JP2010111592A - Agent for local administration containing fluticasone propionate - Google Patents

Abstract

Disclosed is a topical administration agent capable of retaining fluticasone propionate microparticles as an active ingredient in a mucous membrane for a long time to achieve higher therapeutic effect and sustained action.
Fluticasone propionate microparticles, consisting of needle-like crystals grown radially around a fluticasone propionate crystal nucleus, having an average particle size in the range of 10 to 60 μm.
[Selection figure] None

Description

  The present invention relates to a topical preparation containing fluticasone propionate. More specifically, the present invention relates to a topical administration agent that can exert a high therapeutic effect and sustained action by allowing fluticasone propionate particles to adhere efficiently to the mucosa and staying longer on the mucosa.

  Fluticasone propionate (Fluticasone Propionate) is widely used as a corticosteroid that suppresses various inflammations such as allergic rhinitis such as hay fever, vasomotor rhinitis, bronchitis, or bronchial asthma. For rhinitis such as allergic rhinitis and vasomotor rhinitis, a means of applying an aqueous solution containing fluticasone propionate to the nasal mucosa in a fine mist using a quantitative spray type nasal solution is employed. This nasal spray (for example, “Flunase” (registered trademark), sold by GlaxoSmithKline Co., Ltd.) is considered to have local side effects and has almost no side effects on the whole body. Sneezing, runny nose and nose associated with rhinitis Especially effective for clogging.

  The above-mentioned nasal drops containing fluticasone propionate as an active ingredient is an aqueous suspension containing fine particles of fluticasone propionate crystals, which are pulverized into fine particles having an average particle size of about 1 to 10 μm. It is prepared by suspending uniformly in a medium. In addition, cellulose, carmellose sodium, glucose, phenylethyl alcohol, polysorbate 80 and the like are generally used as additives for this nasal preparation as an additive for preparation in order to facilitate atomization. However, the fine particles of fluticasone propionate contained in the sprayed suspension cannot stay on the nasal mucosal surface for a long time, drop off or disappear from the mucosal surface in a short time after spraying, and have a low duration of action. Has the problem of becoming.

  An object of the present invention is to provide a topical preparation containing fluticasone propionate, and more specifically, fluticasone propionate fine particles, which are active ingredients, are retained in the mucosa for a long period of time, resulting in higher therapeutic effect and sustained action. It is in providing the topical administration agent which can achieve.

  In order to solve the above-mentioned problems, the present inventors diligently investigated the relationship between the properties of fluticasone propionate fine particles, mucoadhesiveness and action duration. As a result, the fine radiating needle-like crystal lump with a particle size of 5 to 50 μm obtained by the crystallization method shows high adhesion to the mucous membrane, and an aqueous suspension in which these fine particles are dispersed is locally administered. When used as an agent, it was found that a higher drug retention was obtained compared to conventional topical administration agents, and higher therapeutic effects and sustained action could be achieved. The present invention has been completed based on the above findings.

That is, according to the present invention, there are provided fluticasone propionate microparticles, which are composed of needle-like crystals radially grown around the fluticasone propionate crystal nucleus and having an average particle diameter in the range of 10 to 60 μm.
According to a preferred embodiment of the present invention, the fine particles having a particle size of fluticasone propionate crystal nucleus of 2 to 10 μm; the fine particles of needle crystals having a length of 2 to 30 μm; an average particle size of 10 to 50 μm The above microparticles are provided.

From another aspect, according to the present invention, there is provided a method for producing the above fluticasone propionate microparticles, the step of adding a suspension containing fluticasone propionate crystal nuclei to a homogeneous solution containing fluticasone propionate in a crystallization solvent; And a method comprising adding water to the resulting suspension and stirring.
From yet another aspect, the present invention provides a topical preparation comprising an aqueous suspension of the above fluticasone propionate microparticles.

  Since the fluticasone propionate microparticles of the present invention exhibit high adhesion to mucous membranes, they are characterized by high drug retention compared to conventional topical agents and excellent action persistence. In addition, the fine particles have excellent solubility in biological components, and can achieve a higher therapeutic effect.

  The fluticasone propionate fine particles provided by the present invention are needle-shaped crystals grown radially around the fluticasone propionate crystal nucleus, and are characterized in that they are fine particles having an average particle diameter in the range of 10 to 60 μm (hereinafter referred to as “fine particles”). In the present specification, the fine particles may be referred to as “radiating needle-like crystal lumps”).

