CN102000089A - Compound preparation with ciclesonide and Arformoterol as active constituents - Google Patents
Compound preparation with ciclesonide and Arformoterol as active constituents Download PDFInfo
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- CN102000089A CN102000089A CN2009103064254A CN200910306425A CN102000089A CN 102000089 A CN102000089 A CN 102000089A CN 2009103064254 A CN2009103064254 A CN 2009103064254A CN 200910306425 A CN200910306425 A CN 200910306425A CN 102000089 A CN102000089 A CN 102000089A
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- compound preparation
- ciclesonide
- afromoterol
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- active component
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Abstract
The invention relates to a compound preparation with ciclesonide and Arformoterol as active constituents and application thereof. The compound preparation is formed by mixing the ciclesonide and the Arformoterol, which are used as active constituents, with pharmaceutically acceptable auxiliary materials, is prepared and developed into an aerosol form for buccal delivery according to technical means described in the specification, has the advantages of fast effect-taking, rapid action, convenience in use and the like, and can be used for treating the diseases of various asthma, COPD (Chronic Obstructive Pulmonary Diseases) and the like.
Description
Technical field
The present invention for a kind of be the compound preparation of active component with ciclesonide and Afromoterol, belong to medical technical field.
Background technology
Chronic obstructive pulmonary disease (COPD) is a kind of disease that can prevent and treat with flow limitation feature, and flow limitation is not exclusively reversible, be and carry out sexual development, and is relevant to the abnormal inflammatory reaction of harmful gas such as smoke from cigarette or deleterious particle with pulmonary.COPD is to be the respiratory system disease of feature with stingy road chronic nonspecific inflammation and the respiratory tract obstruction of carrying out property, and essence is air flue, pulmonary parenchyma and pulmonary vascular chronic inflammatory disease.COPD mainly involves lungs, but also can the cause whole body ill effect of (or claim lung outer).COPD comprises chronic bronchitis and emphysema.
Afromoterol is got permission listing in October, 2006 in the U.S., is used for the bronchoconstriction symptom that long term maintenance treatment chronic obstructive pulmonary disease (COPD) causes, comprises chronic bronchitis and emphysema.Afromoterol is that (R, R) enantiomer are a kind of optionally long-acting beta 2 adrenoreceptor agonists to formoterol, and its drug effect is 2 times of formoterol raceme, are (s, s) 1000 of enantiomer times.Beta 2 receptor mainly is distributed in bronchial smooth muscle, and Afromoterol can activate adenyl cyclase in the body, and this enzyme can make adenosine triphosphate (ATP) be converted into 3 '-5 one adenosine cyclophosphate (cA).The increase of the cAMP amount bronchial smooth muscle that can relax in the cell, and can reduce the anaphylaxis medium and particularly discharge the mastocyte from cell.In vitro tests shows, Afromoterol can suppress the release of medium such as histamine, leukotriene in the human lung mast cell, in addition, it can also suppress in the anaesthetized guinea pig body seepage by the plasma-albumin of histamine-mediated, and suppresses in the airway hyperreactivity model dog body the interior stream by the oxyphil cell of allergen-induced.
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.
Inhalant through the oral cavity administration has a bit a lot: but the toxic and side effects to other positions can be avoided or reduce to medicine through sucking rapid subsidence in pulmonary; Pulmonary's sorbent surface is long-pending big, the membrane permeability height, and blood flow is abundant, and drug absorption is rapid; Pulmonary's enzymatic activity is lower, and does not have liver first-pass effect, and these help improving bioavailability of medicament.And pulmonary administration can be used for local disease's treatment of pulmonary.A lot of successful examples have been arranged at present, and as hormones, treatment asthma class medicine, the kind of exploitation is a lot.The technology of pulmonary's inhalation mainly contains 3 kinds at present: Foradil Aerolizer formoterol fumarate, aerosol (also becoming metered dose inhalation aerosol) and spray.
Summary of the invention
Having the purpose of this invention is to provide a kind of is the compound recipe suction preparation of active component with ciclesonide and Afromoterol, through pulmonary's inhalation.These pulmonary's inhalation preparations mainly exist with following three kinds of forms: Foradil Aerolizer formoterol fumarate, aerosol, spray.
