CN101474191B - Pharmaceutical composition for treating asthma and chronic obstructive pulmonary disease - Google Patents

Pharmaceutical composition for treating asthma and chronic obstructive pulmonary disease Download PDF

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Publication number
CN101474191B
CN101474191B CN2009100009109A CN200910000910A CN101474191B CN 101474191 B CN101474191 B CN 101474191B CN 2009100009109 A CN2009100009109 A CN 2009100009109A CN 200910000910 A CN200910000910 A CN 200910000910A CN 101474191 B CN101474191 B CN 101474191B
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ciclesonide
teluo
indenes
spray
pharmaceutical composition
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CN101474191A (en
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李虎山
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WEIFANG ZHONGSHI PHARMACEUTICAL CO Ltd
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Abstract

The invention discloses a pharmaceutical composition for treating asthma and chronic obstructive pulmonary diseases (COPD) which contains the following mixed substances: a first active ingredient indacaterol, or pharmaceutically acceptable salt or solvate thereof, or solvate of the salt; and a second active ingredient ciclesonide; wherein, the mol ratio of the first active ingredient to the second active ingredient is 1:15 to 10:1. The composition is applied to treating asthma, chronic obstructive pulmonary diseases, etc. When the lung function is compared with a base value, the ciclesonide and the indacaterol after being combined to treat has more obvious curative effect than any one to treat. The composition is convenient to take, improves compliance of patients, and obviously improves life quality of patients.

