CN105012237B - Fluticasone furoate nasal spray and preparation method thereof - Google Patents
Fluticasone furoate nasal spray and preparation method thereof Download PDFInfo
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- CN105012237B CN105012237B CN201510485900.4A CN201510485900A CN105012237B CN 105012237 B CN105012237 B CN 105012237B CN 201510485900 A CN201510485900 A CN 201510485900A CN 105012237 B CN105012237 B CN 105012237B
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Abstract
A kind of fluticasone furoate nasal spray preparation method, this method is mainly using the auxiliary material in preparation prescription as the solvent of fluticasone furoate and anti-solvent, the fluticasone furoate particle that grain size D90 is less than 5 μm is obtained by recrystallizing technology, the suspension containing the drug microparticles is mixed with other auxiliary materials of preparation prescription again, it is filling, nasal spray is made.Compared with conventional method, this method is not necessarily to special installation, high income, without dust pollution, production process environmental protection, and obtained fluticasone furoate particle size is small, narrowly distributing, particle size stable, the mist droplet particle size of nasal spray are evenly distributed exquisiteness, have good spray characteristics.
Description
Technical field
The invention belongs to pharmaceutical fields, and in particular to fluticasone furoate nasal spray preparation method, wherein furancarboxylic acid fluorine replace
The granularity D90 of Kathon CG<5μm.
Background technology
Fluticasone furoate is a kind of adrenal hormone class drug of synthesis, is usually used in preventing and treating allergic rhinitis and heavy breathing
Asthma.Fluticasone furoate nasal spray was most listed earlier than 2007, was developed for GlaxoSmithKline PLC company, trade name
Veramyst is a kind of nasal mist of the fluticasone furoate aqueous suspension containing micronizing, for treat 2 years old or more children and
The allergic rhinitis of adult.As the suspension type spray of nose, to ensure curative effect and product quality, the grain of fluticasone furoate
Degree requires control in D90<5μm.
Therefore, prepare fluticasone furoate nasal spray and first have to solve the problems, such as be main ingredient micronizing, about furancarboxylic acid
Fluticasone method of micronization document report is few, and existing micronization technology is mainly mechanical crushing such as air-flow crushing or again
Crystallization.Although mechanical crushing is simple, there are problems that, such as to high equipment cost, crushing process has greater loss, yield
It is relatively low, and unavoidably there is dust and noise pollution in production process.Patent WO2006/108572 discloses a kind of furancarboxylic acid fluorine and replaces
The recrystallization method of Kathon CG, this method select the methyl iso-butyl ketone (MIBK) containing 1~15% different base ketone of methyl as solvent, with heptane
As anti-solvent, operated continuously in the controlled micro crystallization equipment with ultrasound functions, can finally obtain grain size 5 μm with
Under fluticasone furoate particle.The patented method carries out controlled micro crystallization using organic reagent, and special controlled micro crystallization is needed to set
It is standby to realize.In addition, there are one realistic problems, the i.e. recycling of fluticasone furoate for the patented method, finally must try to
These organic solvents and anti-solvent are removed, organic residue detection qualification could be used as bulk pharmaceutical chemicals to carry out preparation and feed intake, this undoubtedly increases
Production cost and difficulty are added.In view of fluticasone furoate is a kind of hormonal medicaments of high activity, it is more suitable for using economic, letter
Just controlled micro crystallization processing is carried out with the method for environmental protection, to facilitate formulation development.
Invention content
In view of this, one of the objects of the present invention is to provide a kind of compositions preparing fluticasone furoate nasal spray
And the preparation method of fluticasone furoate nasal spray.When the composition is used to prepare fluticasone furoate nasal spray, energy
Enough ensure the granularity D90 of fluticasone furoate<5μm.The preparation method is easy to operate, is suitable for industrialized production.