In the middle of above three kinds of dosage forms, preferably Foradil Aerolizer formoterol fumarate and aerosol, from the compliance of administration and the complexity of preparation, the present inventor more is inclined to and Foradil Aerolizer formoterol fumarate.
In this inhalant, its active component is ciclesonide and Afromoterol, and the consumption of ciclesonide is that every suction or spray are 20-320mcg, is preferably 80-160mcg, and the consumption of described Afromoterol is that every suction or spray are 3.75-120mcg.Be preferably 15-30mcg.If in the tartrate Afromoterol then be 5.4-172.3mcg, be preferably 21.6mcg-43.2mcg.
In described dosage and the combination thereof, Afromoterol is in active component.Can be its pharmaceutical salts during use, exist as salifiable form such as tartrate, fumarate, hydrochlorate, sulfate, benzene sulfonate, succinate.Be preferably tartrate.At this moment, the combination of the dosage of described ciclesonide and Afromoterol is preferably every suction or sprays 80mcg/15mcg, 80mcg/30mcg, 160mcg/15mcg, 160mcg/30mcg.
When this inhalant is that form with Foradil Aerolizer formoterol fumarate is when existing, also must add some other adjuvant, these adjuvants include but are not limited to wherein one or more such as microcrystalline Cellulose, lactose, glucose, fructose, sucrose, mannitol, xylitol, maltose alcohol, glycine, Aspartic Acid, alanine, tryptophan, threonine.If necessary, also to add an amount of surface active ingredient, as dipalmitoyl phosphatidyl choline, two Laurel phosphatidyl cholines, cholesterol, poloxamer etc.Also might add suitable polymer substance, as in starch, polylactic acid, polylactic acid-glycolic guanidine-acetic acid, the Polyethylene Glycol one or more.
When medicinal active ingredient mixed with these adjuvants, its weight ratio was 1: 50-1: 1000.And these adjuvants and medicine all need through micronization processes, and their particle size distribution range is preferably between the 1-100 micron between the 0.02-200 micron.
If inhalant described in the invention is the form of aerosol when existing, normally with two kinds of active component dissolvings or be dispersed in certain solvent, these dispersions can be Emulsion or suspensoid.Simultaneously, also must add some propellant, propellant is freon, Hydrocarbon and Compressed Gas etc.
When if inhalant of the present invention is spray, the dispersion that is adopted can be emulsion-type and suspension type liquid.
No matter how institute adopts dispersible carrier, active constituents of medicine all needs to pass through micronization processes, absorbs preferably and utilizes effect thereby reach.
Compound preparation of the present invention can be used for the asthma that a variety of causes causes, the treatment of COPD.
The specific embodiment
Embodiment 1: compound recipe ciclesonide Afromoterol sucks powder spray
Method for making:
Two flavor principal agents are carried out micronization respectively, make its particle diameter about 7um.Under aseptic condition, lactose equivalent incremental method, mix homogeneously.Be respectively charged in No. 3 capsules.Put into specific suction device, get final product.
Embodiment 2: compound recipe ciclesonide Afromoterol sucks spray
Method for making:
Afromoterol is carried out micronization, make its particle diameter about 7um.Ciclesonide is dissolved in the dehydrated alcohol of recipe quantity,, adds the Afromoterol stirring and make evenly, pour the ciclesonide alcoholic solution into, make evenly tween and 80ml water mix homogeneously.Transfer pH value 4-6 with citric acid and sodium salt, add purified water, divide to be filled in the bottle every bottle of 10ml, every spray 100ul to 100ml.
Embodiment 3: compound recipe ciclesonide Afromoterol inhalation aerosol
Method for making:
Afromoterol is carried out micronization, make its particle diameter about 7um.Ciclesonide is dissolved in the dehydrated alcohol of recipe quantity, adds the tween mix homogeneously, add the Afromoterol stirring and make evenly.Quantitatively divide to be filled in the aluminium pot compression set metered valve, quantitative pressurising propellant 134a, every bottle of 10ml, every spray 100ul.
