CN106619594A - Pharmaceutical composition - Google Patents
Pharmaceutical composition Download PDFInfo
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- CN106619594A CN106619594A CN201611197925.5A CN201611197925A CN106619594A CN 106619594 A CN106619594 A CN 106619594A CN 201611197925 A CN201611197925 A CN 201611197925A CN 106619594 A CN106619594 A CN 106619594A
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- CN
- China
- Prior art keywords
- afromoterol
- umeclidinium
- pharmaceutical composition
- composition
- groups
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
- A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
Abstract
The invention belongs to the technical field of pharmaceutical preparations and particularly relates to a pharmaceutical composition. The pharmaceutical composition contains active components including Arformoterol and Umeclidinium bromide, wherein the mass factions of Arformoterol and Umeclidinium bromide are 0.002%-10%; and in necessity, the pharmaceutical composition can be in a form of a solvate or a hydrate and can contain a pharmacologically acceptable aid. The pharmaceutical composition has the beneficial effects of accurate dosage, long treatment effect duration time, good comprehensive effect, high effect taking speed, good safety and stability, convenience in use and low cost.
Description
Technical field
The invention belongs to technical field of medicine, and in particular to a kind of pharmaceutical composition.
Background technology
Asthma is the chronic airway inflammation disease participated in by various kinds of cell and cell component.This chronic inflammation causes air flue
The increase of high response, clinic panted with repeated relapsing, it is out of breath, uncomfortable in chest or cough etc. as its main symptomatic characteristics.WHO is reported
The whole world about 1.5 hundred million patients, there are about every year 100000 people and die from asthma.Over nearly 10 years, asthma includes the illness of asthma in children
The rate whole world is in rising trend, and asthma has become that student is absent from school, adult delays work even affects the main cause of labour, is respiratory tract
The higher disease of the incidence of disease in disease.
Chronic obstructive pulmonary disease(COPD)It is a kind of common respiratory disease, its pathogenesis is because long-term a large amount of
Suction deleterious particle, smog or gas, cause pulmonary abnormalities inflammatory reaction, return to bronchiostenosis obstruction and lung tissue elasticity
Contracting power is reduced, and causes flow limitation relevant, and this flow limitation can not completely be recovered normal and can be increased with progressive.
The prevention of COPD mainly avoids the high risk factor fallen ill, the risk factor and enhancing immunity of organism of acute exacerbation
Power, smoking cessation is the important measures for preventing COPD.Control occupation and environmental pollution, reduce the suction of pernicious gas or deleterious particle,
The abnormal inflammatory reaction of air flue and lung can be mitigated.For the crowd for there are COPD high risk factors, lung function monitoring should be periodically carried out, with
Early detection COPD as far as possible is simultaneously intervened in time.
At present, the treatment method for the treatment of or prevention of asthma and COPD includes using one or more long acting bronchodilator
Medicine, the such as activators of β 2, anticholinergic drug, inhaled hormone (ICS) or its combination.
Anticholinergic agents and β 2 receptor agonist can be constituted jointly is easy to the preparation of clinical practice, and makes two class medicines
Bronchiectasis effect is superimposed.Newest COPD treatment guidelines emphasize that use in conjunction bronchodilator is more more effective than being used alone,
The generation for clinical symptoms can significantly more be alleviated, improving PFT and reduce bad reaction.
Afromoterol(Arformoterol)It is a kind of selective Long-effect β_2 reactant excitomotor agent, it is slow for long term maintenance therapy
Property obstructive lung disease(COPD)The broncho-constriction symptoms for causing, including chronic bronchitis and pulmonary emphysema.Afromoterol is good fortune
Mo Teluo's(R, R)Enantiomter, is a kind of selective long-acting beta 2 adrenoreceptor agonists, and its drug effect is Fu Mote
2 times of sieve raceme, be(S, S)1000 times of enantiomter.Afromoterol generation effect mainly make airway smooth muscle with
The beta 2 receptor on mast cell membrane surface is upset and excited, reaches diastole airway smooth muscle, reduces mast cell, reduces micro-
SOA is alleviated in permeability, swing of increase airway epithelia cilium of blood vessel etc..
