CN104208688A - Pharmaceutical composition containing individually-packaged mometasone furoate and epinephrine beta2-acceptor stimulant placed in inhalation device for synchronous application - Google Patents
Pharmaceutical composition containing individually-packaged mometasone furoate and epinephrine beta2-acceptor stimulant placed in inhalation device for synchronous application Download PDFInfo
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- CN104208688A CN104208688A CN201310205573.3A CN201310205573A CN104208688A CN 104208688 A CN104208688 A CN 104208688A CN 201310205573 A CN201310205573 A CN 201310205573A CN 104208688 A CN104208688 A CN 104208688A
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Abstract
The invention relates to a drug for treating respiratory tract diseases especially asthma, and especially relates to a dry powder inhalation pharmaceutical composition containing mometasone furoate and epinephrine beta2-acceptor stimulant, which are individually packaged and placed in a same inhalation device for synchronous application.
Description
Technical field:
Especially the medicine, particularly momestasone furoate of asthma, epinephrine broxaterol are packed and the dry powder Inhaled pharmaceutical composition simultaneously used at a suction apparatus respectively to the present invention relates to treatment respiratory tract disease.
Background technology:
Asthma is a kind of chronic airway inflammation, it is characterized by Reversible airway obstruction and airway reactivity increases, and the secretions that airway obstruction is caused by bronchial mucosa inflammation increases, myxedema and inflammatory stimulus smooth muscle spasm two kinds of factors cause; And airway reactivity to increase also be the result of the bronchial epithelial cell damage caused due to airway inflammation.People recognize, only have the inflammation controlling airway mucus, just can reach the object finally reducing airway hyperreactivity, relieving asthma symptoms.The medicine of the pulmonary disease such as treatment asthma mainly contains following several: (1) broxaterol, (2) xanthine drug, (3) anticholinergic agent, (4) glucocorticoid, (5) antiallergic agent.China's document " inhaled corticosteroids generation is learned and pharmacodynamics " (Wang Changzheng, practical hospital clinical magazine, volume the 1st phase January the 4th in 2007,16-18) point out, suck the first-line drug that parahormone (ICS) has become asthma long-term treatment, as ciclesonide, fluticasone propionate, momestasone furoate, budesonide etc.The document is also pointed out, desirable ICS should be the perfect adaptation of effectiveness and safety, although ICS has huge progress compared with systemic hormonal in the safety for the treatment of, still can not meet the needs of clinical treatment well.Long-term, high-dose uses ICS still to there will be the untoward reaction such as adrenal cortex function suppression, and the ICS (secondary heavy dose) being used alone so-called safe dose can't control severe asthma in majority effectively.
The compound medicine of the medicine of the pulmonary disease such as current treatment asthma commonly glucocorticoid and epinephrine broxaterol, as budesonide formoterol powders for inhalation, salmaterol fluticasone propionate powders for inhalation, ciclesonide formoterol powders for inhalation etc., such compound medicine achieves fabulous curative effect in the treatment, has obvious advantage compared with glucocorticoid or epinephrine broxaterol folk prescription medicine.
But glucocorticoid is different from the micromeritics characteristic of epinephrine broxaterol, using dosage also exists larger different, and under adjuvant exists, above-mentioned situation is more complicated.Such as aborning in fill to the process in same container because micromeritics characteristic difference keeps the higher uniformity, there is larger difficulty.
Summary of the invention:
In order to ensure the uniformity of compound medicine, retain the curative effect of compound medicine simultaneously, we find that the different activities composition of compound dry powder Inhaled pharmaceutical composition is packed and in the process simultaneously used at a suction apparatus respectively, medicine still can produce same effect, better medicaments uniformity degree is provided,, be surprised to find that this mode can better ensure medicine Emptying Rate in production with in storing, and the stability of medicine also increases simultaneously.
The invention provides following technical scheme.
A kind of compound dry powder Inhaled pharmaceutical composition be made up of momestasone furoate, epinephrine broxaterol, pharmaceutic adjuvant that one or more are applicable to inhalation, it is characterized in that momestasone furoate, epinephrine broxaterol and corresponding excipient substance barrier packaging respectively thereof, and be stored in a suction apparatus.