To achieve the above object, the technical scheme is that：
It is used to prepare the composition of fluticasone furoate nasal spray, it is composed of the following components in parts by weight：
As a preferred option, the composition, it is composed of the following components in parts by weight：
In addition, the method for preparing fluticasone furoate nasal spray with the composition, specifically includes following steps：
1) polyethylene glycol 400 of formula ratio is uniformly mixed with the benzyl carbinol of formula ratio, adds formula ratio
The fluticasone furoate be stirred well to clarification, obtain fluticasone furoate solution；Simultaneously by the Tween 80 of formula ratio
It is fully dissolved in suitable aqueous medium with the benzalkonium chloride, obtains anti-solvent)；
2) the fluticasone furoate solution is placed in the anti-solvent, is sufficiently stirred, it is micro- to obtain fluticasone furoate
Brilliant suspension；
3) DEXTROSE ANHYDROUS of formula ratio and the natrium adetate are substantially soluble in appropriate aqueous medium, addition is matched
The microcrystalline cellulose sodium carboxymethylcellulose and stirring just measured fully are swollen to it, obtain auxiliary material mixture；And by the chaff
Sour fluticasone crystallite suspension is uniformly mixed with the auxiliary material mixture, and fluticasone furoate nasal spray is obtained after filling.
As a preferred option, the method, by the fluticasone furoate solution under stirring in step 2)
It is placed in the anti-solvent.
In above-mentioned technique, it is related to microcrystalline technology.Microcrystalline technology most importantly selects suitable solvent and anti-molten
Agent makes its precipitation using dissolubility difference of the fluticasone furoate in two kinds of solvents, obtains satisfactory particle.In order to
It can make environmental friendly, best bet is exactly that solvent and anti-solvent are all pharmaceutic adjuvants.Polyethylene glycol 400 in component is both one
Kind of good solvent and a kind of pharmaceutic adjuvant, its safety using amount in nasal spray are (non-with reference to FDA drugs up to 30%
Active constituent database).Inventor is found by experiment that, when individually dissolving fluticasone furoate with polyethylene glycol 400, dissolubility
Bad, the fluticasone furoate of a weight at least needs the polyethylene glycol 400 of 95 times of weight to be heated with stirring to 80 degree or more, and
Persistently stirring 1h or more could dissolve completely, and high temperature long agitation can make drug unstable, solution jaundice, and impurity increases
It is long.In order to reduce dissolution conditions, increase dissolubility of the solvent to drug, inventor expects that benzyl carbinol is common in nasal spray
Preservative, what is listedIn, dosage 0.25%, and benzyl carbinol itself can also make solvent, just attempt
Benzyl carbinol is added in polyethylene glycol 400, to increase the dissolubility to fluticasone furoate.It screens, finds by test of many times
When polyethylene glycol 400 and the ratio of benzyl carbinol are 10:1~20:When 1, good dissolving may be implemented in fluticasone furoate；Additionally
, 30~40min or 10~20min of 40HZ ultrasounds is stirred at room temperature and can dissolve, obtains colorless cleared solution.Therefore, exist
Suitable benzyl carbinol is added in polyethylene glycol 400, solubility of the fluticasone furoate in polyethylene glycol 400 can be increased, drops
Low dissolution conditions avoid long-time high-temperature digestion from causing drug degradation, improve stability.Fluticasone furoate is practically insoluble in
Water, therefore water can be used as anti-solvent.Inventor has found, makees anti-solvent with the water containing surfactant, thus it is possible to vary crystal
Pattern is easy to get crystal small and compared with rounding, and surfactant itself can make wetting agent and solubilizer, be conducive to prevent
Only crystallite is reunited, and keeps the stabilization of granularity.Tween 80 is common pharmaceutic adjuvant, can make wetting agent and solubilizer, is sprayed in nose
Maximum safety using amount in mist agent is 0.1%.Benzalkonium chloride is common preservative in nose spray preparation, is usually joined with benzyl carbinol
It closes and uses, enhance inhibitory effect.But benzalkonium chloride is also cationic surfactant simultaneously, has very strong surface-active.Hair
A person of good sense has found Tween 80 and benzalkonium chloride pressing 1 by Experimental Comparison：2 are dissolved in the water, and use the complexed surfactant
Aqueous solution is recrystallized as the anti-solvent of fluticasone furoate, can obtain grain size in 5 μm of fluticasone furoates below
Particle, and the particle size narrowly distributing, crystal size are stablized.It is mixed containing fluticasone furoate particle by recrystallized product
Suspension directly feeds intake, and is mixed with other auxiliary materials of preparation prescription, filling, rolls lid, obtained fluticasone furoate nasal spray,
By accelerating 6 months study on the stability, drug particle size, mist droplet particle size distribution to stablize, have no that grain size becomes larger, spray discharge pattern is good
Good, spray pattern meets USP requirement.
