CN106137964A - A kind of aerosol drug compositions containing beclometasone - Google Patents
A kind of aerosol drug compositions containing beclometasone Download PDFInfo
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- CN106137964A CN106137964A CN201510130084.5A CN201510130084A CN106137964A CN 106137964 A CN106137964 A CN 106137964A CN 201510130084 A CN201510130084 A CN 201510130084A CN 106137964 A CN106137964 A CN 106137964A
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- pharmaceutical composition
- beclometasone
- inhalation aerosol
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- aerosol pharmaceutical
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Abstract
The present invention relates to beclometasone and aminoacid especially leucine or phenylalanine is made and can be sucked suspendible aerosol drug compositions suction suspendible aerosol, this suspendible aerosol keeps preferably suspendible stability, also improves homogeneity and the convenience of drug use simultaneously.
Description
Technical field:
The present invention relates to treat the third of respiratory tract disease especially asthma, chronic obstructive pneumonia, tracheitis etc.
Acid beclometasone sucks suspendible aerosol, the invention still further relates to the preparation method of this medicine.
Background technology:
Asthma is a kind of chronic airway inflammation, it is characterized by that Reversible airway obstruction and airway reactivity increase, gas
Road blocks secretions increase, myxedema and the inflammatory stimulus smooth muscle spasm two caused by bronchial mucosa inflammation
The factor of kind causes；And airway reactivity increases and is also due to bronchial epithelial cell damage that airway inflammation causes
Result.It is recognized that only control the inflammation of airway mucus, can be only achieved finally reduce airway hyperreactivity,
Alleviate the purpose of symptoms of asthma.The drug main treating the pulmonary disease such as asthma at present to have following several: (1) β 2-
Receptor stimulating agent, (2) xanthine drug, (3) anticholinergic agent, (4) glucocorticoid, (5) antiallergic
Medicine.China's document " inhaled corticosteroids generation is learned and pharmacodynamics " (Wang Changzheng, practical hospital clinical magazine, 2007
The 1st phase of volume 4 January year, 16-18) point out, suck parahormone (ICS) and have become as asthma long-term treatment
First-line drug, such as ciclesonide, fluticasone propionate, momestasone furoate, budesonide etc..The document is also
Pointing out, preferable ICS should be the perfect adaptation of effectiveness and safety, although ICS relatively systemic hormonal
Existing huge progress in terms of the safety for the treatment of, but 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 is used alone institute
The ICS (secondary heavy dose) of meaning safe dose can't efficiently control severe asthma in majority, beclometasone
It it is exactly the one in this kind of medicine.
The imbedibility respiratory tract preparations such as treatment asthma common are aerosol and Foradil Aerolizer formoterol fumarate, and wherein aerosol is
Refer to that emulsion or the suspension of pastille jointly fill with suitable propellant and be encapsulated in the resistance to pressure-volume with special valve system
In device, during use by propellant pressure by content be spray ejection, for pulmonary suck preparation；
Foradil Aerolizer formoterol fumarate refers to or one or more medicine, enters in dry powder form after special doser is administered
Respiratory tract, plays whole body or a kind of pharmaceutical dosage form of local action；Aerosol is liquid and uses propellant,
Foradil Aerolizer formoterol fumarate is then the solid containing carrier, exists significantly for galenic pharmacy angle between two kinds of dosage forms
Difference, emulsion or the uniformity of suspension and stability, Foradil Aerolizer formoterol fumarate are studied in it is critical only that of aerosol formulation
Preparation crucial be then the micromeritics technology between the different solid particle of research.
Suspensoid the easiest produced problem unlike Foradil Aerolizer formoterol fumarate is that after placing, the inhomogeneities of medicine is asked
Topic, especially as treatment need life-time service and can be fatal disease, such as medicine during asthma etc., this
Inhomogeneities the most more causes problem, say, that in certain stage, and it is more than labelled amount that medicine feeds dosage,
And certain stage, medicine feeds dosage and is less than labelled amount, can cause untoward reaction more than labelled amount, and is less than
Labelled amount is likely to result in administration deficiency, and disease likely occurs during treating.