Description

A kind of pharmaceutical composition for the treatment of asthma and chronic obstructive pulmonary disease
Technical field
The present invention relates to field of medicaments, particularly a kind of pharmaceutical composition for the treatment of asthma and chronic obstructive pulmonary disease.
Background technology
Bronchial asthma (bronchial asthma, be called for short asthma) is by the various kinds of cell chronic airway inflammation that participates in of mastocyte, eosinophilic granulocyte and T lymphocyte particularly; This kind inflammation can cause repeatedly symptoms such as the panting of outbreak, tachypnea, uncomfortable in chest and/or cough in the susceptible person, how to take place at night or morning; This type of symptom is often limited with extensive and changeable exhalation flow rate, but natural remission or alleviate through treatment partly; This kind symptom also increases multiple stimulating factor reactivity with air flue.
Chronic obstructive pulmonary disease (Chronic Obstructive Pulmonary Disease, COPD) be a kind of PD, comprise a series of symptoms such as chronic cough, expectoration, exertional dyspnea and tangible reversible or irreversible carrying out property of air-flow minimizing.Generally popular or significantly increase in industrialized country.Cause in the dead disease in the present whole world, COPD arranges the 4th, predicts the year two thousand twenty, and the financial burden that global range endogenous cause of ill COPD is caused will be discharged to the 5th.
The imbedibility glucocorticoid improves patient's pulmonary function and reduces the disease symptoms deterioration rate because of effectively controlling airway inflammation, by a clinical line and the medication of the most effective long term maintenance therapy that is known as the persistence Asthma Population.Ciclesonide is new suction 17-hydroxy-11-dehydrocorticosterone, has its treatment asthma safety and effective of novel and excellent kinetics character and clinical research confirmation.
Indenes Da Teluo is new long-acting beta 2Receptor stimulating agent, clinical trial shows: indenes Da Teluo takes bronchodilatation is reached more than the 24h every day, and its diastole bronchus time ratio salmaterol and formoterol are long; Onset is faster than salmaterol.
The independent application of said two devices all can be treated bronchial asthma.We are through discovering that the applied in any combination of indenes Da Teluo and ciclesonide has good complementary cooperative effect, can better be used for the treatment of asthma and COPD patient.
Summary of the invention
The object of the present invention is to provide that a kind of to have produce effects fast, treatment asthma easy to use and chronic obstructive pulmonary disease (COPD) pharmaceutical composition.
Another object of the present invention is to provide preparation of drug combination method of the present invention.
Pharmaceutical composition of the present invention comprises following two kinds of active component:
(1) first kind of active component indenes Da Teluo, or its pharmaceutically acceptable salt or solvate, or the solvate of this salt;
(2) second kinds of active component ciclesonides;
Wherein, the weight ratio of above-mentioned first kind of active component and second kind of active component is
12-200∶10-320μg
Preferred weight ratio is:
25-100∶40-160μg
The most preferred weight ratio of the present invention gets through screening:
50∶80μg
It is single dose that above-mentioned prescription composition can be made into pharmaceutical preparation, maximum one day secondary of medication number of times.
Ciclesonide is a kind of glucocorticoid with efficient local anti-inflammatory effect, can strengthen the stability of endotheliocyte, smooth muscle cell and lysosome membrane, suppress immunoreation, it is synthetic to reduce antibody, make the release minimizing of allergy active mediums such as histamine, the active reduction, and can alleviate antigen-antibody in conjunction with the time enzymatic processes that excites, suppress the synthetic of bronchoconstriction material and discharge, thereby alleviate the contractile response of smooth muscle.
Indenes Da Teluo is a kind of new long-acting beta 2 receptor stimulating agents, and indenes Da Teluo takes bronchodilatation is reached more than the 24h every day, and its diastole bronchus time ratio salmaterol and formoterol are long; Onset is faster than salmaterol.In addition under static state, the onset time of indenes Da Teluo significantly is shorter than formoterol, and this has just remedied the slower shortcoming of ciclesonide onset, the optional acute asthma etc. that acts on of said composition.In addition, compare the bronchus relexation that indenes Da Teluo can the fugitive beta 2 receptor agonist of antagonism with salmaterol.