Umeclidinium(Umeclidinium bromide)It is a kind of long-acting anticholinergic agent, it is with M-ChR M1-M5
Hypotype has close compatibility, and pharmacological action is presented by suppressing smooth muscle M3 acceptors, causes diastole bronchus.People with it is dynamic
This competitive and reversible antagonism is shown on object inner recipient and isolated organ sample.2014, FDA approval Ge Lan
The umeclidinium inhalant of plain SmithKline Products is listed as long-term anticholinergic drug, and umeclidinium is a kind of new cholinolytic
Energy medicine, acts on, rapid-action, long action time similar with Tiotropium Bromide.Additionally, also safer after umeclidinium use.
COPD patient using after single dose and multi-agent umeclidinium, well-tolerated and clinical symptoms improve notable.
Afromoterol acts on the beta 2-receptor on airway smooth muscle cells film, makees airway smooth muscle diastole, umeclidinium
For big airways surrounding smooth flesh and muscle tonue is blocked, two kinds of mechanism play diastole bronchus work jointly during two kinds of drug combinations
With.
The content of the invention
The present invention provides the pharmaceutical composition that a kind of active component is Afromoterol and umeclidinium, its can be used for treatment or
Prevention of asthma and COPD.
A kind of composition of medicine, the active component in said composition is Afromoterol and umeclidinium, active component
Weight fraction be 0.002% to 10%, it may be necessary to be solvate or hydrate forms and if necessary can with pharmacologically may be used
The auxiliary agent for bearing is constituted together;
Preferably, Afromoterol and umeclidinium weight ratio are 1:1 to 1:20,
It is more highly preferred to, Afromoterol and umeclidinium weight ratio are 1:3 to 1:12.
Heretofore described Afromoterol can be tartrate, maleate, sulfate, hydrochloride, hydrobromate,
Phosphate, acetate, fumarate, citrate etc., preferably sulfate and hydrochloride.
Heretofore described pharmaceutical composition, first use active material dosage is 5ug to 500ug, preferably 20ug
To 200ug.
The suction preparation of Afromoterol and umeclidinium pharmaceutical composition, described suction preparation bag are provided in the present invention
Include inhalation aerosol, inhalation powder spray, suction atomized liquid.Said preparation also includes corresponding auxiliary agent and carrier.
The active ingredient particle diameter of heretofore described pharmaceutical composition need to be controlled, preferably 0.1 to 5 μm of particulate
The form of change.
When the active ingredient of composition is aerosol delivery, can be suspended or dissolved in propellant mixture, can use
Propellant include hydrofluoroalkane(It is preferred that HFA227 and HFA134A, R-152A), carbon dioxide, nitrogen, propane, iso-butane, wherein
Every kind of propellant mixedly can in the composition be used individually or with other propellants.In said preparation, preferred propellant is
HFA134 and/or HFA227;The mixture for HFA-134A and HFA-227 being more highly preferred to, wherein HFA-134A and HFA-227
The grain density that the density of mixture suspends with composition is same or like;Absolute ethyl alcohol, isopropanol, propane diols can also be added
Deng the surfactant such as dispersant and oleic acid, polyvinylpyrrolidone, lecithin, tween.
When composition active ingredient is used as powder spray, optional carrier is lactose, mannitol, trehalose, malt
One or more of sugar etc. or amino acid such as glycine, above-mentioned carrier can be used first with one or more, can add magnesium stearate
It is used in combination Deng lubricant.