  As the crystal nucleus used for the production of the fine particles of the present invention, for example, a fine powder of acicular crystals of fluticasone propionate can be used. The average particle size of the fine powder is not particularly limited, but is, for example, about 0.5 to 10 μm, preferably about 2 to 10 μm. The upper limit of the particle size is not particularly limited, but is, for example, 50 μm or less, preferably 20 μm or less. The above fine powder is generally obtained by pulverizing acicular crystals of fluticasone propionate by an appropriate means and sizing as necessary. For example, the fine powder is pulverized by a means such as a hammer mill or a colloid mill. Things can be used.

  The fine particles of the present invention include the above crystal nuclei and needle-like crystals grown radially around the crystal nuclei. The size of the acicular crystal is not particularly limited, but generally the length (major axis) is about 2 to 30 μm, preferably about 5 to 20 μm, and the width (minor axis) is about 0.5 to 5 μm, preferably It is about 0.5-2 μm.

  Generally, the fine particles of the present invention contain needle-like crystals grown radially in at least two directions, preferably in three directions or more, more preferably in multiple directions around the crystal nucleus, for example, substantially spherical or rugby balls. It is a crystal lump having a three-dimensional shape like a mold. The average particle size of the fine particles of the present invention is in the range of about 10 to 60 μm, preferably in the range of about 10 to 50 μm. The upper limit of the particle size of the fine particles of the present invention is about 100 μm or less, preferably about 80 μm or less.

  The fine particles of the present invention are prepared by, for example, uniformly dissolving fluticasone propionate in a crystallization solvent, adding a suspension containing fluticasone propionate crystal nuclei to the obtained solution, and further adding water to lower the solubility. It can manufacture by stirring it. As the crystallization solvent, an organic solvent which can be mixed with water and can dissolve fluticasone propionate can be used. For example, ethanol, methanol, acetone, tetrahydrofuran and the like can be used, but ethanol is preferably used from the viewpoint of the safety of the residual solvent. The concentration of fluticasone propionate in this solution is not particularly limited, but is, for example, 1 to 3.5 g / L, preferably about 2 to 3.5 g / L, and is preferably a concentration close to the saturation concentration. When ethanol is used as the crystallization solvent, the concentration can be, for example, about 2.0 to 4.0 g / L, preferably about 3.0 to 3.5 g / L.

  As the fluticasone propionate crystal nuclei, the crystal nuclei having the average particle diameter described above can be used. Generally, the crystal nuclei are suspended in a mixture of a crystallization solvent and water or water, and the fluticasone propionate is used. Can be added to the solution. For example, when ethanol is used as a crystallization solvent, crystal nuclei can be suspended in a mixture of water and ethanol. For example, 1 to 10% by mass, preferably about 5% by mass of ethanol as a mixture of water and ethanol. Water containing can be used. The concentration of crystal nuclei in the suspension is not particularly limited. For example, the concentration may be about 10 to 100 g / L, preferably about 30 to 60 g / L, and more preferably about 40 g / L. Yes, but not limited to this concentration. The volume of the crystal nucleus suspension to be added can be, for example, about 1 to 5 parts by volume with respect to 100 parts by volume of the solution containing fluticasone propionate. It can be appropriately selected depending on the concentration. Moreover, the mass of the crystal nucleus to be added is 0.1 to 5 parts by mass, preferably 0.5 to 2 parts by mass, and more preferably about 1 part by mass with respect to 100 masses of fluticasone propionate in the solution.

  Add the above crystal nucleus suspension to a solution in which fluticasone propionate is uniformly dissolved and stir to obtain a uniform suspension, and then add water to this suspension to increase the solubility of fluticasone propionate. By gradually agitating while decreasing, acicular crystals grow around the crystal nucleus, and the fine particles of the present invention can be obtained. The volume of water to be added is not particularly limited, and a volume capable of forming a supersaturated state by sufficiently reducing the solubility of fluticasone propionate in a solution containing fluticasone propionate may be appropriately selected. For example, when preparing a fluticasone propionate solution with a concentration close to saturation using ethanol as a crystallization solvent, the volume of the solution is about 2 to 10 times, preferably about 3 to 5 times the volume of the solution. Water can be added. Although the speed at which water is added is not particularly limited, it should be added as slowly as possible, and it is not preferable to add all or most of the water at one time. For example, it is preferable to gradually form a supersaturated state by dropping or injecting water over 30 minutes to several hours. Moreover, it is preferable to stir the solution when adding water, and it is preferable to continue stirring after the addition of water. According to the above method, needle crystals can be grown radially around the crystal nucleus to produce the fine particles of the present invention, but the fine particle production method of the present invention is not limited to the above specific method. . The obtained fine particles can be collected and dried according to a conventional method.