Compositions of the present invention, when being prepared into medicament, optionally add suitable medicine acceptable carrier, described medicine acceptable carrier is selected from: meglumine, mannitol, sorbitol, sodium pyrosulfite, sodium sulfite, sodium thiosulfate, cysteine hydrochloride, TGA, methionine, vitamin C, the EDTA disodium, EDTA calcium sodium, the alkali-metal carbonate of monovalence, acetate, phosphate or its aqueous solution, hydrochloric acid, acetic acid, sulphuric acid, phosphoric acid, aminoacid, sodium chloride, potassium chloride, sodium lactate, xylitol, maltose, glucose, fructose, dextran, glycine, starch, sucrose, lactose, mannitol, ethanol, sucralose, citric acid, silicon derivative, cellulose and derivant thereof, alginate, gelatin, polyvinylpyrrolidone, glycerol, soil temperature 80, agar, calcium carbonate, calcium bicarbonate, surfactant, Polyethylene Glycol, cyclodextrin, beta-schardinger dextrin-, the phospholipid material, Kaolin, Pulvis Talci, calcium stearate, magnesium stearate, essence etc., preferably especially select lactose and monohydrate thereof for use, the carrier consumption is preferably 60 μ g-15mg/ agent, more preferably 80 μ g-6mg/ agent.
The most preferred prescription of pharmaceutical composition of the present invention in an embodiment.
Pharmaceutical composition of the present invention, its medicine type can be any pharmaceutically useful dosage form, and these dosage forms comprise: tablet, capsule, oral liquid, suck agent, granule, electuary, pill, powder, unguentum, sublimed preparation, suspensoid, injection, suppository, cream, spray, drop, patch.
Preferred dosage form is as follows: active component of the present invention can be made powder spray, and preferred dosage form is micronized granule.The imbedibility granule can make the specific position of being distributed in of medicine orientation, and this just is fit to the next directed effect that reaches pulmonary administration of combination that we design two kinds of active component very much.Compare with common administering mode, pulmonary's amount of absorbing the drug significantly increases.Pharmaceutical composition of the present invention can also be made dosage forms such as spray or aerosol.
Preparation of drug combination method of the present invention, its concrete steps are as follows:
At ambient temperature, get ciclesonide, indenes Da Teluo mixing is pulverized; Get dry back lactose and pulverize,, this powder is filled into makes powder spray in the filling machine then with above-mentioned powder mixing.The present invention can also make dosage forms such as spray, aerosol as required.
Other preferred manufacturing procedure of the present invention in an embodiment.
Among the present invention to the research repeatedly of the pharmacology aspect of first active component and second active component, its result shows that the combination that the compositions of indenes Da Teluo and ciclesonide has a broad compares scope, when being used for the treatment of the patient of asthma and COPD, compare during with first active component of independent application or second active component, composition of active components of the present invention provides better effect.Dosage of the present invention is accurate, and curative effect lasting time is long, and resultant effect is good, instant effect, and safety is good, and good stability is quality controllable, and is easy to use, and low price is fit to large-scale production.
The specific embodiment
To further illustrate the present invention in following examples, these embodiment only are used to the present invention is described and to the present invention without limits.
Embodiment 1, powder spray
At ambient temperature, get 12kg indenes Da Teluo, the 20kg ciclesonide, mixing is crushed to mean diameter 1-5 μ m; Get dry back lactose and be crushed to mean diameter 1-5 μ m,, this powder is filled into makes powder spray in the filling machine then with above-mentioned powder mixing.
Embodiment 2, powder spray
At ambient temperature, get 1.2kg indenes Da Teluo, the 32kg ciclesonide, mixing is crushed to mean diameter 1-5 μ m; Get dry back lactose and be crushed to mean diameter 1-5 μ m,, this powder is filled into makes powder spray in the filling machine then with above-mentioned powder mixing.
Embodiment 3, powder spray
At ambient temperature, get 20kg indenes Da Teluo, the 2kg ciclesonide, mixing is crushed to mean diameter 1-5 μ m; Get dry back lactose and be crushed to mean diameter 1-5 μ m,, this powder is filled into makes powder spray in the filling machine then with above-mentioned powder mixing.
Embodiment 4, spray
At ambient temperature, get 25kg indenes Da Teluo, other gets the 40kg ciclesonide and adds mixing dosage in the solvent, and spray is made in fill.
Embodiment 5, spray
At ambient temperature, get 2.5kg indenes Da Teluo, other gets the 16kg ciclesonide and adds mixing dosage in the solvent, and spray is made in fill.
Embodiment 6, spray
At ambient temperature, get 10kg indenes Da Teluo, other gets the 4kg ciclesonide and adds mixing dosage in the solvent, and spray is made in fill.
Embodiment 7, spray
At ambient temperature, get 10kg indenes Da Teluo, other gets the 16kg ciclesonide and adds mixing dosage in the solvent, and spray is made in fill.50∶80μg
Embodiment 8, powder spray
At ambient temperature, get 5kg indenes Da Teluo, the 8kg ciclesonide, mixing is crushed to mean diameter 1-5 μ m; Get dry back lactose and be crushed to mean diameter 1-5 μ m,, this powder is filled into makes powder spray in the filling machine then with above-mentioned powder mixing.
Embodiment 9, spray
At ambient temperature, get 1kg indenes Da Teluo, other gets the 1.6kg ciclesonide and adds mixing dosage in the solvent, and spray is made in fill.
Embodiment 10, aerosol