Aminoacid is a kind of common medicine, it is also possible to use as excipient substance, and especially aminoacid can be made
Use for the carrier in Foradil Aerolizer formoterol fumarate (powder spray), aerosol has no report.
Summary of the invention:
We have surprisingly found that, making when beclometasone, aminoacid especially leucine or phenylalanine can
When sucking suspendible aerosol drug compositions, can effectively improve beclometasone in suspendible aerosol
Stability and homogeneity, it is the most electrically charged mutually with beclometasone microgranule that this is probably amino acid molecular
Impact, forms complex by electrostatic attraction effect；Complex can change the physico of beclometasone microgranule
Learn character, make beclometasone microgranule be easier to the liquid of propellant, solvent composition and mix faster all
Even, thus keep preferably suspendible stability, also improve homogeneity and the convenience of drug use simultaneously！
A kind of inhalation aerosol pharmaceutical composition, containing beclometasone or its ester, aminoacid, one or more fit
For inhalation aerosol be administered pharmaceutic adjuvant, beclometasone or its ester are beclometasone.
Above-mentioned inhalation aerosol pharmaceutical composition, it is characterised in that aminoacid is in leucine, phenylalanine
One or more.
Above-mentioned inhalation aerosol pharmaceutical composition, it is characterised in that aminoacid is leucine.
Above-mentioned inhalation aerosol pharmaceutical composition, it is characterised in that aminoacid is phenylalanine.
Above-mentioned inhalation aerosol pharmaceutical composition, described pharmaceutic adjuvant includes being applicable to the pharmaceutically acceptable of aerosol
Propellant and other optional additives；Described propellant is one or more in fluorohydrocarbon compounds.Preferably
For the one in 1,1,1,2-tetrafluoroethane (HFA134a) and 1,1,1,2,3,3,3-heptafluoro-propane (HFA 227)
Or a combination thereof, it is preferred to use HFA134a.Described additives comprise solvent, selected from glycerol, propylene glycol,
Polyethylene Glycol, ethanol or oleic acid, be preferably used ethanol.
Above-mentioned inhalation aerosol pharmaceutical composition, it is characterised in that beclometasone with amino acid whose weight ratio is
1:0.1-10。
Above-mentioned inhalation aerosol pharmaceutical composition, it is characterised in that beclometasone with amino acid whose weight ratio is
1:0.5-2。
Above-mentioned inhalation aerosol pharmaceutical composition, it is characterised in that the D90 particle diameter of beclometasone is 0.1-10
μm。
Described additives can also include other low volatility component, including other alcohol, glycol, such as alkanol,
Such as decanol (decyl alcohol), include Sorbitol, mannitol, lactose, the sugar alcohol of maltose alcohol, glycofural
(tetrahydrofuran base methanol) and dipropylene glycol.Dodecylic acid and ten is such as included including vegetable oil, organic acid
Four alkanoic acids and stearic saturated carboxylic acid；Including the unsaturated carboxylic acid of sorbic acid, particularly oleic acid, known should
For aerosol, to improve the physical stability of drug suspension, it is used for keeping particle as dispersant
Na non agglomerating composition has: saccharin, ascorbic acid, cyclamic acid, aminoacid or aspartame；Alkane such as ten
Dioxane and octadecane；Terpenes such as menthol, eucalyptol, limonene；Sugar is such as lactose, glucose, sucrose；Many
Sugar is such as ethyl cellulose, dextran；Antioxidant such as Yoshinox BHT, ascorbic acid, pyrosulfurous acid
Sodium, butylated hydroxyanisol；Polymer such as polyvinyl alcohol, polyvinyl acetate, polyvinylpyrrolidone；
Amine such as ethanolamine, diethanolamine, triethanolamine；Steroid such as cholesterol, cholesteryl ester.Can be added without other
Low volatile component.