Aforementioned pharmaceutical compositions, is characterized in that described epinephrine broxaterol is one or more in albuterol, terbutaline, fenoterol, procaterol, formoterol, salmaterol, bambuterol, zilpaterol, Mabuterol, western Boot sieve, bromine Boot sieve, Afromoterol, QAB-149 and officinal salt thereof; One in preferably sulfuric acid albuterol, terbutaline sulphate, tartaric acid Afromoterol, formoterol fumarate, SALMETEROL XINAFOATE, maleic acid QAB-149; More preferably formoterol fumarate.
Aforementioned pharmaceutical compositions, it is characterized in that the momestasone furoate of described active component and epinephrine broxaterol are micropowder, the particle diameter of micropowder is 0.5 ~ 10 μm.
Aforementioned pharmaceutical compositions, is characterized in that described pharmaceutic adjuvant comprises carrier and additives, and the particle diameter of described carrier is 20 ~ 60 μm, and preferable particle size is 30 ~ 60 μm.Carrier is one or more in carbohydrate carrier, aminoacid, lecithin or phosphatidylcholine.Described aminoacid is glycine, valine, leucine.Described saccharide is one or more of monosaccharide, disaccharide or its derived carbohydrate, and derived carbohydrate refers to that the straight or branched hydrocarbon chain of involved 20 carbon atoms at the most of at least one hydroxyl on glycan molecule replaces.Described monosaccharide is mannitol, fructose, glucose.Described disaccharide is maltose, trehalose, cellobiose, lactose, sucrose.Described derived carbohydrate is eight acetate fiber two sugar esters, sucrose octa-acetate, eight acetic acid lactose esters, five acetic acid glucose esters, six acetic acid Nitranitols and eight acetic acid Sargassum sugar esters.Preferred vector is lactose, and described lactose is alpha-lactose monohydrate, β-Lactis Anhydrous, one or more in amorphous spray-dried lactose, crystallizing and drying lactose, and described lactose is more preferably crystallizing and drying lactose.
Described pharmaceutical composition, is characterized in that additives are one or more in surfactant, lubricant, antistatic additive.
Surfactant is poloxamer.Lubricant is one or more in magnesium stearate, micropowder silica gel, Pulvis Talci.
The summation of active component and the weight ratio of carrier are 1:5 ~ 100.
Aforementioned pharmaceutical compositions, the method for micronization of described active component adopts spray drying method, fluid bed supersonic jet mill method, speed lapping method, ball-milling method, fluid energy mill method or solvent method.
Aforementioned pharmaceutical compositions, is characterized in that momestasone furoate single using dosage is 50-500 μ g, epinephrine broxaterol single using dosage 1-100 μ g.
Should be appreciated that because known reason, as the retention of active component in suction apparatus, the amount of often kind of active component that patient sucks can be different from the amount of metering.Therefore the applicating ratio between active component can be different from the ratio of metering.The ratio preferably used is in the described metered proportions indicated.
Particle diameter in the present invention is as being D99 mass median diameter (mass mean diameter) without refering in particular to, and this particle diameter is the particle diameter corresponding when reaching 99% of the cumulative particle sizes percentile detecting a sample by laser particle analyzer.
Detailed description of the invention
Micronization of the present invention can use known mechanical crushing method or spray drying method.Mechanical crushing method refers to and utilizes the method for fluid energy mill respectively active component and carrier powder to be broken into required particle diameter.Spray drying method refers to and momestasone furoate or carrier is dissolved in organic solvent entirely as in ethanol, through spray dryer, solid material is made required particle diameter.Use during spray drying method and can also add surfactant as poloxamer etc.
Capsule type dry powder inhalant can adopt No. 3 plant capsules (sino-america joint-venture Suzhou Capsule Co., Ltd produces, trade name: Vcaps), and each embodiment feeds intake according to 1000 capsules.The capsule loading bubble-cap type of powder spray is aluminum-plastic packaged, takes out, load powder spray inhaler (Shanghai balance pharmaceutical factory) and use during use.