The second object of the present invention is to provide a kind of method improving fluticasone furoate solution solubility, this method behaviour
Make simply, to be suitable for industrial applications.
To achieve the above object, the technical scheme is that：
The method for improving fluticasone furoate solution solubility, after the polyethylene glycol 400 is mixed with the benzyl carbinol
As double solvents, for dissolving fluticasone furoate.
As a preferred option, the polyethylene glycol 400 and the volume ratio of the benzyl carbinol 10~20：1.
The volume ratio 18 of scheme more preferably, the polyethylene glycol 400 and the benzyl carbinol：1.
The third object of the present invention is to provide a kind of method of recrystallization fluticasone furoate, and this method can be easy
It obtains grain size D90 and is less than 5 μm of fluticasone furoate particles.In addition, also providing a kind of suspension containing fluticasone furoate particle
Liquid, grain size D90 are less than 5 μm.
To achieve the above object, the technical scheme is that：
A method of recrystallization fluticasone furoate includes the following steps：
The preparation of A crystalline substance fluticasone furoate solution
The polyethylene glycol 400 is uniformly mixed with the benzyl carbinol, adds the fluticasone furoate of formula ratio
It is stirred well to clarification, obtains fluticasone furoate solution；
B is recrystallized
The fluticasone furoate solution is placed in the anti-solvent, is sufficiently stirred, the furancarboxylic acid fluorine recrystallized replaces
Kathon CG crystallite suspension；The Tween 80 and the benzalkonium chloride are fully dissolved in suitable aqueous medium, obtain anti-solvent.
Further, the volume ratio of the Tween 80 and the benzalkonium chloride is 1:2.
Suspension containing fluticasone furoate particle, the suspension include following components by weight：
Specifically preparation method is：1) polyethylene glycol 400 is uniformly mixed with the benzyl carbinol, adds formula ratio
The fluticasone furoate is stirred well to clarification, obtains fluticasone furoate solution；2) Tween 80 and the benzene are pricked into chlorine
Ammonium fully dissolves in suitable aqueous medium, obtains anti-solvent；The fluticasone furoate solution is placed in the anti-solvent again,
It is sufficiently stirred, the fluticasone furoate crystallite suspension recrystallized.
Advantageous effect
Fluticasone furoate nasal spray preparation method disclosed by the invention using the auxiliary material in preparation prescription make solvent and
Anti-solvent first recrystallizes drug, realizes and is obtained grain size D90 using more environmentally friendly, simple, economy, reliable way and be less than
5 μm of fluticasone furoate crystallites.The drug suspension that the process generates can be directly used for the production of nose spray preparation, and there is no tie again
The recycling of brilliant solvent and anti-solvent and residue problem, reduce processing step, greatly shorten working hour, reduce production cost, often
Rule production equipment can be realized.The accelerated study on the stability of fluticasone furoate nasal spray prepared using this method, it was demonstrated that
Drug particle size and mist droplet granularity have good spray discharge pattern without significant change.
Specific implementation mode
Illustrated embodiment is to preferably be illustrated to present disclosure, but is not that present disclosure only limits
In illustrated embodiment.So those skilled in the art carry out nonessential change according to foregoing invention content to embodiment
Into and adjustment, still fall within protection scope of the present invention.
Embodiment 1
Preparation process is as follows：
1) polyethylene glycol 400 is uniformly mixed with benzyl carbinol, adds fluticasone furoate, 30min is stirred at room temperature, obtained
Clear solution, for use.
2) Tween 80 and benzalkonium chloride is complete with 47.5g water dissolutions, auxiliary material solution is obtained, for use.
3) under stiring, the clear solution of step 1) is poured into the auxiliary material solution of step 2), it is lasting to stir
20min obtains fluticasone furoate crystallite suspension.
4) after dissolving DEXTROSE ANHYDROUS and natrium adetate completely with 43.145g, it is fine that microcrystalline cellulose carboxymethyl is added
The plain sodium of dimension1h is stirred, so that it is fully swollen, obtains the suspension of swelling.
5) the fluticasone furoate crystallite suspension described in step 3) is added in the suspension of the step 4) swelling, is stirred
It mixes uniformly mixed.
6) filling, 50 μ l nasal sprays pump is often sprayed in every bottle of 10g, installation, and Zha Gai is to get finished product.
