CN103588846B - A kind of preparation method and its usage of fluticasone propionate microgranule - Google Patents
A kind of preparation method and its usage of fluticasone propionate microgranule Download PDFInfo
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Abstract
A kind of prepared sizes D98 are less than the method for the fluticasone propionate microgranule of 5 μm, use recrystallization method, fluticasone propionate raw material is dissolved in solvent and makes solution, then this solution is added in the water containing surfactant, separate out the fluticasone propionate microgranule of desired particle size.Compared with traditional method, this method yield is higher, and production cost is low, it is not necessary to depend on use special installation, and energy consumption is little.This method does not produce dust, agents useful for same nonhazardous, environmental protection；Product particle size is little, narrow particle size distribution, and roundness is high, good fluidity, is highly suitable for as pharmaceutical preparation raw material.
Description
Technical field
The invention belongs to pharmaceutical field, the method being specifically related to a kind of prepared sizes D98 fluticasone propionate microgranule below 5 μm, and this fluticasone propionate microgranule purposes in terms of preparing nasal spray, inhalation aerosol and inhalation powder spray.
Background of invention
Fluticasone propionate is a kind of adrenal hormone class medicine, is used for preventing and treat the disease such as rhinitis or asthma.
The common formulations of fluticasone propionate is nasal spray, inhalation aerosol and inhalation powder spray etc..In these formulations, fluticasone propionate is entered in human body by respiratory tract, in order to make it arrive focus and be efficiently absorbed utilization, the granularity of fluticasone propionate is had relatively strict requirements.As in American Pharmacopeia, the standard of fluticasone propionate nasal spray is: granularity requirements D98 of fluticasone propionate is below 5 μm.And the fluticasone propionate obtained by general synthetic method or recrystallization method, granularity is often as high as more than 50 μm.Therefore, the fluticasone propionate microgranule less in order to obtain granularity, need to take special method to reduce its granularity (i.e. it being carried out micronized).The method mainly using mechanical micronization in prior art.
As CN1098680C prepares fluticasone propionate mixed suspension preparation, raw material fluticasone propionate used is prepared by micronization.
CN101106975A discloses several concrete fluticasone propionate method of micronization: Strong shear mixing, spheroidal graphite, comminution by gas stream, high pressure homogenizer grinding etc..
But, there is the biggest problem for the commercial production of medicine in mechanical activation comminution means, one is intended to depend on the disintegrating apparatus of costliness, such as ball mill, high pressure homogenizer etc., relatively costly；It addition, fluticasone propionate belongs to the medicine that formulation dosage is less, the batch of crude drug is the most little, therefore has bigger loss in mechanical milling processes, and yield is low；And, crushing process is inevitably generated a large amount of dust, pollutes environment.
Accordingly, it would be desirable to a kind of the most economic, easy, the method preparing fluticasone propionate microgranule of environmental protection.
Summary of the invention:
It is an object of the invention to provide a kind of simplicity, economy, environmental protection prepare D98 less than the method for 5 μm fluticasone propionate microgranules, it is to avoid the method using mechanical micronization.
D98 refers in the fluticasone propionate fine grain final product prepared less than 5 μm, and particle diameter accounts for the 98% of granule total amount less than the grain amount of 5 μm.
Use crystallization process, the method separating out crystallization after fluticasone propionate is made solution again, although the problems that mechanical activation comminution is brought can be avoided.But, the fluticasone propionate grain size number that conventional method for crystallising obtains is relatively big, can only obtain the microgranule of tens microns, and the granularity of the formulation requirements fluticasone propionates such as fluticasone propionate spraying, suction is below 5 μm.
Crystallization process to be used obtains the fluticasone propionate of low granularity, it is necessary to find out the principal element affecting grain size number, by Experimental comparison, the condition of crystallization is selected and is optimized.
Inventor finds: it is crucial that search out suitable fluticasone propionate solvent, and select a kind of suitable anti-solvent.Described anti-solvent is the liquid substance of insoluble fluticasone propionate.Inventor passes through repetition test; have found the solvent dimethyl sulfoxide of key, N; dinethylformamide or Polyethylene Glycol; and anti-solvent surfactant and the mixture of water; fluticasone propionate micronized can well be obtained the D98 the being suitable to preparation fluticasone propionate microgranule less than 5 μm.
Concrete technical scheme is:
A kind of method preparing fluticasone propionate microgranule, uses recrystallization method, is dissolved in solvent by fluticasone propionate raw material and makes solution, then mixed with anti-solvent by this solution, separates out the fluticasone propionate microgranule of desired particle size；It is characterized in that:
1) described solvent is selected from dimethyl sulfoxide, N, one or more in N-METHYLFORMAMIDE or Polyethylene Glycol.