The mixed method of compound medicine: the medicine that the amount of the medicine that taken amount is little and equivalent is large, be placed in blender to mix simultaneously, then add with the large drug dilution of the amount of mixture equivalent even, till times amount like this is increased to and adds the large component of whole amount, mixing, the time of each mixing is 10 minutes.
The method (equal increments method) that medicine mixes with adjuvant: the adjuvant component of get it filled thing and equivalent, be placed in blender to mix simultaneously, add again and dilute evenly with the adjuvant component of mixture equivalent, till times amount like this is increased to and adds whole supplementary material component, mixing, the time of each mixing is 10 minutes.
Mixing machinery adopts FGD stationary hopper mixer (sky, Shanghai nine enginerring works).
In following embodiment, bitubular suction apparatus is the device introduced in Chinese patent ZL201080031347.2.
Monotubular suction apparatus is the KRT-D01 type inhaler that Tai'an Kai Rui extra high molecular company limited produces.
Medicine assay method: momestasone furoate, formoterol fumarate, SALMETEROL XINAFOATE sulfur is according to the method for American Pharmacopeia 34 editions, tartaric acid Afromoterol is according to " HPLC measures the Afromoterol in Foradil Aerolizer formoterol fumarate " (West China pharmaceutical journal, (chromatographic column is C18 post (150 mm × 4.6 mm to method 2011(3)), 5 μm), mobile phase is 23.9 mmolL-1 sodium dihydrogen phosphate-acetonitrile (PH3.1) (84:16), flow velocity is 1 mLmin-1, determined wavelength is 214 nm.), salbutamol sulfate, terbutaline sulphate is according to the method for Chinese Pharmacopoeia 2010 editions.
Embodiment 1
Momestasone furoate, epinephrine broxaterol are pulverized respectively, particle diameter sees the following form, medicine after pulverizing is that 20 times of weight lactoses of 30 μm mix according to the method described above respectively with mean diameter, according to momestasone furoate 100 μ g/ grain, the standard fill medicament capsule of epinephrine broxaterol 10 μ g/ grain, aluminium foil blister is packed, and often kind of medicine is got 10 and measured medicament contg, is designated as 0 day numerical value.Often kind of medicine is got 100 and is preserved under temperature 30 ± 2 DEG C, relative humidity 65 ± 5% condition and get 10 capsules at random after 6 months and again measure medicament contg, Emptying Rate, the uniformity afterwards, is designated as 6 months numerical results and sees the following form.
Cloud test method: detect according to Chinese Pharmacopoeia 2010 editions two annex XE " Content uniformity test ".
Emptying Rate assay method: detect according to Chinese Pharmacopoeia 2010 editions two annex 13 pages " Emptying Rate inspection technique ".
Comparative examples 1
Momestasone furoate, the epinephrine broxaterol pulverized in Example 1, particle diameter sees the following form, medicine after pulverizing mix homogeneously according to the method described above, be that 20 times of weight lactoses of 30 μm mix according to the method described above afterwards with mean diameter, according to momestasone furoate 100 μ g/ grain, the standard fill medicament capsule of epinephrine broxaterol 10 μ g/ grain, aluminium foil blister is packed, often kind of compound medicine is got 10 and is measured medicament contg, is designated as 0 day numerical value.Often kind of medicine is got 100 and is preserved under temperature 30 ± 2 DEG C, relative humidity 65 ± 5% condition and get 10 capsules at random after 6 months and again measure medicament contg, Emptying Rate, the uniformity afterwards, is designated as 6 months numerical result conditions and sees the following form.
Embodiment 2
Momestasone furoate, epinephrine broxaterol are pulverized respectively, particle diameter sees the following form, medicine after pulverizing is that 20 times of weight lactoses of 45 μm mix according to the method described above respectively with mean diameter, according to momestasone furoate 100 μ g/ grain, the standard of epinephrine broxaterol 10 μ g/ grain is inserted in bitubular suction apparatus.