  Among the topical retention preparations containing the fine particles of the present invention, nasal drops can be prepared as a quantitative spray type nasal drop in the form of an aqueous suspension in the same manner as a commercially available fluticasone propionate nasal drop. In addition, it can be used for the treatment and / or prevention of rhinitis such as allergic rhinitis and vasomotor rhinitis in the same manner as commercially available fluticasone propionate. Several types of fluticasone propionate nasal drops are commercially available, and the use of pharmaceutical additives such as cellulose, carmellose sodium, glucose, phenylethyl alcohol, polysorbate 80, etc. Nasal agents can be prepared. The concentration of fluticasone propionate in the nasal drops of the present invention can be appropriately selected, but is generally about 0.5 to 0.6 mg / mL, preferably about 0.51 mg / mL as in the case of commercially available preparations. It is desirable to prepare the formulation so that about 50 μg of fine particles are sprayed per dose (one spray). Furthermore, these fine particles (locally retained type) can be mixed with an appropriate powder and used as a transpulmonary inhaler to be used for the treatment of asthma. In this case, other drugs such as β stimulants may be added.

EXAMPLES Hereinafter, although an Example demonstrates this invention further more concretely, the scope of the present invention is not limited to the following Example.
Example 1
A. Materials and Methods PLGA (polylactic acid / glycolic acid copolymer: PLGA 5008, Wako Pure Chemical Industries, Ltd.) having a composition ratio (molar ratio) of D, L-lactic acid and glycolic acid as a biodegradable polymer of 50:50 and a weight average molecular weight of 8,000 CVP (carboxyvinyl polymer: Hibiswako 104, manufactured by Wako Pure Chemical Industries, Ltd.) was used as mucoadhesive fine particles. Purified water was used as the water. As fluticasone propionate (hereinafter sometimes abbreviated as “FP” in the examples), a powder obtained by pulverizing acicular crystals (average particle size of about 1 μm) is used as a starting material, and FP is quantified by measuring the absorbance with a spectrophotometer. Analysis was performed under the following conditions using measurement or high performance liquid chromatography (HPLC).

Absorbance measurement spectrophotometer: Hitachi U-1800
Cell: Quartz glass optical path length: 1cm
Wavelength: UV 236 nm
HPLC measurement
HPLC: Hitachi L-2000 Series Column: Inert Sil ODS-3 4.6φ x 250mm (GL Sciences)
Column temperature: 40 ° C
Eluent: Acetonitrile / 0.6% ammonium acetate (80/20, v / v)
Flow rate: 0.8 mL / min
Detector: UV 239 nm (peak area value)
Retention time: FP approx. 5.7 min

(1) Preparation method of adhesive FP particles
FP was granulated to have a particle size of several tens of μm. For particle preparation, (a) O / W method in which FP is dissolved in dichloromethane together with the polymer to form an oil-in-water emulsion in a dispersion solvent, and (b) FP is dissolved in acetone or ethanol, and water is added while stirring. A crystallization method was used in which crystals were gradually added to precipitate crystals. As the conditions for granulation, the following 4 types of A to D are adopted, and among these fine particles A and C, 5% CVP is added to the weight of the particles, and a rotation and revolution mixer (Awa) CVP coating was performed by stirring for 5 minutes with Tori Netaro AR-250 (Sinky) and the effect was evaluated.

