CN106137965A - A kind of aerosol drug composition containing ciclesonide - Google Patents
A kind of aerosol drug composition containing ciclesonide Download PDFInfo
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- CN106137965A CN106137965A CN201510130924.8A CN201510130924A CN106137965A CN 106137965 A CN106137965 A CN 106137965A CN 201510130924 A CN201510130924 A CN 201510130924A CN 106137965 A CN106137965 A CN 106137965A
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- pharmaceutical composition
- ciclesonide
- inhalation aerosol
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Abstract
The present invention relates to ciclesonide and amino acid especially leucine or phenylalanine is made and can be sucked the suspended aerosol of suspended aerosol drug composition suction, this suspended aerosol keeps preferably suspended stability, also improves homogeneity and the convenience of drug use simultaneously.
Description
Technical field:
The ciclesonide that the present invention relates to treat breathing problem especially asthma, chronic obstructive pneumonia, tracheitis etc. sucks suspended 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, and secretion increase, myxedema and two kinds of factors of inflammatory stimulus smooth muscle spasm that airway obstruction is caused by tunica mucosa bronchiorum inflammation cause；And airway reactivity increases the result being also due to the bronchial epithelial cell damage that airway inflammation causes.It is recognized that only control the inflammation of airway mucus, can be only achieved final reduction airway hyperreactivity, the purpose alleviating SOA.The drug main of the PUD Ds such as treatment asthma to have following several at present: (1) broxaterol, (2) xanthine drug, (3) anticholinergic agent, (4) glucocorticoid, (5) antiallergic.China's document " inhaled corticosteroids generation is learned and pharmacodynamics " (Wang Changzheng, practical hospital clinical magazine, the 1st phase of volume 4 in January, 2007,16-18) point out, suck parahormone (ICS) and have become as the first-line drug of asthma long-term treatment, such as budesonide, fluticasone propionate, momestasone furoate, ciclesonide etc..The document also indicates that, preferable ICS should be the perfect adaptation of validity and security, though ICS existing huge progress in terms of the security for the treatment of compared with systemic hormonal, still can not meet the needs of clinical treatment well.Long-term, high-dose uses ICS still to there will be the bad reactions such as adrenal cortex function suppression, and the ICS (secondary heavy dose) being used alone so-called safe dose can't efficiently control severe asthma in majority, ciclesonide is exactly one particularly important in this kind of medicine.
The imbedibility respiratory tract preparations such as treatment asthma common are aerosol and Foradil Aerolizer formoterol fumarate, wherein aerosol refers to that the emulsion of pastille or suspension and suitable propellant fill jointly and is encapsulated in the pressure vessel with special valve system, during use by propellant pressure by content be spray ejection, for lung suck preparation；Foradil Aerolizer formoterol fumarate refers to or one or more medicine, enters respiratory tract through special doser after being administered in dry powder form, plays a kind of pharmaceutical dosage form of whole body or local action；Aerosol is liquid and uses propellant, Foradil Aerolizer formoterol fumarate is then the solid containing carrier, exist significantly different for galenic pharmacy angle between two kinds of formulations, aerosol formulation it is critical only that research emulsion or the uniformity of suspension and stability, the preparation of Foradil Aerolizer formoterol fumarate is crucial is then the micromeritics technology between the different solid particle of research.
Supensoid agent produced problem the easiest from unlike Foradil Aerolizer formoterol fumarate is the non-uniformity problem of medicine after placement, need Long-Time Service and disease that can be fatal especially as treatment, such as medicine during asthma etc., this inhomogeneities just more causes problem, that is in certain stage, it is more than labelled amount that medicine feeds dosage, and certain stage, medicine feeds dosage and is less than labelled amount, bad reaction can be caused more than labelled amount, and it is likely to result in administration deficiency less than labelled amount, disease is possible to occur during treating.
Amino acid is a kind of common medicine, it is also possible to use as excipient substance, and especially amino acid can use as the carrier in Foradil Aerolizer formoterol fumarate (powder spray), has no report in aerosol.
Content of the invention:
We have surprisingly found that, when ciclesonide, amino acid especially leucine or phenylalanine are made and can be sucked suspended aerosol drug composition, can effectively improve stability in suspended aerosol for the ciclesonide and homogeneity, this is probably, and amino acid molecular is electrically charged in the solution with ciclesonide particulate to influence each other, and forms compound by electrostatic attraction effect；Compound can change the physicochemical properties of ciclesonide particulate, the liquid that ciclesonide particulate is easier to propellant, solvent form is made to mix faster, thus keep preferably suspended stability, also improve homogeneity and the convenience of drug use simultaneously！
A kind of inhalation aerosol pharmaceutical composition, the pharmaceutic adjuvant being administered containing ciclesonide, amino acid, the inhalation aerosol that one or more are applicable to.