Embodiment 3
Momestasone furoate, epinephrine broxaterol are pulverized respectively, particle diameter sees the following form, medicine after pulverizing is that 10 times of weight lactoses of 60 μm mix according to the method described above respectively with mean diameter, inserts in bitubular suction apparatus according to the ratio of single administration amount (unit) Chinese medicine in following table.
| Embodiment code name | Medicine name | Particle diameter (μm) | Weight (μ g/ unit) |
| 3-1 | Momestasone furoate | 4.4 | 50 |
| Formoterol fumarate | 6.5 | 2 | |
| 3-2 | Momestasone furoate | 3.3 | 100 |
| Formoterol fumarate | 7.5 | 5 | |
| 3-3 | Momestasone furoate | 2.7 | 200 |
| Formoterol fumarate | 8.5 | 10 | |
| 3-4 | Momestasone furoate | 5.8 | 200 |
| SALMETEROL XINAFOATE | 5.1 | 50 | |
| 3-5 | Momestasone furoate | 6.6 | 200 |
| SALMETEROL XINAFOATE | 2.9 | 50 | |
| 3-6 | Momestasone furoate | 7.4 | 400 |
| Salbutamol sulfate | 5.8 | 100 | |
| 3-7 | Momestasone furoate | 1.3 | 100 |
| Terbutaline sulphate | 2.7 | 100 |
Embodiment 4
Momestasone furoate, epinephrine broxaterol are pulverized respectively, particle diameter sees the following form, medicine after pulverizing is that 20 times of weight lactoses of 20 μm mix according to the method described above respectively with mean diameter, according to momestasone furoate 100 μ g/ grain, the standard of epinephrine broxaterol 20 μ g/ grain is inserted in bitubular suction apparatus.
Embodiment 5
Momestasone furoate, epinephrine broxaterol are pulverized respectively, particle diameter sees the following form, according to momestasone furoate 100 μ g/ grain after medicine after pulverizing mixes according to the method described above with adjuvant respectively, the standard of epinephrine broxaterol 10 μ g/ grain is inserted in bitubular suction apparatus.
Pharmacological Examples 1 asthma pharmacological evaluation
1, animal model
Choose healthy male Wistar rat (there is antibacterial to checking out, the rat of bacteriological infection will not select), body weight is 200 ± 10g, put into the bell glass of about 5 liters, spray into 3% chlorination second phthalein choline and 0.1% histamine phosphate's volume mixed liquor 15 second with the pressure of 400mmHg.After spraying stops, observing the asthmatic latent period (namely asthma occur, breathe be the devil, until twitch time of falling) of rat, draw and breathe heavily the rat that the latent phase is less than 70 seconds or is greater than 120 seconds and will not select.
2, experimental technique
Learn from else's experience and measure the qualified rat of asthmatic latent period, random packet is carried out according to the group in following table, often organize 10, every day carries out administration in the bell glass of about 5 liters, simultaneously experimental group is loaded in bitubular suction apparatus by the medicine in embodiment to give 2 kinds of medicines according to inhalation route, model group 1 gives according to inhalation route the Lactis Anhydrous that mean diameter is 55 μm, dosage is 5mg/Kg, comparative examples group medicine is loaded conventional monotubular suction apparatus inhalation route and gives corresponding dosage compound medicine by matched group, within the 4th day of administration, give 0.3% 2 hydrochloric acid histamine when spraying after after giving whole medicine 1.5 hours, observe the change (draw animal when breathing heavily and do not occur in 6 minutes that to breathe heavily the volt phase be calculate for 360 seconds to the person of falling to draw) of asthmatic latent period and tic incidence rate before and after drug.
Dosage in experimental group, matched group is all as the criterion with momestasone furoate drug dose.
3, experimentation and result: animal generation asthma until the time of falling of twitching see the following form.
Have multiple form to be the result of this experiment in the present embodiment, problem for convenience of explanation, splits experimental result.
Table 1-1 comparative examples experimental result (n=10, mean ± SD)
Difference is not had afterwards before administration by the asthmatic latent period of T testing identity asthmatic model animal by above-mentioned experimental data, basically identical with not administration group, can illustrate that asthmatic model animal only gives anti-bacterial drug, cannot Paroxysmal asthma be extended.