The preparation method of described aerosol is: adds the active component micropowder of recipe quantity in aerosol bottle, beats
Valve in corkage, is imported the mixture of the propellant of premixing with optional additives by valve, closes valve closing
Door, obtains required aerosol.Optional aerosol bottle is carried out ultra sonic bath with solubilising
Or following preparation method can be used: be distributed in additives by micronized active component, add
Propellant after pre-cooling mixes, then is dispensed in aerosol bottle.
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 profit
Respectively active component and carrier powder are broken into required particle diameter by the method for fluid energy mill.Spray drying method refer to by
Ciclesonide or carrier are dissolved in organic solvent such as ethanol entirely, through spray dryer, solid material are made institute
The particle diameter needed.Surfactant such as poloxamer etc. can also be added when using spray drying method.
Micronized medicine embodiment: by introducing the method for drug micronization in following microgranule embodiment, by following
Method can be according to Particle size requirements by solid drugs micronization.
D90 particle diameter refers to that the cumulative particle sizes percentile of a sample reaches particle diameter corresponding when 90%.
Microgranule embodiment 1
Beclometasone is dissolved in ethanol, and after filtration, filtrate is spray-dried, and micronization is allowed to D90 particle diameter
Reach 2 μm.
Process conditions are: inlet temperature is 105 DEG C, and outlet temperature is 68 DEG C, and throughput 90%, nozzle goes out
Mouth internal diameter is 0.1cm, nozzle air flow velocity 800ml/min, sample introduction speed 50mL/h
Microgranule embodiment 2
Beclometasone is dissolved in ethanol, and after filtration, filtrate is spray-dried, and micronization is allowed to D90 particle diameter
Reach 4 μm.
Process conditions are: inlet temperature is 105 DEG C, and outlet temperature is 68 DEG C, and throughput 90%, nozzle goes out
Mouth internal diameter is 0.1cm, nozzle air flow velocity 800ml/min, sample introduction speed 50mL/h.
Microgranule embodiment 3
Beclometasone is dissolved in ethanol, and after filtration, filtrate is spray-dried, and is allowed to D90 particle diameter and reaches 5 μm.
Process conditions are: inlet temperature is 105 DEG C, and outlet temperature is 68 DEG C, and throughput 90%, nozzle goes out
Mouth internal diameter is 0.1cm, nozzle air flow velocity 800ml/min, sample introduction speed 50mL/h.
Microgranule embodiment 4
Take beclometasone fluid energy mill and be micronized to D90 particle diameter 7 μm.
The preparation of aerosol, ethanol used is dehydrated alcohol, and active component used for being micronized to D90 particle diameter is
0.5-10μm.The dose valve system using different size makes the aerosol prepared can reach required often pressing
Dosage.
Embodiment 1
Preparation technology: beclometasone and the leucine of recipe quantity are added ethanol, stirs, divided dose
Fill, sealing-in dose valve system, repressurization injects HFA134a respectively, to obtain final product.Often press propanoic acid times chlorine rice
Pine 50 μ g.
Embodiment 2
Preparation technology: beclometasone and leucine, the phenylalanine of recipe quantity are added ethanol, and stirring is all
Even, divided dose fill, sealing-in dose valve system, repressurization injects HFA227 respectively, to obtain final product.Often press third
Acid beclometasone 200 μ g.
Comparative examples
Preparation technology: the glucocorticoid of recipe quantity is added ethanol, stirs, divided dose fill, sealing-in
Dose valve system, repressurization injects propellant respectively, to obtain final product.
Redistribution EXPERIMENTAL EXAMPLE
Sedimentation volume ratio detects
According to the detection method of the ophthalmically acceptable aqueous suspension disclosed in 2010 editions annex 10 of Chinese Pharmacopoeia, detection is implemented
The settling ratio H of the suspensoid of example 1-1 embodiment 5-4, reference examples 1-1～reference examples 5-4.All through detection
The settling ratio of sample is all higher than 0.90, meets the requirement in Chinese Pharmacopoeia 2010 editions.