Above-mentioned inhalation aerosol pharmaceutical composition, it is characterised in that amino acid is leucine, one or more in phenylalanine.
Above-mentioned inhalation aerosol pharmaceutical composition, it is characterised in that amino acid is leucine.
Above-mentioned inhalation aerosol pharmaceutical composition, it is characterised in that amino acid is phenylalanine.
Above-mentioned inhalation aerosol pharmaceutical composition, described pharmaceutic adjuvant includes pharmaceutically useful propellant and other the optional additives being applicable to aerosol；Described propellant is one or more in fluorohydrocarbon compounds.It is preferably the one in HFA 134a (HFA134a) and HFC-227ea (HFA 227) or a combination thereof, it is preferred to use HFA134a.Described additives comprise solvent, selected from glycerine, propane diols, polyethylene glycol, ethanol or oleic acid, ethanol is preferably used.
Above-mentioned inhalation aerosol pharmaceutical composition, it is characterised in that the weight of ciclesonide and amino acid is than for 1:0.1-10.
Above-mentioned inhalation aerosol pharmaceutical composition, it is characterised in that the weight of ciclesonide and amino acid is than for 1:0.5-2.
Above-mentioned inhalation aerosol pharmaceutical composition, it is characterised in that the D90 particle diameter of ciclesonide is 0.1-10 μm.
Described additives can also include other low volatility component, including other alcohol, glycol, such as alkanol, such as decyl alcohol (decyl alcohol), includes D-sorbite, mannitol, lactitol, the sugar alcohol of maltitol, glycofural (tetrahydrofuran base methyl alcohol) and dipropylene glycol.Including vegetable oil, organic acid such as include dodecylic acid and tetradecanoic acid and stearic saturated carboxylic acid；Including sorbic acid, the particularly unsaturated carboxylic acid of oleic acid, known to be applied to aerosol, to improve the physical stability of drug suspension, it is used for keeping the na non agglomerating composition of suspended particulate to have as dispersant: saccharin, ascorbic acid, cyclamic acid, amino acid or Aspartame；Alkane such as dodecane and octadecane；Terpenes such as menthol, eucalyptol, citrene；Sugar is such as lactose, glucose, sucrose；Polysaccharide such as ethyl cellulose, dextran；Antioxidant such as Yoshinox BHT, ascorbic acid, sodium pyrosulfite, butylated hydroxyanisol；Polymer such as polyvinyl alcohol, polyvinyl acetate, polyvinylpyrrolidone；Amine such as monoethanolamine, diethanol amine, triethanolamine；Steroid such as cholesterol, cholesteryl ester.Other low volatile components can be added without.
The preparation method of described aerosol is: adds the active component micro mist of recipe quantity in aerosol bottle, opens the valve on bottle, imported the mixture of the propellant of premixing and optional additives by valve, closes valve, obtains required aerosol.Optional ultra sonic bath is carried out with solubilising to aerosol bottle
Or following preparation method can be used: be distributed to micronized active component in additives, add in the propellant after precooling and mix, then be dispensed in aerosol bottle.
Detailed description of the invention
Micronizing of the present invention can use known mechanical crushing method or spray drying process.Mechanical crushing method refers to the particle diameter required for utilizing the method for fluid energy mill to be broken into active component and carrier powder respectively.Spray drying process refers to entirely be dissolved in ciclesonide or carrier in organic solvent such as ethanol, through spray dryer, the particle diameter required for making solid material.Surfactant such as poloxamer etc. can also be added when using spray drying process.
Micronized medicine embodiment: will introduce the method for drug micronization in following particulate embodiment, by the following method can be according to Particle size requirements by solid drugs micronizing.
D90 particle diameter refers to that the cumulative particle sizes percentile of a sample reaches particle diameter corresponding when 90%.
Particulate embodiment 1
Ciclesonide is dissolved in ethanol, and after filtration, filtrate is spray-dried, and micronizing is allowed to D90 particle diameter and reaches 2 μm.