(1-A) Preparation of Fine Particle A The fine particle A was prepared using an O / W method. 10 mg of the polymer and 90 mg of the drug were weighed, 6 mL of dichloromethane was added, and the mixture was stirred and dissolved in an ultrasonic water bath to obtain an oil phase. This was put into 18 mL of 0.1% polyvinyl alcohol (PVA) aqueous solution as a dispersion solvent, and stirred to form an O / W emulsion. This O / W emulsion was further poured into 900 mL of a 0.1% PVA aqueous solution and stirred for 5 hours to volatilize dichloromethane and atomize. The obtained particles were washed with water, and the particle suspension was freeze-dried to obtain spherical particles having an average particle size of about 20 to 30 μm.

(1-B) Preparation of Fine Particle B Fine particle B was prepared using a crystallization method. FP crystals were precipitated by dissolving 100 mg of the FP drug substance in 10 mL of acetone, and adding and mixing 40 mL of water over about 1 minute while stirring. The obtained crystal was washed with water, and the particle suspension was freeze-dried to obtain a needle-like crystal having a length of about 50 to 100 μm.

(1-C) Preparation of Fine Particle C Fine particle C was prepared using a crystallization method. 200 mg of FP drug substance was dissolved in 60 mL of ethanol to prepare an almost saturated FP solution. Separately, 20 mg of FP bulk was weighed and suspended in 0.5 mL of a 5% ethanol water mixture to prepare an FP crystal nucleus additive solution. By adding the entire amount of the FP crystal nucleus addition solution into the FP solution, undissolved FP bulk particles were suspended in the FP solution. While stirring this with a stirrer, 240 mL of water was gently added at a rate of 2 mL / min for 120 minutes using an HPLC pump, and the precipitated FP was grown to reach the core FP particles. The obtained crystals were washed with water, and the particle suspension was freeze-dried to obtain radial needle-like crystals having an average particle size of about 30 to 50 μm.

(1-D) Preparation of Fine Particle D Fine particle D was prepared by a crystallization method under the condition that the precipitation time of fine particle C was shortened and the amount of precipitation was halved. 100 mg of the FP drug substance was dissolved in 30 mL of ethanol to prepare an almost saturated FP solution. Separately, 20 mg of FP bulk was weighed and suspended in 0.5 mL of 5% ethanol in water to prepare an FP crystal nucleus additive solution. By adding the entire amount of the FP crystal nucleus addition solution into the FP solution, undissolved FP bulk particles were suspended in the FP solution. While stirring this with a stirrer, 120 mL of water was dropped from the center of stirring at a rate of 5 mL / min for 24 minutes using an HPLC pump, and the precipitated FP was grown to reach the core FP particles. The obtained crystals were washed with water, and the particle suspension was freeze-dried to obtain a mixture of radial needle crystals having an average particle diameter of about 30 to 50 μm and needle crystals having a length of about 50 μm.

(2) Evaluation of mucoadhesiveness Evaluation of mucoadhesiveness was performed on the inverted intestinal tract of rat small intestine cut to 8 cm with known amounts of each microparticle and control commercial preparation (Millicarette: sold by Asuka Pharmaceutical Co., Ltd. and Skylon: Dainippon Sumitomo Pharma Co., Ltd.) was brought into contact, 1 mL of PBS was added, and the mixture was allowed to stand at 37 ° C. for a certain time. The intestinal tract sufficiently in contact with the drug particles was submerged in 20 mL of PBS and gently shaken to separate the non-adherent drug particles. The supernatant was used as a measurement sample by adding 20 mL of acetonitrile to the intestinal tract to which the drug was attached, extracting the drug, and diluting by adding 10 mL of water. Absorbance at a wavelength of 236 nm was measured with a spectrophotometer to quantify the amount of drug attached. The adhesion rate was evaluated by determining the percentage of the drug amount adhering to the intestinal tract with respect to the added drug amount.

(3) Evaluation of local retention over time in the nasal mucosa 10 μL of suspension suspension was injected into the right nasal cavity of rats under ether anesthesia, and each group was euthanized by collecting whole blood under ether anesthesia over time. The right nasal cavity was removed. The excised nasal tissue was taken into a glass vial, added with 3 mL of HPLC mobile phase, and finely crushed with an ophthalmic scissor. After treatment with ultrasonic waves (water bath) for 5 minutes, the drug was extracted and homogenized by stirring. A part of the extract was taken in a microtube, centrifuged to precipitate the solid component, and the supernatant was analyzed by HPLC. The drug solution for administration was adjusted so that the particle concentration of FP was 2.5 to 3 mg / mL based on the detection sensitivity and the amount of nasal fluid that could be applied to rats. Since the FP particle concentration is 0.51 mg / mL for both the commercial preparations Millicalet and Skylon as controls, the drug substance concentration is increased by adding the FP drug substance to the commercial preparation solution in accordance with this evaluation system. It was.

