CN102000090A - Compound preparation with Budesonide and Arformoterol as active ingredients - Google Patents
Compound preparation with Budesonide and Arformoterol as active ingredients Download PDFInfo
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- CN102000090A CN102000090A CN2010101352067A CN201010135206A CN102000090A CN 102000090 A CN102000090 A CN 102000090A CN 2010101352067 A CN2010101352067 A CN 2010101352067A CN 201010135206 A CN201010135206 A CN 201010135206A CN 102000090 A CN102000090 A CN 102000090A
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- budesonide
- compound preparation
- afromoterol
- 30mcg
- spray
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Abstract
The invention relates to a compound preparation with Budesonide and Arformoterol as active ingredients and application thereof. The compound preparation is a medical composition which is formed by mixing Budesonide and Arformoterol used as active ingredients with pharmaceutically acceptable auxiliary materials; and the compound preparation is developed into an aerosol which is administrated through an oral cavity according to the technical means in the invention. The compound preparation has the advantages of fast absorption, quick effect acting and the like, is convenient to use and can be used for treating various asthma, COPD (Chronic Obstructive Pulmonary Disease) and other diseases.
Description
Technical field
The present invention for a kind of be the compound preparation of active component with budesonide 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) 1 000 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.
Budesonide is one to have the glucocorticoid of efficient local anti-inflammatory effect.It can strengthen the stability of endotheliocyte, smooth muscle cell and lysosome membrane, suppress immunoreation and reduce antibody synthetic, thereby the release that makes irritated active mediums such as histamine reduces and active the reduction, and can alleviate antigen-antibody in conjunction with the time enzymatic processes that excites, suppress the synthetic of bronchoconstriction material and discharge and alleviate the contractile response of smooth muscle.Be applied topically to bronchus, its antiinflammatory action is strong approximately 1000 times than cortisone.Be applicable to local non-special inflammation of antagonism and antiallergic, as bronchial asthma and airway hyperreactivity state.
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 budesonide 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 budesonide and Afromoterol, and the consumption of described budesonide is that every suction or spray are 50-400mcg, is preferably 100-800mcg.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.The form of expression of budesonide can for, the budesonide of raceme, the budesonide of d-isomer and their pharmaceutical salts thereof.
The dosage combination of described budesonide and Afromoterol is preferably every suction or sprays 100mcg/15mcg, 200mcg/15mcg, 400mcg/15mcg, 800mcg/15mcg, 100mcg/30mcg, 200mcg/30mcg, 400mcg/30mcg, 800mcg/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 budesonide 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 budesonide Afromoterol sucks spray
Method for making:
Afromoterol is carried out micronization, make its particle diameter about 7um.Budesonide is dissolved in the dehydrated alcohol of recipe quantity,, adds the Afromoterol stirring and make evenly, pour the budesonide 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 budesonide Afromoterol inhalation aerosol
Method for making:
Afromoterol is carried out micronization, make its particle diameter about 7um.Budesonide 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 budesonide 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 budesonide+Afromoterol treatment group (B group), budesonide 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, budesonide+Afromoterol, budesonide, 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 budesonide+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 budesonide 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 budesonide+Afromoterol treatment group (B group), budesonide 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 * 30cmx20cm 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, so the antiinflammatory action of people's compound recipe budesonide+Afromoterol is fit to COPD significantly better than budesonide or Afromoterol folk prescription administering effect long-term treatment is inhaled in atomizing.
Total white blood cells and classification among table 2 BALF (%, x ± s)
Claims (10)
- The present invention for a kind of be the compound preparation of active component with budesonide and Afromoterol, it is characterized in that it is a budesonide 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 the form of expression of formoterol is tartrate, fumarate, hydrochlorate, sulfate, benzene sulfonate, succinate, is preferably tartrate.
- 3. compound preparation as claimed in claim 1 is characterized in that, the form of expression of budesonide is racemization budesonide, dextrorotation budesonide and their pharmaceutical salts thereof.
- 4. compound preparation as claimed in claim 1 is to exist with inhalant dosage form, includes but are not limited to suck powder spray, inhalation aerosol, suction spray.
- 5. compound preparation as claimed in claim 3 is characterized in that, the consumption of described budesonide is 50-2400mcg for whenever pressing or spraying, and is preferably 100-800mcg.
- 6. compound preparation as claimed in claim 3 is characterized in that, 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.
- 7. compound preparation as claimed in claim 3, it is characterized in that the dosage combination of described budesonide and Afromoterol is preferably every suction or sprays 100mcg/15mcg, 200mcg/15mcg, 400mcg/15mcg, 800mcg/15mcg, 100mcg/30mcg, 200mcg/30mcg, 400mcg/30mcg, 800mcg/30mcg.
- 8. compound preparation as claimed in claim 3 is characterized in that, what its pharmaceutically acceptable pharmaceutic adjuvant that sucks powder spray was used always is glycine or lactose, is 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.
- 9. compound preparation as claimed in claim 3 is characterized in that, the pharmaceutically acceptable 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.
- 10. compound preparation as claimed in claim 3 is characterized in that, it sucks spray can be the dispersion of emulsion-type and suspension type.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2010101352067A CN102000090A (en) | 2009-08-31 | 2010-03-30 | Compound preparation with Budesonide and Arformoterol as active ingredients |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200910306394 | 2009-08-31 | ||
| CN200910306394.2 | 2009-08-31 | ||
| CN2010101352067A CN102000090A (en) | 2009-08-31 | 2010-03-30 | Compound preparation with Budesonide and Arformoterol as active ingredients |
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| CN102000090A true CN102000090A (en) | 2011-04-06 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN2010101352067A Pending CN102000090A (en) | 2009-08-31 | 2010-03-30 | Compound preparation with Budesonide and Arformoterol as active ingredients |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1271287A (en) * | 1997-09-19 | 2000-10-25 | 阿斯特拉公司 | New use of budesonide and formoterol |
| 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 |
-
2010
- 2010-03-30 CN CN2010101352067A patent/CN102000090A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1271287A (en) * | 1997-09-19 | 2000-10-25 | 阿斯特拉公司 | New use of budesonide and formoterol |
| 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 (2)
| Title |
|---|
| 《药学进展》 20081231 金璐燕 长效beta2肾上腺素受体激动剂酒石酸阿福特罗 91-92 1-10 第32卷, 第2期 * |
| 金璐燕: "长效β2肾上腺素受体激动剂酒石酸阿福特罗", 《药学进展》 * |
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Application publication date: 20110406 |