Described Polyethylene Glycol can be liquid, such as polyethylene glycol 200, PEG400, it is also possible to be solid-state, such as Macrogol 4000, polyethylene glycol 6000, preferably PEG400.When the solvent used is solid-state, again by fluticasone propionate material dissolution the method for heating can be used to be melted by solvent after.
2) described anti-solvent is the mixed solvent of surfactant and water, and described surfactant can select anion surfactant (such as dodecyl sodium sulfate), cationic surfactant (such as Cetyltrimethylammonium bromide, benzalkonium chloride), zwitterionic surfactant (such as lecithin) or the nonionic surfactant (such as peregal 0, tween) being suitable in pharmaceutical preparation.Surfactant is 0.01 ~ 1: 500 with the mass ratio of water.
3) addition direction when fluticasone propionate solution mixes with anti-solvent must be that solution joins in anti-solvent.
The granularity of the fluticasone propionate microgranule that this method obtains is that D98 is less than 5 μm.
Hereinafter the effect of material each in this method, consumption etc. are illustrated:
The consumption of solvent: the purpose of solvent is that raw material fluticasone propionate is made homogeneous solution, and therefore, those skilled in the art can select suitable consumption according to the actual needs, as long as homogeneous solution can be formed.When solvent is solid-state, again by material dissolution the method for heating can be used to be melted by solvent after；When solvent is liquid, in order to make dissolution velocity faster, it is also possible to heating.In order to make finished particle separate out faster, the concentration of fluticasone propionate solution can be carried out certain restriction, accordingly, it is preferred that solvent load is 1g fluticasone propionate uses 30 ~ 600g solvent.
The consumption of anti-solvent: the effect of anti-solvent is to reduce raw material dissolubility in system so that fluticasone propionate microgranule separates out.In order to make fluticasone propionate microgranule preferably separate out, the ratio of solvent and anti-solvent can be determined by test.Preferably mass ratio is 1:2 ~ 60.
Anti-solvent adds the innovation that surfactant is the present invention.Often using the atent solvent such as water, hexane as anti-solvent in traditional antisolvent crystallisation method, the present invention is off the beaten track, adds surfactant as anti-solvent in water.Test proves, time in anti-solvent without surfactant, the granularity of finished product does not reaches requirement (see comparative example 1)；And product grading D98 after adding the surfactant of trace, just can be made to reach below 5 μm.
The hybrid mode of solution and anti-solvent is another innovation of the present invention.Only using the mode joining in anti-solvent by solution to can be only achieved the purpose of the present invention and effect, the experiment proved that, anti-solvent is joined the mode in solution by employing can make the granularity (see comparative example 2) bigger than normal of finished particle.
The following is one preparation method of the present invention:
1) being joined by the fluticasone propionate of 5 ~ 30 weight portions in the Polyethylene Glycol of 500 ~ 7000 weight portions, heated and stirred makes to be completely dissolved, and obtains solution A；
2) take the dodecyl sodium sulfate of 0.2 ~ 20 weight portion, tween, lecithin, benzalkonium chloride, paregal O or/and Cetyltrimethylammonium bromide, be dissolved in the water, add water to 17000 ~ 70000 weight portions, obtain anti-solvent B；
3) under agitation, solution A is added in anti-solvent B, continuously stirred 5 ~ 30min, obtain the suspension containing fluticasone propionate microgranule.
The fluticasone propionate microgranule that this method obtains, may be used for preparing the preparation of the different dosage forms such as nasal spray, aerosol or powder spray.
Prepare nasal spray: after separating out fluticasone propionate microgranule formation suspension in solvent and anti-solvent system, the most treated, directly being fed intake as raw material by this suspension, the adjuvant conventional with nasal spray mixes, and prepares fluticasone propionate nasal spray by the conventional production process of nasal spray.
Prepare aerosol: feed intake after the suspension containing fluticasone propionate microgranule obtained above filtration, washing, be used for preparing aerosol.
Prepare powder spray: filtered by the suspension containing fluticasone propionate microgranule obtained above, wash, feed intake after drying, be used for preparing powder spray.
The solution have the advantages that:
1. production cost is low.The inventive method need not rely upon the use special installation such as ball mill, homogenizer, and energy consumption is little, and production cost is low.
2. environmental protection.Production process of the present invention does not produce dust, agents useful for same nonhazardous, is a kind of eco-friendly method.
3. product roundness height, good fluidity, be suitable to preparation.Different from general method for crystallising, products therefrom of the present invention is oval, has the advantages such as roundness height, good fluidity, is highly suitable for preparation.