(4) Solubility of microparticles C in biological components Rat heparin plasma was used as a biological sample, and diluted 25-fold and 4-fold with PBS to prepare 25% and 50% rat plasma. As a control, PBS was used as a sample containing no biological component. 1 mL of the sample solution was added to 1 mg of fine particles C, and the mixture was gently stirred in a constant temperature bath at 37 ° C. Immediately after preparation (0 hours), remove the drug particles from 0.20μm filtration filter (DISMIC-25CS ADVANTEC) and prepare FP concentration in the filtrate by HPLC. did.

B results
(1) FP granulation method and particle shape
(1-A) Fine particles A:
Particles A prepared by the O / W method were spherical with an average particle size of about 20 to 30 μm, and the surface was relatively smooth (FIG. 1).
(1-B) Fine particle B:
FP was crystallized by changing the solubility by adding water to the FP solution completely dissolved in acetone to obtain needle-like crystals having a length of about 50-100 μm (FIG. 1). In this crystallization method, it is considered that crystals grew in one direction to form needle-like crystals. No coating was performed on the particles.

(1-C) Fine particles C:
In the fine particles C, the granular FP base material, which is the core, was suspended in advance and crystals were grown in multiple directions. FP was dissolved to near saturation using ethanol as a solvent for FP, and after the introduction of the original FP core particles, water was added slowly to grow crystals. The obtained crystal lump was a needle-like crystal lump (radial needle-like crystal lump) having a substantially spherical outer shape and radially extending with an average particle diameter of about 30 to 50 μm (FIG. 1).
Moreover, the surface of this crystal lump was not smooth, but the particle diameter was uniform. A portion of this crystal was coated with CVP to compare its mucoadhesive properties. However, when CVP coating was applied, a portion of the radiating needle-like crystal lump on the particle surface collapsed, resulting in a mixed state with a large amount of needle-like crystals. (Figure 2).

(1-D) Fine particles D:
The obtained crystals were a mixture of radiating needle-like crystals with an average particle diameter of about 30-50 μm, similar to that of fine particles C, and needle-like crystals with a length of about 50 μm, similar to fine particles B (Fig. 1). . As a result of increasing the flow rate of water and dripping water into the stirring center and accelerating the diffusion and mixing of water more rapidly, the dripping instantaneously creates new crystal nuclei near the interface between water and ethanol, which are acicular crystals. It is thought that it became. Since the fine particles D are not homogeneous and contain acicular crystals, the CVP coating was not performed.

(2) Evaluation of mucoadhesiveness In the microparticles using PLGA in this evaluation system conducted with other drugs, the adhesion rate to the rat inverted intestinal tract was about 20%. When the adhesion rate of FP (the raw material before granulation) was confirmed, it was about 40%, and it was confirmed that FP is relatively easy to adhere to the inverted intestinal tract even without adding a mucoadhesive component such as CVP. Therefore, the fine particles A to D and the FP drug substance prepared to adhere to the rat inversion intestinal tract were compared. The results are shown in Table 1. The average adherence rate of the base particles was 40.5%, whereas the adherence rate of the granulated particles was generally high, and the highest fine particle C was 77.1%, which was about twice as high. .

  CVP coating was applied to the fine particles A that are easy to coat CVP, a polymer with mucoadhesive properties, and the fine particles C, which had the highest particle adhesion rate, and the adhesion due to the presence or absence of coating was compared. The adhesion rate of fine particle A was increased by coating CVP, but no difference was observed with fine particle C due to the presence or absence of CVP. In either case, the adhesion rate was as high as about 80% (Table 2). .

  Since the fine particles C showed a high adhesion rate even without coating with CVP, the adhesion in the state of suspension preparations was compared for the commercial preparations Millicalet and Skylon. Fine particles C were suspended in a suspension medium obtained by centrifuging drug particles from a commercially available millicaret to prepare a test preparation. Compared to about 80% when suspended in PBS, the average value was 47.3%, but the adhesion rate was about 47.3%, compared to 23.9% for millicaret and 21.6% for Skylon. Shown (Table 3). From these facts, the fine particles C have high mucoadhesive properties in the particles themselves, and even when diluted to the concentration of commercial preparations and in viscous suspension media, they have higher mucoadhesive properties than conventional FP drug particles. It was confirmed to show sex.