When composition active ingredient for suction liquid medicine when, optional solvent be water, ethanol, propane diols, polyethylene glycol,
Glycerine etc. or one or more solvents therein, can also add polyvinylpyrrolidone, oleic acid, ethyl oleate, lecithin, dehydration
The surfactants such as Span such as tween, can also add glucose sugar, sodium chloride isosmoticity conditioning agent or EDTA chelas
The pH adjusting agent such as mixture or hydrochloric acid, sulfuric acid, phosphoric acid, citric acid, NaOH.
The preparation method of heretofore described preparation is consistent with prior art.
Research repeatedly in terms of pharmacology to Afromoterol and cholinolytic class medicine of the invention, with finding Afromoterol and grassland
The composition of bromine ammonium has wider combination than scope, when for the patient for treating asthma and COPD, and is used alone A Fu
Compare when special sieve or umeclidinium, the effect of the composition of the active component of the present invention is more preferable.Composition of the present invention with
Afromoterol Ipratropium Bromide composition, Wei Lanteluo umeclidinium compositions are compared, and with latency period length, are more suitable for COPD
Long-term treatment advantage.Simultaneously accurately, curative effect lasting time is long, and resultant effect is good, instant effect for dosage of the present invention, safety
Good, the good stability of property, easy to use, low price.
Specific embodiment
Embodiment 1
Formulation in the present embodiment is aerosol, and its concrete component and parts by weight are as follows:
Component:Weight:(%)
Maleic acid Afromoterol 0.006
Umeclidinium 0.060
Absolute ethyl alcohol 1.00
HFC-134a 98.934
Its preparation method is as follows:
(1), by the solid material air-flow crushing of said components, and using Particle Size Analyzer inspection crush after solid material,
Qualified raw material is placed in and is dried vessel interior sealing and saves backup;
(2), by said components proportioning crush after solid material and absolute ethyl alcohol, propellant be collectively disposed at sealing high pressure prepare
In tank, after high speed is homogeneous, inspection prepare liquid content, by recipe quantity will prepare liquid pour into add cap valve and sealing and taken out
In the pressure vessel of vacuum.
Embodiment 2
Formulation in the present embodiment is aerosol, and its concrete component and parts by weight are as follows:
Component:Weight:(%)
Maleic acid Afromoterol 0.014
Umeclidinium 0.086
HFC-134a 14.400
Heptafluoro-propane 85.500
(1), by solid material air-flow crushing, and using Particle Size Analyzer inspection crush after solid material, qualified raw material
It is placed in and is dried vessel interior sealing and saves backup;
(2), the raw material and propellant of recipe quantity be collectively disposed in the high pressure preparing tank of sealing, after high speed is homogeneous, inspection is prepared
The content of liquid, is poured in the pressure vessel for having added cap valve and having sealed and vacuumized by recipe quantity by liquid is prepared.
Embodiment 3
Formulation in the present embodiment is powder spray, and its concrete component and parts by weight are as follows:
Component:Weight:(%)
Maleic acid Afromoterol 0.82
Umeclidinium 6.56
Lactose 92.62
Preparation process is as follows:
(1)By solid material air-flow crushing, and using the solid material after Particle Size Analyzer inspection crushing, qualified raw material is put
Save backup in vessel interior sealing is dried;
(2)The raw material of recipe quantity is well mixed with lactose.
(3)Fill into capsule, bubble-cap or bank.
Embodiment 4
Formulation in the present embodiment is powder spray, and its concrete component and parts by weight are as follows:
Component:Weight:(%)
Sulfuric acid Afromoterol 0.064
Umeclidinium 0.576
Lactose 99.360
Preparation process is as follows:
(1)By solid material air-flow crushing, and using the solid material after Particle Size Analyzer inspection crushing, qualified raw material is put
Save backup in vessel interior sealing is dried;
(2)The raw material of recipe quantity is well mixed with lactose.
(3)Fill into capsule, bubble-cap or bank.