Get 5kg indenes Da Teluo micropowder, other gets 8kg ciclesonide micropowder and puts in the vacuum drying oven and dry, and it is standby to be cooled to room temperature.Temperature is controlled at below 15 ℃, will dry material and add tween and place stainless steel cask to add the propellant mixing, stirs, and aerosol is made in fill.
Embodiment 11
At ambient temperature, get the 20kg ciclesonide, 25kg indenes Da Teluo mixing is crushed to mean diameter 1-5 μ m; Get dry back lactose and be crushed to mean diameter 1-5 μ m,, this powder is filled into makes powder spray in the filling machine then with above-mentioned powder mixing.
Embodiment 12
At ambient temperature, get the 15kg ciclesonide, other gets 20kg indenes Da Teluo mixing, is crushed to mean diameter 1-5 μ m; Get dry back lactose and be crushed to mean diameter 1-5 μ m,, this powder is filled into makes powder spray in the filling machine then with above-mentioned powder mixing.
Embodiment 13
At ambient temperature, get the 20kg ciclesonide, other gets 18kg indenes Da Teluo and adds mixing dosage in the solvent, and spray is made in fill.
Embodiment 14
At ambient temperature, get the 10kg ciclesonide, other gets 24kg indenes Da Teluo and adds mixing dosage in the solvent, and spray is made in fill.
Embodiment 15
Get 12kg ciclesonide micropowder, other gets 36kg indenes Da Teluo micropowder and puts in the vacuum drying oven and dry, and it is standby to be cooled to room temperature.Temperature is controlled at below 15 ℃, will dry material and add tween and place stainless steel cask to add the propellant mixing, stirs, and aerosol is made in fill.
Embodiment 16
Get 25kg ciclesonide micropowder, other gets 12kg indenes Da Teluo micropowder and puts in the vacuum drying oven and dry, and it is standby to be cooled to room temperature.Temperature is controlled at below 15 ℃, will dry material and add tween and place stainless steel cask to add the propellant mixing, stirs, and aerosol is made in fill.
Embodiment 17,
Test 1. physical data:
1.1, select COPD stable phase patient, be divided into approximately equalised 3 groups of number---treatment group and matched group 1 and 2 then at random, every index of 3 groups of patients more all has comparability before treatment, the treatment group is a pharmaceutical composition of the present invention, 1 administration indenes of matched group Da Teluo, 2 administration ciclesonides of matched group, each 1 inhales, every day 2 times, the time is 6 months.
1.2, research method: three groups are adopted following method to treat respectively: 30 examples are organized in treatment, and the patient goes into the group back and uses ciclesonide/indenes Da Teluo powder spray (every suction 80 μ g/50 μ g) of making by embodiment each 1 and inhale every day 1 time.Matched group 1 and 2 each 30 example are used indenes Da Teluo powder spray (every suction 50 μ g), ciclesonide powder spray (every suction 80 μ g), and each 1 inhales every day 1 time.30min respectively surveys PEF3 time before and after sucking, and gets maximum PEF value, calculates the improvement rate of PEF.
Figure G2009100009109D00061
In one week of the course of treatment, finish back check FEV 1% compares.
Criterion of therapeutical effect: PEF improvement rate: outstanding:＞36%, good: 26% ~ 35%, general 16% ~ 25%, relatively poor:＜15%.FEV 1% improves degree: outstanding:＞26%, good: 16% ~ 25%, general: 0 ~ 15%.
1.3 experimental data and result:
1. respectively organize the PEF situation of change and see Table 1
Table 1 respectively organize PEF improvement rate relatively (example, %)
Group Outstanding Well Generally Relatively poor
Matched group 1 (n=30) 7(23.3％) 13(43.3％) 6(20％) 4(13.3％)
Matched group 2 (n=30) 6(20％) 12(40％) 5(16.7％) 7(23.3％)
Treatment group (n=30) 10(33.3％) 14(46.7％) 4(13.3％) 2(6.7％)
Three groups of PEF improvement rates compare, and the outstanding and good rate of treatment group is 80.0%, is higher than matched group.
2. respectively organize FEV 1The % situation of change sees Table 2
Table 2 FEV before and after the course of treatment 1The comparison of % increase situation (example, %)
Group Outstanding Well Generally
Matched group 1 (n=30) 9(30.0％) 11(36.7％) 10(33.3％)
Matched group 2 (n=30) 8(26.7％) 10(33.3％) 12(40％)
Treatment group (n=30) 12(40％) 13(43.3％) 5(16.7％)
Three groups of FEV 1% all has increase, but the outstanding and good rate of treatment group is 83.3%, is higher than matched group.
3. respectively organize the situation of clinical symptoms change
Panting behind matched group 1 and the 2 suction 5-10min begins to alleviate, and finishes symptoms such as back cough, expectoration the course of treatment and is clearly better.The beginning of panting behind the treatment group suction 5-10min is obviously alleviated, and cough after finishing the course of treatment, expectoration symptom and the every index of quality of life all are clearly better.Two groups of patients all do not have untoward reaction such as obvious xerostomia, cardiopalmus and heart rate and tachypnea during treating.
By top data and analysis, use in conjunction indenes Da Teluo and ciclesonide are the ideal measure of quick relieving asthma and the various acute attacks of COPD, severe asthma is solved bronchospasm especially fast, improves anoxybiotic critical treatment means, and easy and simple to handle, safe and reliable.