The experimental result (n=10, mean ± SD) of table 1-2 embodiment
In sum, can illustrate due under Different Package form by embodiment 1 and the contrast of comparative examples 1, the uniformity of compound medicine, content, Emptying Rate all have obvious difference, that separately packs is better than hybrid packed form, and can illustrate under Different Package form by embodiment 2 and the contrast of comparative examples 1, the curative effect of compound medicine is similar to, but separately packaging be slightly better than hybrid packed form.
Claims (10)
1. the compound dry powder Inhaled pharmaceutical composition be made up of momestasone furoate, epinephrine broxaterol, pharmaceutic adjuvant that one or more are applicable to inhalation, it is characterized in that momestasone furoate, epinephrine broxaterol and corresponding excipient substance barrier packaging respectively thereof, and be stored in a suction apparatus.
2. pharmaceutical composition as claimed in claim 1, is characterized in that described epinephrine broxaterol is one or more in albuterol, terbutaline, fenoterol, procaterol, formoterol, salmaterol, bambuterol, zilpaterol, Mabuterol, western Boot sieve, bromine Boot sieve, Afromoterol, QAB-149 and officinal salt thereof.
3. pharmaceutical composition as claimed in claim 1, it is characterized in that the momestasone furoate of described active component and epinephrine broxaterol are micropowder, the particle diameter of micropowder is 0.5 ~ 10 μm.
4. pharmaceutical composition as claimed in claim 1, is characterized in that described pharmaceutic adjuvant comprises carrier and additives.
5. pharmaceutical composition as claimed in claim 4, is characterized in that the particle diameter of described carrier is 20 ~ 60 μm.
6. pharmaceutical composition as claimed in claim 4, is characterized in that described carrier is one or more in carbohydrate carrier, aminoacid, lecithin or phosphatidylcholine.
7. pharmaceutical composition as claimed in claim 4, is characterized in that additives are one or more in surfactant, lubricant, antistatic additive.
8. pharmaceutical composition as claimed in claim 4, is characterized in that the summation of described active component and the weight ratio of carrier are 1:5 ~ 100.
9. pharmaceutical composition as claimed in claim 1, the method for micronization of described active component adopts spray drying method, fluid bed supersonic jet mill method, speed lapping method, ball-milling method, fluid energy mill method or solvent method.
10. pharmaceutical composition as claimed in claim 1, is characterized in that momestasone furoate single using dosage is 50-500 μ g, epinephrine broxaterol single using dosage 1-100 μ g.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN107243080A (en) * | 2017-06-21 | 2017-10-13 | 上海上药信谊药厂有限公司 | A kind of Inhaled aerosol, its feedstock composition and preparation method |
| CN111729087A (en) * | 2020-07-24 | 2020-10-02 | 成都大学 | Lipid modifier of selective beta 2 receptor agonist and preparation method and application thereof |
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| US20030075172A1 (en) * | 2001-10-19 | 2003-04-24 | Johnson Keith A. | Method and apparatus for dispensing inhalator medicament |
| CN101756942A (en) * | 2008-12-25 | 2010-06-30 | 天津金耀集团有限公司 | Oral lung inhalation aerosol powder |
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- 2013-05-29 CN CN201310205573.3A patent/CN104208688A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| US20030075172A1 (en) * | 2001-10-19 | 2003-04-24 | Johnson Keith A. | Method and apparatus for dispensing inhalator medicament |
| CN101756942A (en) * | 2008-12-25 | 2010-06-30 | 天津金耀集团有限公司 | Oral lung inhalation aerosol powder |
Non-Patent Citations (1)
| Title |
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| 王德炳: "《内科学》", 31 January 2012 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107243080A (en) * | 2017-06-21 | 2017-10-13 | 上海上药信谊药厂有限公司 | A kind of Inhaled aerosol, its feedstock composition and preparation method |
| CN107243080B (en) * | 2017-06-21 | 2021-11-12 | 上海上药信谊药厂有限公司 | Inhalation type aerosol, raw material composition and preparation method thereof |
| CN111729087A (en) * | 2020-07-24 | 2020-10-02 | 成都大学 | Lipid modifier of selective beta 2 receptor agonist and preparation method and application thereof |
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