Embodiment 5
Formulation in the present embodiment is atomized liquid, and its concrete component and parts by weight are as follows:
Component:Weight:(%)
Maleic acid Afromoterol 0.0008
Umeclidinium 0.0024
Hydrochloric acid 0.0001
Sodium chloride 0.7100
Water for injection 99.2867
The preparation process of Neulized inhalation liquid is as follows:
(1)Raw material is dissolved in water for injection;
(2)Adjust pH;
(3)Filtration sterilization, in filling plastic bottle.
The present invention is tested its compound effect with Afromoterol umeclidinium as representative by following pharmacological test procedures
Card.
Embodiment 6:Antagonism of the Afromoterol umeclidinium to asthma attack
Experimental technique:60 qualified cavys of primary dcreening operation are randomly divided into into 6 groups, 10 per group.Respectively saline control group(A
Group), Afromoterol treatment control group(B groups), umeclidinium treatment group(C groups), Afromoterol Ipratropium Bromide treatment group(D
Group), Afromoterol umeclidinium treatment group(E groups), Wei Lanteluo umeclidiniums treatment group(F groups).Put cavy close in 4L containers
Close in vial, by Central oxygen-supply, inhaled with the jet atomization of 5L/rain flows and treated.Difference Inhale physiological saline,
Afromoterol, umeclidinium, Afromoterol Ipratropium Bromide, Afromoterol umeclidinium, Wei Lanteluo umeclidiniums 120s.Even
Continue 4 days empirically administrations, after administration 0.5h (the 1st day), 1h (the 2nd day), 2h (the 3rd day), 3h (the 4th day), by cavy
In 4L container closure vials, inhale 0.8% histamine phosphate solution 10s and lure with the jet atomization of 5L/rain flows and breathe heavily, record globefish
There is III degree of asthma in mouse(Twitch and fall)Incubation period, if there is not III degree of asthma in 360s, incubation period is with 360s calculating.
The each treatment group of table 1 causes the preclinical impact of asthma to cavy induction
Group | Dosage(mg/L) | Before administration | 30min after administration | 1h after asthmatic latent period administration | 2h after administration | 3h after administration |
A groups | 58.1±7.8 | 60.3±9.3 | 58.4±8.7 | 61.2±9.6 | 59.7±10.1 | |
B groups | 0.03mg | 61.4±8.3 | 98.5±9.8 | 118.2±9.2 | 128.1±7.8 | 118.8±6.8 |
C groups | 0.28mg | 59.7±5.5 | 121.4±6.9 | 137.7±8.5 | 154.9±7.3 | 158.3±5.4 |
D groups | 0.28mg | 58.8±6.2 | 138.8±7.1 | 154.3±7.8 | 163.1±7.2 | 172.0±7.6 |
E groups | 0.28mg | 60.6±7.4 | 151.9±6.8 | 161.5±7.3 | 178.8±7.6 | 182.2±9.2 |
F groups | 0.28mg | 59.3±5.9 | 141.5±6.7 | 148.7±7.2 | 169.0±7.4 | 171.9±7.5 |
Above table as shown by data, in the group using the Afromoterol with dosage, umeclidinium, Afromoterol and Ipratropium Bromide
Close, the combination of Afromoterol and umeclidinium, when the combination of Wei Lanteluo umeclidiniums is used to test, each treatment group substantially prolongs
Long asthma attack incubation period, but Afromoterol is long with the asthmatic latent period of the combination of umeclidinium, acts on more notable, and than dimension
Lan Teluo umeclidiniums effect lasts are stablized.