Process conditions are: inlet temperature is 105 DEG C, and outlet temperature is 68 DEG C, throughput 90%, and jet expansion internal diameter is 0.1cm, nozzle air flow velocity 800ml/min, sample introduction speed 50mL/h
Particulate embodiment 2
Ciclesonide is dissolved in ethanol, and after filtration, filtrate is spray-dried, and micronizing is allowed to D90 particle diameter and reaches 4 μm.
Process conditions are: inlet temperature is 105 DEG C, and outlet temperature is 68 DEG C, throughput 90%, and jet expansion internal diameter is 0.1cm, nozzle air flow velocity 800ml/min, sample introduction speed 50mL/h.
Particulate embodiment 3
Ciclesonide 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, throughput 90%, and jet expansion internal diameter is 0.1cm, nozzle air flow velocity 800ml/min, sample introduction speed 50mL/h.
Particulate embodiment 4
Take ciclesonide fluid energy mill and be micronized to D90 particle diameter 7 μm.
The preparation of aerosol, ethanol used is absolute ethyl alcohol, and active component used is 0.5-10 μm for being micronized to D90 particle diameter.The dose valve system using different size makes the aerosol preparing can reach required and often presses dosage.
Embodiment 1
Preparation technology: ciclesonide and the phenylalanine of recipe quantity being added ethanol, stirring, divided dose is filling, sealing-in dose valve system, and repressurization injects HFA227 respectively, to obtain final product.Often press ciclesonide 50 μ g.
Embodiment 2
Preparation technology: ciclesonide and the leucine of recipe quantity being added ethanol, stirring, divided dose is filling, sealing-in dose valve system, and repressurization injects HFA134a respectively, to obtain final product.Often press ciclesonide 100 μ g.
Comparative examples
Preparation technology: the glucocorticoid of recipe quantity being added ethanol, stirring, divided dose is filling, 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, detect embodiment 1-1 embodiment 5-4, the settling ratio H of the supensoid agent of reference examples 1-1～reference examples 5-4.Settling ratio through detection all samples 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 colorimetric cylinder or the medicine once referring to will be equipped with test medicine, around by its center of gravity according to one's conscience with the axis of horizontal plane at vertical plane inward turning turnback to the mouth of pipe or bottleneck towards the original opposite direction pointed 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 towards the opposite direction of original sensing.It is sub-packed in 25mL nessler colorimetric tube, after room temperature static placement 2d, spin upside down colorimetric cylinder to bottom without precipitation, without grumeleuse in suspension.Record average upset number of times.When upset experiment 1 shows to use 25ml nessler colorimetric tube as experimental facilities, the sample redisperse characteristic of all embodiments and reference examples is basically identical without significant difference.
Upset experiment 2
Use embodiment 1-1 embodiment 2-4 having dispensed, reference examples 1-1～reference examples 2-2, after standing 2d, often group sampling 10 bottles, after overturning 4 times, samples 0.1ml at the bottom of bottle, survey the concentration of wherein insoluble drugs and the ratio of nominal value, and carry out experimental result and see table, Data Processing in Experiment uses the independent samples t-test (X average ± s, n=10) of SAS system
Upset experiment 2 shows, the suspension that the embodiment of the present invention provides, and after the packaging being distributed into 20ml specification, after carrying out upset experiment, the content of its insoluble drugs recording from sampling at the bottom of bottle is basically identical with nominal value.And the aerosol suspension of comparative examples, then there is obvious gap (P ＜ 0.05) from the content of insoluble drugs that sampling at the bottom of bottle records with nominal value.Illustrate in fact, the redisperse characteristic using the supensoid agent of different prescription when carrying out upset experiment is not consistent, and the present invention passes through optimizing prescriptions, provides a kind of redisperse characteristic more preferable aerosol suspension.
Shaking experiment 1
Aerosol suspension after the packing that the employing embodiment of the present invention and reference examples provide, method of testing is: forearm stretches out and plane-parallel, hand-held eye drops medicine bottle, bottleneck vertically upward, with ancon as axle, in vertical guide quick rotate 90 ° of forearm to and horizontal plane, now bottleneck direction is and plane-parallel, then quickly rotating forearm to original position, completing this process for shaking once, each shaking activity should complete in 1s.
