therefore, infer that the said preparation oral absorption is fast, metabolism is also fast, acute toxic reaction is mainly the performance that the central nervous system poisons.LD
50(95% fiducial limit) dosage is 2043.38 (1813.32～2273.44) mg/kg, is 600 times of people's clinic trial dosage approximately.
By above test as can be known, the compound anisodine of being made up of cholinoceptor antagonist Anisodine hydrobromide and procaine hydrochloride has good antiasthmatic effect and the therapeutical effect that is better than using separately Anisodine hydrobromide.
Claims (6)
1, a kind of medicine that is used for the treatment of bronchial asthma is characterized in that it is made up of cholinoceptor antagonist and procaine hydrochloride and suitable carrier; Wherein said cholinoceptor antagonist is selected from Anisodine or its salt or Anisodamine or its salt, and the weight ratio of cholinoceptor antagonist and procaine hydrochloride is 1: 40～100.
2, according to the medicine of claim 1, wherein the cholinoceptor antagonist is an Anisodine hydrobromide.
3, according to the medicine of claim 1, wherein the cholinoceptor antagonist is an Anisodamine.
4, cholinoceptor antagonist and the procaine hydrochloride complex purposes in the medicine of preparation treatment bronchial asthma, wherein said cholinoceptor antagonist is selected from Anisodine or its salt or Anisodamine or its salt, and the weight ratio of cholinoceptor antagonist and procaine hydrochloride is 1: 40～100.
5, according to the purposes of claim 4, wherein the cholinoceptor antagonist is Anisodine hydrobromide or Anisodamine.
6, the method for preparing the described medicine of claim 1, comprise cholinoceptor antagonist and procaine hydrochloride and suitable carrier mix homogeneously, make tablet, wherein said cholinoceptor antagonist is selected from Anisodine or its salt or Anisodamine or its salt.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB021001936A CN1194690C (en) | 2002-01-22 | 2002-01-22 | Composition for treating bronchial asthma and allergic rhinitis |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB021001936A CN1194690C (en) | 2002-01-22 | 2002-01-22 | Composition for treating bronchial asthma and allergic rhinitis |
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| Publication Number | Publication Date |
|---|---|
| CN1365666A CN1365666A (en) | 2002-08-28 |
| CN1194690C true CN1194690C (en) | 2005-03-30 |
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|---|---|---|---|
| CNB021001936A Expired - Fee Related CN1194690C (en) | 2002-01-22 | 2002-01-22 | Composition for treating bronchial asthma and allergic rhinitis |
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|---|---|
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