Claims (6)

  1. One kind treat asthma and chronic obstructive pulmonary disease pharmaceutical composition, it is characterized in that, be that indenes Da Teluo and the ciclesonide of 25-100: 40-160 made as active constituents of medicine by weight ratio.
  2. 2. the described pharmaceutical composition of claim 1 is characterized in that, the weight ratio of indenes Da Teluo and ciclesonide is 50: 80.
  3. 3. the described pharmaceutical composition of claim 1 is characterized in that, is powder spray, spray or aerosol.
  4. 4. the described preparation of drug combination method of claim 3 is characterized in that the powder spray preparation process is as follows: at ambient temperature, get ciclesonide, indenes Da Teluo mixing, pulverizing; Get dry back lactose and pulverize,, this powder is filled into makes powder spray in the filling machine then with above-mentioned powder mixing.
  5. 5. the described preparation of drug combination method of claim 3 is characterized in that the spray preparation process is as follows: at ambient temperature, get ciclesonide and indenes Da Teluo and add mixing dosage in the solvent, spray is made in fill.
  6. 6. the described preparation of drug combination method of claim 3 is characterized in that the aerosol preparation process is as follows: get ciclesonide micropowder and indenes Da Teluo micropowder and put in the vacuum drying oven and dry, it is standby to be cooled to room temperature; Temperature is controlled at below 15 ℃, will dry material and add tween and place stainless steel cask to add the propellant mixing, stirs, and aerosol is made in fill.
CN2009100009109A 2009-01-21 2009-01-21 Pharmaceutical composition for treating asthma and chronic obstructive pulmonary disease Expired - Fee Related CN101474191B (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20140147393A1 (en) * 2010-10-12 2014-05-29 Cipla Limited Pharmaceutical Composition

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CN102266344A (en) * 2010-06-04 2011-12-07 北京阜康仁生物制药科技有限公司 Pharmaceutical composition used for treating respiration disorders

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1430508A (en) * 2000-05-19 2003-07-16 阿斯特拉曾尼卡有限公司 Novel composition
CN101249093A (en) * 2008-03-19 2008-08-27 李虎山 Combination for curing chronic obstructive disease of lung
CN101321539A (en) * 2005-12-21 2008-12-10 Meda制药有限及两合公司 Novel combination of anticholinergics, ss2-adrenoceptor agonists, antileukotrienes (leukotriene receptor antagonists), glucocorticoids and/or PDE 4 inhibitors for the treatment of inflammatory disease

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1430508A (en) * 2000-05-19 2003-07-16 阿斯特拉曾尼卡有限公司 Novel composition
CN101321539A (en) * 2005-12-21 2008-12-10 Meda制药有限及两合公司 Novel combination of anticholinergics, ss2-adrenoceptor agonists, antileukotrienes (leukotriene receptor antagonists), glucocorticoids and/or PDE 4 inhibitors for the treatment of inflammatory disease
CN101249093A (en) * 2008-03-19 2008-08-27 李虎山 Combination for curing chronic obstructive disease of lung

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20140147393A1 (en) * 2010-10-12 2014-05-29 Cipla Limited Pharmaceutical Composition

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