4. product particle size is little, narrow particle size distribution.The present invention can obtain the D98 fluticasone propionate microgranule less than 5 μm.
Accompanying drawing explanation
Fig. 1 is embodiment 1 products therefrom fluticasone propionate microgranule image under 1000 times of optical microscopes.(in figure, the minimum scale of gage is 1 μm).
Detailed description of the invention
Below by the method for embodiment, technical scheme is specifically described, but the kind of various materials used by embodiment and consumption are not intended that the restriction to inventive technique scheme.
In the detection of following embodiment product grading: method therefor is the 3rd method (light scattering method) in " Chinese Pharmacopoeia " 2010 editions two annex IXE granularities and particle size distribution method, and instrument is Malvern laser particle size analyzer.
Prepared by embodiment 1 fluticasone propionate microgranule
Method:
1) fluticasone propionate solution A is prepared: being joined by 10g fluticasone propionate in 550g PEG400, heated and stirred makes to be completely dissolved, and obtains solution A；
2) anti-solvent B is prepared: take 2.05g Tween 80 and 1.91g benzalkonium chloride, be dissolved in the water, add water to 17050g, obtain anti-solvent B；
3) solution A and anti-solvent B hybrid mode: under agitation, solution A is added in anti-solvent B, continuously stirred 10min, obtain suspension.
Result:
Detecting with laser particle analyzer, in suspension, the D98 of fluticasone propionate microgranule is 3.47 μm, sees Fig. 1.
Embodiment 2～6
According to the kind of each material in the operational approach of embodiment 1 and table 1 and consumption, prepare fluticasone propionate microgranule.
The granularity of products therefrom fluticasone propionate microgranule is shown in Table 1.
Table 1 prepares each material variety of fluticasone propionate microgranule use, consumption, product particle size
Comparative example 1 anti-solvent is not added with surfactant and prepares fluticasone propionate microgranule
Method:
1) fluticasone propionate solution A is prepared, with embodiment 1；
2) anti-solvent B:17050g water (without surfactant)；
3) solution A and anti-solvent B hybrid mode, with embodiment 1.
Result: detecting with Malvern laser particle analyzer, in suspension, the D98 of fluticasone propionate microgranule is 19.45 μm.
Conclusion: when preparing desired particle size fluticasone propionate microgranule, surfactant plays a key effect in anti-solvent.
The method that comparative example 2 uses anti-solvent to add solution prepares fluticasone propionate microgranule
Method:
1) fluticasone propionate solution A is prepared, with embodiment 1；
2) anti-solvent B is prepared, with embodiment 1；
3) solution A and anti-solvent B hybrid mode: under agitation, adds anti-solvent B in solution A, continuously stirred 10min, obtains suspension.
Result: detecting with Malvern laser particle analyzer, in suspension, the D98 of fluticasone propionate microgranule is 13.23 μm.
Conclusion: reverse feed postition can not get the fluticasone propionate microgranule of desired particle size.Fluticasone propionate nasal spray prepared by the embodiment 7 fluticasone propionate microgranule of the present invention
Take 880g embodiment 1 obtains the suspension containing fluticasone propionate microgranule, 0.5g Tween 80,2.5g phenethanol, 5g glucose, 1.2g microcrystalline Cellulose, 2.5g sodium carboxymethyl cellulose, 0.2gBHT, add water to 1000g, stirring, mix homogeneously, the medicinal liquid Brown Glass Brown glass bottles and jars only fill mixed, every bottled amount 16g, installs spraying pump head, obtains fluticasone propionate nasal spray.
Fluticasone propionate powder spray prepared by the embodiment 8 fluticasone propionate microgranule of the present invention
The suspension containing fluticasone propionate microgranule obtained in Example 1, with organic membrane filtration of 0.45 μm, washes filter cake with water 6 ~ 8 times, collects medicine filter cake, in 80 DEG C of drying under reduced pressure 6h, obtains fluticasone propionate microgranule.
Take 100mg fluticasone propionate microgranule, lactose 100g, use equal increments method to be mixed evenly, fill No. 3 capsules, obtain fluticasone propionate capsule-type powder spray 300.
Fluticasone propionate aerosol prepared by the embodiment 9 fluticasone propionate microgranule of the present invention
The suspension containing fluticasone propionate microgranule obtained in Example 1, with organic membrane filtration of 0.45 μm, washes filter cake with water 6 ~ 8 times, and collection medicine filter cake, as raw material, is prepared by the method for CN1168630, obtained fluticasone propionate aerosol.