Upset experiment 1 rotates in vertical plane around its center of gravity
Test often overturns the color comparison tube or medicine once referring to will be equipped with testing medicine, puts down around by its center of gravity
The axis of the heart and horizontal plane at vertical plane inward turning turnback to the mouth of pipe or bottleneck towards the original negative side pointed to
To.Reversal rate is upset per second 2 times.At major axis place, plane carries out dextrorotation turnback, to the mouth of pipe
Or bottleneck is towards the original opposite direction pointed to.It is sub-packed in 25mL nessler colorimetric tube, room temperature static placement 2d
After, spin upside down color comparison tube to bottom without precipitation, without grumeleuse in suspension.Record averagely overturns number of times.Upset
When experiment 1 shows to use 25ml nessler colorimetric tube as experimental facilities, all embodiments and the sample of reference examples
Redispersion characteristic is basically identical without significant difference.
Upset experiment 2
Use embodiment 1-1 embodiment 2-4 that subpackage is good, reference examples 1-1～reference examples 2-4, stand 2d
After, often group sampling 10 bottles, after overturn 4 times, at the bottom of bottle sample 0.1ml, survey wherein insoluble drugs concentration and
The ratio of nominal value, and carry out experimental result and see table, Data Processing in Experiment uses the t in groups of SAS system
Inspection (X average ± s, n=10)
Upset experiment 2 shows, the suspension that the embodiment of the present invention provides, in the packaging being distributed into 20ml specification
After, after carrying out upset experiment, it is from content and the nominal value basic sampling the insoluble drugs recorded at the bottom of bottle
Cause.And the aerosol suspension of comparative examples, from the content and the nominal that sample the insoluble drugs recorded at the bottom of bottle
Value then also exists obvious gap (P ＜ 0.05).Illustrate it practice, use the suspensoid of different prescription turning over
Redispersion characteristic when turning experiment is not consistent, and the present invention passes through optimizing prescriptions, it is provided that a kind of redispersion is special
The more preferable aerosol suspension of property.
Shaking experiment 1
Using the aerosol suspension after the subpackage of the embodiment of the present invention and reference examples offer, method of testing is: front
Arm stretches out and plane-parallel, hand-held eye drop medicine bottle, bottleneck vertically upward, with ancon as axle, at vertical guide
In quickly rotate 90 ° of forearm to and horizontal plane, now bottleneck direction is and plane-parallel, then exists
Quickly rotating forearm to original position, complete this process for shaking once, each shaking activity should be at 1s
Inside complete.
Use embodiment 1-1 embodiment 2-4 that subpackage is good, reference examples 1-1～reference examples 2-4, stand 2d
After, often group sampling 10 bottles, after shake 4 times, at the bottom of bottle sample 0.1ml, survey wherein insoluble drugs concentration and
The ratio of nominal value, and carry out experimental result and see table, Data Processing in Experiment uses the t in groups of SAS system
Inspection (X average ± s, n=10)
Shaking experiment shows, the suspension that the embodiment of the present invention provides, after the packaging being distributed into 10ml specification,
After carrying out upset experiment, the content of its insoluble drugs recorded from bottleneck sampling is basically identical with nominal value.And
The aerosol suspension of comparative examples, then deposits with nominal value from the content sampling the insoluble drugs recorded at the bottom of bottle
In substantially gap (P ＜ 0.05).Illustrate it practice, use the suspensoid of different prescription carrying out upset experiment
Time redispersion characteristic not consistent, and the present invention passes through optimizing prescriptions, it is provided that a kind of redispersion characteristic is more preferable
Aerosol suspension.Prior art provides suspensoid, is not more suitable for using the redispersion mode of shaking.