Embodiment 4: compound recipe ciclesonide Afromoterol is to the antagonism of asthma attack
Experimental technique: 40 Cavia porcelluss that primary dcreening operation is qualified are divided into 4 groups, 10 every group at random.Be respectively normal saline matched group (A group), compound recipe ciclesonide+Afromoterol treatment group (B group), ciclesonide treatment group (C group), Afromoterol treatment group (D group).Put Cavia porcellus in the airtight vial of 4L volume,, inhale human therapy with the jet atomization of 5L/rain flow by Central oxygen-supply.Human physiology saline, ciclesonide+Afromoterol, ciclesonide, Afromoterol 120s are inhaled in jet atomization respectively.Pressed the experimental program administration in continuous 4 days, behind administration 0.5h (the 1st day), 1h (the 2nd day), 2h (the 3rd day), 3h (the 4th day), Cavia porcellus is placed in the airtight vial of 4L volume, sucking the 0.8% solution 10S of histamine phosphate with the jet atomization of 5L/rain flow lures and breathes heavily, the incubation period of III degree asthma (tic is fallen) appears in the record Cavia porcellus, if do not occur III degree asthma in the 360s, then calculate with 360S incubation period.
Experimental result: the result shows, with matched group relatively, each treatment group all significantly prolongs asthma attack incubation period, but ciclesonide+Afromoterol treatment group effect is more remarkable, and effect is continual and steady.
Each treatment group of table 1 is drawn Cavia porcellus and is breathed heavily preclinical influence (s, x ± s)
Embodiment 5: compound recipe ciclesonide Afromoterol is to the influence of COPD airway inflammation
Experimental technique: 40 rats are divided into four groups at random, 10 every group.Be respectively model control group (A group), compound recipe ciclesonide+Afromoterol treatment group (B group), ciclesonide treatment group (C group), Afromoterol treatment group (D group).Each group is all injected lipopolysaccharide 1mg/kg in the 1st, 20 day trachea of experiment, the 2nd～19,21～40 days put passive smoking in people 80cm * 60cm * 58cm lucite case with rat, every day 2 times (4h at interval), continue 1h (10 medicated cigarette) at every turn.Each treatment group was all given corresponding treatment medicine+normal saline 5ml in the 2nd～19,21～40 days respectively in modeling, sucked (placing in 30cm * 30cm x 20cm glass box), 1 time/d, 25min/ time, successive administration 40 days with the 5L/rain atomizing.Model control group only gives the normal saline atomizing and sucks.Other gets 10 healthy rats as blank (O group), and experimental session only gives the normal saline atomizing on time and sucks, and does not do other any processing.Detect bronchoalveolar lavage fluid (BALF) numeration of leukocyte and classification after 40 days.
The result: each administration group all has certain antiinflammatory protective effect to COPD induced lung function, and atomizing is inhaled the antiinflammatory action of people's compound recipe ciclesonide+Afromoterol significantly better than ciclesonide or Afromoterol folk prescription administering effect, so be fit to the long-term treatment of COPD.
Total white blood cells and classification among table 2 BALF (%, x ± s)
| Group | Sum | Macrophage | Neutrophilic granulocyte | Lymphocyte |
| O | 1.52±0.11 | 98.14±0.97 | 2.89±1.08 | 3.18±0.37 |
| A | 6.82±0.17 | 68.74±1.64 | 20.82±1.07 | 8.14±0.47 |
| B | 2.49±0.20 | 87.68±2.10 | 9.68±2.01 | 4.12±0.22 |
| C | 4.57±0.18 | 78.32±1.58 | 13.58±1.84 | 6.06±0.43 |
| D | 5.18±0.23 | 71.95±0.89 | 16.45±1.53 | 7.03±0.54 |
Claims (10)
- The present invention for a kind of be the compound preparation of active component with ciclesonide and Afromoterol, it is characterized in that it is a ciclesonide and the active component of Afromoterol formation, with the Pharmaceutical composition of mixing acceptable accessories formation.