Embodiment 2
Preparation process is as follows：
Polyethylene glycol 400 is uniformly mixed with benzyl carbinol, adds fluticasone furoate, 40HZ ultrasound 15min must be clarified
Solution, for use.Tween 80 and benzalkonium chloride is complete with 39g water dissolutions, auxiliary material solution is obtained, for use.It under stiring, will be described
Clear solution pours into the auxiliary material solution, persistently stirs 30min, obtains fluticasone furoate crystallite suspension.It will be anhydrous
After glucose and natrium adetate are dissolved completely with 52.645g, microcrystalline cellulose sodium carboxymethylcellulose is added1h is stirred, so that it is fully swollen, obtains the suspension of swelling.Fluticasone furoate crystallite suspension is added
In the suspension for entering swelling, it is uniformly mixed.It is filling, every bottle of 10g, installation often spray 50 μ l nasal sprays pump, Zha Gai to get at
Product.
Embodiment 3
With reference to commercially available fluticasone furoate nasal sprayComposition, the chaff obtained with air-flow crushing
(D90=4.2 μm) of sour fluticasone is bulk pharmaceutical chemicals, carries out the preparation of preparation.
Preparation process is as follows：
Tween 80 and benzalkonium chloride is complete with 40g water dissolutions, auxiliary material solution is obtained, for use.The furancarboxylic acid fluorine of micronizing is replaced
Kathon CG is added in the auxiliary material solution, and homogenous disperse, obtains drug suspension, for use.By DEXTROSE ANHYDROUS and natrium adetate
After 52.2g dissolvings completely, microcrystalline cellulose sodium carboxymethylcellulose is added1h is stirred, makes it fully
Swelling, obtains the suspension of swelling.
The drug suspension is added in the suspension of the swelling, is uniformly mixed.It is filling, every bottle of 10g, installation
50 μ l nasal sprays pump is often sprayed, Zha Gai is to get finished product.
4 fluticasone furoate nasal spray quality versus of embodiment
Subjects：The nasal spray that embodiment 1 and comparative example 3 obtain
Test method：Two kinds of samples are investigated 10 days for 60 DEG C respectively at high temperature, 40 DEG C accelerate to investigate 6 months.0 is detected respectively
It, high temperature factors influencing and accelerate to investigate the drug particle size distribution, mist droplet granularity distribution and jet mode of sample (injection be horizontal
The length ratio of long axis X and short axle Y in cross-sectional image, USP requirement X/Y≤1.7).As a result it see the table below.
In terms of upper table result, the fluticasone furoate nasal spray that embodiment 1 obtains, drug particle size and mist droplet granularity ratio are real
It is small to apply example 3, and very stable, does not occur crystallite and grow up phenomenon.In addition, jet mode is also preferable, through study on the stability, jet mode
Also very stable, good spray discharge pattern can be kept.
Finally illustrate, the above examples are only used to illustrate the technical scheme of the present invention and are not limiting, although with reference to compared with
Good embodiment describes the invention in detail, it will be understood by those of ordinary skill in the art that, it can be to the skill of the present invention
Art scheme is modified or replaced equivalently, and without departing from the objective and range of technical solution of the present invention, should all be covered at this
In the right of invention.
Claims (8)
1. the method for preparing fluticasone furoate nasal spray with composition, which is characterized in that the composition is according to weight
Part meter is composed of the following components：
The double solvents is by polyethylene glycol 400 and benzyl carbinol according to 10~20:1 volume ratio composition；
Specifically include following steps：
1) polyethylene glycol 400 of formula ratio is uniformly mixed with the benzyl carbinol of formula ratio, adds the institute of formula ratio
It states fluticasone furoate and is stirred well to clarification, obtain fluticasone furoate solution；Simultaneously by the Tween 80 of formula ratio and institute
It states benzalkonium chloride fully to dissolve in suitable aqueous medium, obtains anti-solvent；
2) the fluticasone furoate solution is placed in the anti-solvent, is sufficiently stirred, it is mixed to obtain fluticasone furoate crystallite
Suspension；
3) DEXTROSE ANHYDROUS of formula ratio and the natrium adetate are substantially soluble in appropriate aqueous medium, formula ratio is added
The microcrystalline cellulose sodium carboxymethylcellulose and stir fully be swollen to it, obtain auxiliary material mixture；And by the furancarboxylic acid fluorine
It is uniformly mixed with the auxiliary material mixture for Kathon CG crystallite suspension, fluticasone furoate nasal spray is obtained after filling.