Later stage uniformity testing
Each 10 bottles of aerosol suspension after the subpackage of the embodiment of the present invention and reference examples offer is provided, the most bottled
There is aerosol 50ml.After standing 180 days, overturn 2 times according to method in upset experiment 2, ejection gas at once
The 2% of mist agent, remaining time aerosol uprightly places, the concentration of the insoluble drugs measuring aerosol on the 50th day
With the ratio of nominal value, experimental result see table, and Data Processing in Experiment uses the independent samples t-test of SAS system
(X average ± s, n=10)
It is experimentally confirmed, uses the insoluble drugs aerosol suspension of different prescription, persistently using process
In, there is bigger difference in phase insoluble drugs content after a procedure, the suspension that the embodiment of the present invention provides,
Less even with aforementioned number of times, the most violent concussion and flipped form carry out redispersion, in whole use
Period, the most also can also keep the homogeneity of content, embody preferable redispersion characteristic, and reference examples
In suspension use same upset or concussion form time, redispersibility is the most poor, phase medicinal liquid after a procedure
Concentration there occurs significant change.
Claims (10)
1. an inhalation aerosol pharmaceutical composition, containing beclometasone or its ester, aminoacid, one or more fit
For inhalation aerosol be administered pharmaceutic adjuvant.
2. inhalation aerosol pharmaceutical composition as claimed in claim 1, it is characterised in that beclometasone or its ester are propanoic acid
Beclometasone.
3. inhalation aerosol pharmaceutical composition as claimed in claim 1, it is characterised in that aminoacid is leucine, phenylpropyl alcohol
One or more in propylhomoserin.
4. inhalation aerosol pharmaceutical composition as claimed in claim 1, described pharmaceutic adjuvant includes being applicable to gas
The pharmaceutically useful propellant of mist agent and other optional additives.
5. inhalation aerosol pharmaceutical composition as claimed in claim 4, is characterized in that described propellant is fluorohydrocarbon
One or more in compounds.
6. inhalation aerosol pharmaceutical composition as claimed in claim 4, is characterized in that described propellant is 1,1,1,2
One in-tetrafluoroethane (HFA134a) and 1,1,1.2,3,3,3-heptafluoro-propane (HFA 227) or its group
Close.
7. inhalation aerosol pharmaceutical composition as claimed in claim 4, is characterized in that containing solvent in additives,
Solvent is selected from glycerol, one or more in propylene glycol, Polyethylene Glycol, ethanol or oleic acid.
8. inhalation aerosol pharmaceutical composition as claimed in claim 7, is characterized in that described solvent is ethanol.
9. inhalation aerosol pharmaceutical composition as claimed in claim 1, it is characterised in that beclometasone or its ester and amino
The weight ratio of acid is 1:0.1-10.
10. inhalation aerosol pharmaceutical composition as claimed in claim 1, it is characterised in that beclometasone or the D90 of its ester
Particle diameter is 0.1-10 μm.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510130084.5A CN106137964A (en) | 2015-03-25 | 2015-03-25 | A kind of aerosol drug compositions containing beclometasone |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510130084.5A CN106137964A (en) | 2015-03-25 | 2015-03-25 | A kind of aerosol drug compositions containing beclometasone |
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| Publication Number | Publication Date |
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| CN106137964A true CN106137964A (en) | 2016-11-23 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN201510130084.5A Pending CN106137964A (en) | 2015-03-25 | 2015-03-25 | A kind of aerosol drug compositions containing beclometasone |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1328473A (en) * | 1998-09-22 | 2001-12-26 | 气体药品技术公司 | Medicinal aerosol formulation |
| US6458338B1 (en) * | 1998-09-22 | 2002-10-01 | Aeropharm Technology Incorporated | Amino acid stabilized medicinal aerosol formulations |
-
2015
- 2015-03-25 CN CN201510130084.5A patent/CN106137964A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1328473A (en) * | 1998-09-22 | 2001-12-26 | 气体药品技术公司 | Medicinal aerosol formulation |
| US6458338B1 (en) * | 1998-09-22 | 2002-10-01 | Aeropharm Technology Incorporated | Amino acid stabilized medicinal aerosol formulations |
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