Embodiment 7:Impact of the Afromoterol umeclidinium to COPD airway inflammations
Experimental technique:60 qualified cavys of primary dcreening operation are randomly divided into into 6 groups, 10 per group.Respectively saline control group(A
Group), Afromoterol treatment control group(B groups), umeclidinium treatment group(C groups), Afromoterol Ipratropium Bromide treatment group(D
Group), Afromoterol umeclidinium treatment group(E groups), Wei Lanteluo umeclidiniums treatment group(F groups).Each group experiment the 1st,
Tracheal strips inject lipopolysaccharides 1mg/kg within 20 days, in 2-19, rat are put in 80cmX60cmX60cm lucite in 21-40 days
Passive smoking, daily 2 times(Interval 4h), lasting 1h every time(It is approximately equivalent to passively suck 10 cigarettes).Each treatment group is making
Mould 2-19, gives respectively corresponding medicine+physiological saline 5ml for 21-40 days, with 5L/rain Neulized inhalations,(It is placed in
In 30cmX30cmX20cm glass boxs), 1 time/d, 25min/ time, successive administration 40 days.Model control group is given only physiological saline
Neulized inhalation.10 healthy rats are separately taken as blank(0 group), only give physiological saline atomization during experiment on time and inhale
Enter, do not do other any process.Bronchoalveolar lavage fluid is detected after 40 days(BALF)White blood cell count(WBC) and classification.
The classification of total white blood cells in the BALF of table 2(%, x ± s)
Group | Sum | Macrophage | Neutrophil leucocyte | Lymphocyte |
0 group(Normally) | 2.14±0.28 | 98.36±1.82 | 4.02±1.31 | 3.72±0.27 |
A groups | 6.39±0.45 | 63.16±2.19 | 21.58±1.52 | 8.94±0.43 |
B groups | 4.82±0.37 | 78.36±1.56 | 18.73±1.46 | 6.32±0.29 |
C groups | 4.36±0.42 | 79.32±1.93 | 16.15±1.37 | 6.12±0.27 |
D groups | 3.41±0.43 | 85.39±1.25 | 12.47±1.63 | 5.18±0.31 |
E groups | 2.94±0.32 | 92.21±0.89 | 9.35±1.26 | 4.62±0.21 |
F groups | 3.24±0.38 | 82.34±1.12 | 11.25±1.49 | 5.21±0.32 |
In above table data, each administration group has certain anti-inflammatory protective effect, the leucocyte of E groups to COPD pulmonary functions
Sum sum in each administration group is minimum, and from macrophage, neutrophil leucocyte also indicates that atomization is inhaled with the quantity of lymphocyte
Enter Afromoterol umeclidinium antiinflammatory action significantly better than Ipratropium Bromide or Afromoterol or Wei Lanteluo umeclidiniums, so
It is more suitable for the long-term treatment of COPD.
Claims (5)
1. a kind of composition of medicine, it is characterised in that:Active component in said composition is Afromoterol and umeclidinium, is lived
Property composition weight fraction be 0.002% to 10%.
2. pharmaceutical composition according to claim 1, it is characterised in that:Described Afromoterol and umeclidinium weight ratio
For 1:1-1:20.
3. pharmaceutical composition according to claim 2, it is characterised in that:Described Afromoterol and umeclidinium weight ratio
For 1:3-1:12.
4. according to the composition of the medicine in claim 1, it is characterised in that:Described Afromoterol is tartrate, Malaysia
One kind in hydrochlorate, sulfate, hydrochloride, hydrobromate, phosphate, acetate, fumarate, citric acid.
5. according to the composition of the medicine in claim 4, it is characterised in that:Described Afromoterol is sulfate or hydrochloric acid
Salt.
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Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
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CN103930095A (en) * | 2011-08-08 | 2014-07-16 | 普罗索尼克斯有限公司 | Eutectic mixture for pulmonary administration |
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Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
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CN103930095A (en) * | 2011-08-08 | 2014-07-16 | 普罗索尼克斯有限公司 | Eutectic mixture for pulmonary administration |
Non-Patent Citations (1)
Title |
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M CAZZOLA等: "The scientific rationale for combining long-acting beta(2)-agonists and muscarinic antagonists in COPD", 《PULMONARY PHARMACOLOGY & THERAPEUTICS》 * |
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