2. according to the method described in claim 1, it is characterized in that：The composition is in parts by weight by following components group
At：
3. according to the method described in claim 1, it is characterized in that, the furancarboxylic acid fluorine is replaced card under stirring in step 2)
Loose solution is placed in the anti-solvent.
4. the method for improving fluticasone furoate solution solubility, which is characterized in that after mixing polyethylene glycol 400 with benzyl carbinol
As double solvents, for dissolving fluticasone furoate, the volume ratio 10~20 of the polyethylene glycol 400 and the benzyl carbinol：
1。
5. according to the method described in claim 4, it is characterized in that, the volume ratio of the polyethylene glycol 400 and the benzyl carbinol
18：1.
6. a kind of method of recrystallization fluticasone furoate, it is characterised in that：
The preparation of A fluticasone furoate solution
Polyethylene glycol 400 is uniformly mixed with benzyl carbinol, add formula ratio the fluticasone furoate be stirred well to it is clear
Clearly, fluticasone furoate solution is obtained；The polyethylene glycol 400 and the volume ratio of the benzyl carbinol 10~20：1；
B is recrystallized
Tween 80 and benzalkonium chloride are fully dissolved in suitable aqueous medium, obtain anti-solvent；Again by fluticasone furoate solution
It is placed in the anti-solvent, is sufficiently stirred, the fluticasone furoate crystallite suspension recrystallized.
7. according to the method described in claim 6, it is characterized in that：The volume ratio of the Tween 80 and the benzalkonium chloride is 1:
2。
8. the suspension containing fluticasone furoate particle, which is characterized in that the suspension includes with the following group by weight
Point：
Fluticasone furoate 0.05-0.06；
3-6 parts of polyethylene glycol 400；
0.15-0.35 parts of benzyl carbinol；
0.002-0.02 parts of Tween 80；
0.005-0.035 parts of benzalkonium chloride；
Specifically preparation method is：
1) polyethylene glycol 400 is uniformly mixed with the benzyl carbinol, the fluticasone furoate for adding formula ratio fills
Divide and stir to clarify, obtains fluticasone furoate solution；The polyethylene glycol 400 and the volume ratio of the benzyl carbinol 10~20：1；
2) Tween 80 and the benzalkonium chloride are fully dissolved in suitable aqueous medium, obtains anti-solvent；Again by the chaff
Sour fluticasone solution is placed in the anti-solvent, is sufficiently stirred, the fluticasone furoate crystallite suspension recrystallized.
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| CN106806342A (en) * | 2015-12-01 | 2017-06-09 | 四川海思科制药有限公司 | A kind of azelastine hydrochloride fluticasone propionate nasal spray pharmaceutical composition and preparation method thereof |
| CN111380969A (en) * | 2018-12-29 | 2020-07-07 | 天津药业研究院有限公司 | Detection method for content of fluticasone furoate and related substances |
| CN112823009A (en) * | 2019-08-28 | 2021-05-18 | 上海谷森医药有限公司 | Fluticasone furoate liposome preparation and preparation method thereof |
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| CN1335787A (en) * | 1998-12-24 | 2002-02-13 | 葛兰素集团有限公司 | Apparatus and process for preparing crystalline particles |
| CA2841644A1 (en) * | 2011-08-02 | 2013-02-07 | Cipla Limited | Pharmaceutical composition comprising ebastine and fluticasone |
| CN103588846A (en) * | 2012-08-15 | 2014-02-19 | 重庆华邦制药有限公司 | Preparation method of fluticasone propionate particles and applications of the particle |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1335787A (en) * | 1998-12-24 | 2002-02-13 | 葛兰素集团有限公司 | Apparatus and process for preparing crystalline particles |
| CA2841644A1 (en) * | 2011-08-02 | 2013-02-07 | Cipla Limited | Pharmaceutical composition comprising ebastine and fluticasone |
| CN103588846A (en) * | 2012-08-15 | 2014-02-19 | 重庆华邦制药有限公司 | Preparation method of fluticasone propionate particles and applications of the particle |
Non-Patent Citations (1)
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| 糠酸氟替卡松喷鼻剂获准用于治疗季节性和常年性变应性鼻炎;雷敏;《药学进展》;20081231;第32卷(第2期);第89页 * |
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