Use embodiment 1-1 embodiment 2-4 having dispensed, reference examples 1-1～reference examples 2-2, after standing 2d, often group sampling 10 bottles, after shaking 4 times, samples 0.1ml at the bottom of bottle, survey the concentration of wherein insoluble drugs and the ratio of nominal value, and carry out experimental result and see table, Data Processing in Experiment uses the independent samples t-test (X average ± s, n=10) of SAS system
Shaking experiment shows, the suspension that the embodiment of the present invention provides, and after the packaging being distributed into 10ml specification, after carrying out upset experiment, its content sampling the insoluble drugs recording from bottleneck is basically identical with nominal value.And the aerosol suspension of comparative examples, then there is obvious gap (P ＜ 0.05) from the content of insoluble drugs that sampling at the bottom of bottle records with nominal value.Illustrate in fact, the redisperse characteristic using the supensoid agent of different prescription when carrying out upset experiment is not consistent, and the present invention passes through optimizing prescriptions, provides a kind of redisperse characteristic more preferable aerosol suspension.Prior art provides supensoid agent, is not more suitable for using the redisperse mode of shaking.
Later stage uniformity testing
Each 10 bottles of aerosol suspension after the packing that the employing embodiment of the present invention and reference examples provide, often bottled have aerosol 50ml.After standing 180 days, overturn 2 times according to method in upset experiment 2, spray the 2% of aerosol at once, remaining time aerosol is uprightly placed, the concentration of the insoluble drugs measuring aerosol on the 50th day and the ratio of nominal value, experimental result see table, and Data Processing in Experiment uses the independent samples t-test (X average ± s, n=10) of SAS system
It is experimentally confirmed, use the insoluble drugs aerosol suspension of different prescription, during persistently using, 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, less violent concussion and flipped form carry out redisperse, during whole use, to the last also can also keep the homogeneity of content, embody preferable redisperse characteristic, and the suspension in reference examples is when using same upset or concussion form, redispersibility is just poor, the concentration of phase liquid there occurs significant change after a procedure.
Claims (10)
1. an inhalation aerosol pharmaceutical composition, containing ciclesonide, amino acid, one or more are applicable to
The pharmaceutic adjuvant that inhalation aerosol is administered.
2. inhalation aerosol pharmaceutical composition as claimed in claim 1, it is characterised in that amino acid is leucine, phenylpropyl alcohol
One or more in propylhomoserin.
3. 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.
4. inhalation aerosol pharmaceutical composition as claimed in claim 3, is characterized in that described propellant is fluorohydrocarbon
One or more in compounds.
5. inhalation aerosol pharmaceutical composition as claimed in claim 3, is characterized in that described propellant is 1,1,1,2
One in-HFC-134a (HFA134a) and 1,1,1.2,3,3,3-heptafluoro-propane (HFA227) or its group
Close.
6. inhalation aerosol pharmaceutical composition as claimed in claim 3, is characterized in that containing in additives solvent,
Solvent is selected from glycerine, one or more in propane diols, polyethylene glycol, ethanol or oleic acid.
7. inhalation aerosol pharmaceutical composition as claimed in claim 6, is characterized in that described solvent is ethanol.
8. inhalation aerosol pharmaceutical composition as claimed in claim 1, it is characterised in that the weight of ciclesonide and amino acid
Amount ratio is 1:0.1-10.
9. inhalation aerosol pharmaceutical composition as claimed in claim 1, it is characterised in that the weight of ciclesonide and amino acid
Amount ratio is 1:0.5-2.
10. inhalation aerosol pharmaceutical composition as claimed in claim 1, it is characterised in that the D90 particle diameter of ciclesonide is
0.1-10μm。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510130924.8A CN106137965A (en) | 2015-03-25 | 2015-03-25 | A kind of aerosol drug composition containing ciclesonide |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510130924.8A CN106137965A (en) | 2015-03-25 | 2015-03-25 | A kind of aerosol drug composition containing ciclesonide |
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| CN106137965A true CN106137965A (en) | 2016-11-23 |
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| CN201510130924.8A Pending CN106137965A (en) | 2015-03-25 | 2015-03-25 | A kind of aerosol drug composition containing ciclesonide |
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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 |
| WO2002005784A1 (en) * | 2000-07-17 | 2002-01-24 | Aeropharm Technology, Inc. | A medicinal aerosol formulation |
-
2015
- 2015-03-25 CN CN201510130924.8A patent/CN106137965A/en active Pending
Patent Citations (3)
| 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 |
| WO2002005784A1 (en) * | 2000-07-17 | 2002-01-24 | Aeropharm Technology, Inc. | A medicinal aerosol formulation |
Non-Patent Citations (1)
| Title |
|---|
| 张庆宪，等: "《常用新药精汇手册》", 28 February 2009, 河南科学技术出版社 * |
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Application publication date: 20161123 |