Claims (8)
1. prepared sizes D98 are less than a method for the fluticasone propionate microgranule of 5 μm, are first dissolved in solvent by fluticasone propionate raw material and make solution, then are mixed with anti-solvent by this solution, separate out the fluticasone propionate microgranule of desired particle size；It is characterized in that:
1) anti-solvent: the water containing surfactant, surfactant is 0.01～1: 500 with the mass ratio of water consumption；
2) addition direction when fluticasone propionate solution mixes with anti-solvent: must be that fluticasone propionate solution is joined in anti-solvent, and can not inversely add；
3) solvent: one or more in dimethyl sulfoxide, N,N-dimethylformamide or Polyethylene Glycol；
Described surfactant is selected from the acceptable anion surfactant of pharmaceutical preparation, cationic surfactant, zwitterionic surfactant or nonionic surfactant.
2. the method described in claim 1, described solution mixes with anti-solvent, is that fluticasone propionate solution under agitation joins in anti-solvent, and continues stirring 5min～30min, forms the suspension of the fluticasone propionate microgranule containing desired particle size.
3. the method described in claim 1, described Polyethylene Glycol is selected from polyethylene glycol 200, PEG400, Macrogol 4000 or polyethylene glycol 6000.
4. the method described in claim 1, described surfactant is selected from dodecyl sodium sulfate, Cetyltrimethylammonium bromide, benzalkonium chloride, lecithin, paregal O or tween.
5. the method described in claim 1, described solvent load is that 1g fluticasone propionate uses 30g～600g solvent.
6. the method described in claim 1, solvent is 1: 2～60 with the mass ratio of anti-solvent.
7. prepared sizes D98 are less than a method for the fluticasone propionate microgranule of 5 μm, and step is as follows:
1) being joined by the fluticasone propionate of 5～30 weight portions in the Polyethylene Glycol of 500～7000 weight portions, heated and stirred makes to be completely dissolved, and obtains solution A；
2) take the dodecyl sodium sulfate of 0.2～20 weight portions, tween, lecithin, benzalkonium chloride, paregal O or/and Cetyltrimethylammonium bromide, be dissolved in the water, add water to 17000～70000 weight portions, obtain anti-solvent B；
3) under agitation, solution A is added in anti-solvent B, continuously stirred 5min～30min, obtain the suspension containing fluticasone propionate microgranule.
8. the fluticasone propionate microgranule that in claim 1～6 prepared by arbitrary described method application in preparing nasal spray, aerosol or powder spray.
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| CN105012237B (en) * | 2015-08-10 | 2018-09-11 | 重庆华邦制药有限公司 | Fluticasone furoate nasal spray and preparation method thereof |
| 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 |
| CN113069415B (en) * | 2021-04-09 | 2022-09-09 | 湖北中医药大学 | Insoluble drug nanosuspension and preparation method thereof |
| CN114272842A (en) * | 2022-01-13 | 2022-04-05 | 南昌百济制药有限公司 | Preparation method of nasal spray |
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| US5785952A (en) * | 1990-11-09 | 1998-07-28 | Glaxo Group Limited | Aerosol medicament formulation having a surface coating of surfactant |
| CN1819818A (en) * | 2003-07-07 | 2006-08-16 | 阿斯利康(瑞典)有限公司 | Process for the preparation of micron-size crystalline particles using a solvent, a non-solvent and ultrasonic energy |
| CN101106975A (en) * | 2004-11-23 | 2008-01-16 | 维克特拉有限公司 | Dry powder inhaler formulations comprising surface-modified particles with anti-adherent additives |
| CN101636150A (en) * | 2007-04-06 | 2010-01-27 | 株式会社活效制药 | Method for producing pulverized organic compound particle |
| CN102526066A (en) * | 2010-11-23 | 2012-07-04 | 天津金耀集团有限公司 | Separate type water suspension medicament of fluticasone propionate containing auxiliary materials for treating skin disease |
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5785952A (en) * | 1990-11-09 | 1998-07-28 | Glaxo Group Limited | Aerosol medicament formulation having a surface coating of surfactant |
| CN1819818A (en) * | 2003-07-07 | 2006-08-16 | 阿斯利康(瑞典)有限公司 | Process for the preparation of micron-size crystalline particles using a solvent, a non-solvent and ultrasonic energy |
| CN101106975A (en) * | 2004-11-23 | 2008-01-16 | 维克特拉有限公司 | Dry powder inhaler formulations comprising surface-modified particles with anti-adherent additives |
| CN101636150A (en) * | 2007-04-06 | 2010-01-27 | 株式会社活效制药 | Method for producing pulverized organic compound particle |
| CN102526066A (en) * | 2010-11-23 | 2012-07-04 | 天津金耀集团有限公司 | Separate type water suspension medicament of fluticasone propionate containing auxiliary materials for treating skin disease |
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