- 2. compound preparation as claimed in claim 1 is characterized in that, Afromoterol is that the form with salt exists, and includes but are not limited to tartrate, fumarate, hydrochlorate, sulfate, benzene sulfonate, succinate.Be preferably tartrate.
- 3. compound preparation as claimed in claim 1 is to exist with inhalant dosage form, comprises sucking powder spray, inhalation aerosol, suction spray.
- 4. compound preparation as claimed in claim 3 is characterized in that, the consumption of described ciclesonide is that every suction or spray are 20-320mcg, is preferably 80-160mcg.
- 5. compound preparation as claimed in claim 3 is characterized in that, the consumption of described Afromoterol is counted with active component and whenever pressed or every spray is 3.75-120mcg.Be preferably 15-30mcg.
- 6. compound preparation as claimed in claim 3 is characterized in that, the combination of the dosage of described ciclesonide and Afromoterol is preferably whenever presses or spray 80mcg/15mcg, 80mcg/30mcg, 160mcg/15mcg, 160mcg/30mcg.
- 7. compound preparation as claimed in claim 3 is characterized in that, its suck powder spray pharmaceutic adjuvant commonly used be glycine or lactose, be preferably lactose.They need to carry out micronization processes, and particle size distribution range is preferably between the 1-100 micron between the 0.02-200 micron.
- 8. compound preparation as claimed in claim 3 is characterized in that, the pharmaceutic adjuvant of its inhalation aerosol is commonly used comprises dispersion and propellant.Wherein dispersion can exist with the form of Emulsion, suspension.Propellant is freon, Hydrocarbon and Compressed Gas etc.
- 9. compound preparation as claimed in claim 3 is characterized in that, it sucks spray can be the dispersion of emulsion-type and suspension type.
- 10. compound preparation as claimed in claim 1 can be used for the asthma that a variety of causes causes, the treatment of COPD.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2009103064254A CN102000089A (en) | 2009-09-01 | 2009-09-01 | Compound preparation with ciclesonide and Arformoterol as active constituents |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2009103064254A CN102000089A (en) | 2009-09-01 | 2009-09-01 | Compound preparation with ciclesonide and Arformoterol as active constituents |
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| CN102000089A true CN102000089A (en) | 2011-04-06 |
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| CN2009103064254A Pending CN102000089A (en) | 2009-09-01 | 2009-09-01 | Compound preparation with ciclesonide and Arformoterol as active constituents |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN107929257A (en) * | 2017-12-01 | 2018-04-20 | 广东力集团制药股份有限公司 | A kind of tartaric acid Afromoterol powders for inhalation capsule and preparation method thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101264092A (en) * | 2008-04-11 | 2008-09-17 | 北京润德康医药技术有限公司 | Compound preparations with ciclesonide and formoterol as active component and preparation and application thereof |
-
2009
- 2009-09-01 CN CN2009103064254A patent/CN102000089A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101264092A (en) * | 2008-04-11 | 2008-09-17 | 北京润德康医药技术有限公司 | Compound preparations with ciclesonide and formoterol as active component and preparation and application thereof |
Non-Patent Citations (1)
| Title |
|---|
| 金卢燕: "长效肾上腺素受体激动剂酒石酸阿福特罗", 《药学进展》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN107929257A (en) * | 2017-12-01 | 2018-04-20 | 广东力集团制药股份有限公司 | A kind of tartaric acid Afromoterol powders for inhalation capsule and preparation method thereof |
| CN107929257B (en) * | 2017-12-01 | 2019-04-16 | 广东一力集团制药股份有限公司 | A kind of tartaric acid Afromoterol powders for inhalation capsule and preparation method thereof |
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Address after: 100070 Beijing City, Fengtai District science and Technology Park Fung Fu Road No. 4 Building 16 layer 16A02 Federation of science and technology Applicant after: Beijing Lelijian Biotechnology Co., Ltd. Address before: 100070 Beijing City, Fengtai District science and Technology Park Fung Fu Road No. 4 Building 16 layer 16A02 Federation of science and technology Applicant before: Beijing Lilesheng Pharmaceutical Technology Co., Ltd. |
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Application publication date: 20110406 |