(3) Evaluation of nasal mucosal retention Suspension of fine particles C was suspended using the test preparation prepared by adding FP active particles to the commercial preparations Millicalet and Skylon and the centrifugal supernatant of Millicalet as the suspension medium. The test preparation was dropped into the rat nasal cavity so that the amount of drug administered was about 25-30 μg, and the amount of drug remaining over time at the administration site was measured. The amount of residual drug at the administration site 6 hours after administration was compared. The average residual drug amounts of millicaret and skylon at 6 hours after administration were 0.4 and 0.3 μg, respectively, and about 1-2% of the dose. In contrast, the test preparation prepared from microparticles C gave an average value of 3.4 μg. This residual drug amount was equivalent to about 11% of the dose, and the residual rate was about 8 to 10 times that of the test preparation prepared from the commercial preparation (Table 4).

  Compared to FP particles contained in commercially available preparations, microparticle C was considered to have a very high retention in the nasal mucosa, so it remained over time at the administration site of the test preparation prepared from millicaret or microparticle C. We compared the transition of quantity. The dosage was 25 μg / animal for the test preparation prepared from millicaret and 30 μg / animal for the test preparation prepared from microparticle C. The results are shown in Figure 3. In the test preparation prepared from millicaret, the drug decreased from the administration site over time, whereas the microparticle C had an almost constant residual amount at about 10% of the dose from 3 hours to 12 hours after administration. Was showing. Further, since the residual amount of the fine particles C at 24 hours after the administration was smaller than the residual amount at 12 hours after the administration, it was considered that the risk of residual and accumulation of these particles was low. In the group of test preparations prepared from millicaret, 1 of 3 cases was observed at 12 hours after administration, and 2 of 3 cases were below the lower limit of quantification at 24 hours after administration. For the residual FP amount of these individuals, the lower limit of quantification of 0.2 μg was substituted, and all time points were expressed as the mean value and SD of 3 cases. Further, in the test preparation group prepared from millicaret, the value at 24 hours after administration is not reliable as an absolute value, so in FIG. 3, the period from 12 hours to 24 hours after administration is shown as a broken line.

(4) Solubility in biological components To confirm the solubility of microparticles C in biological components, microparticles C were added to diluted rat plasma, and the FP concentration in the sample excluding the particles was measured over time (Figure 4). . The FP concentration in the sample suspended in phosphate buffered saline (PBS) was below the lower limit of detection at any time, and it was confirmed that undissolved FP particles were not mixed in the operation. It was considered that the FP concentration was higher in the sample with a lot of rat plasma components, and the biological components contained in the plasma solubilized FP. From these facts, it can be concluded that the microparticles C are taken into the living body in the presence of biological components.

(5) Preparation of preparation for transpulmonary administration For pulmonary administration, it is preferable that the radial particles are small and monodispersed. Therefore, in order to prevent aggregation, an aqueous solution in which polyvinyl alcohol (PVA) was added at 0.5% in the water for precipitation was prepared. This was added using a pump in the same manner as in 1-C above, to obtain FP radial needle crystals. The crystals had a needle-like crystal length distribution of 5 to 30 μm and an average particle size of about 15 μm. When suspended in water, it was dispersed in a monodispersed state. To these particles, pulverized mannitol was mixed at a ratio (weight) of 98 to obtain a powder preparation for pulmonary administration.

It is a microscope picture of granulated FP particle. It is the microscope picture before and behind CVP coating of fine particle C. FIG. 6 is a graph showing the change (n = 3) in the amount of nasal mucosa remaining over time after the FP particle simulated preparation was instilled into the rat nasal cavity. It is the figure which showed the solubility (n = 1) to the rat diluted plasma of microparticles | fine-particles.

Claims (7)

Fluticasone propionate microparticles, consisting of acicular crystals grown radially around the fluticasone propionate crystal nucleus, having an average particle size in the range of 10 to 60 μm. The fine particles according to claim 1, wherein the particle diameter of the fluticasone propionate crystal nucleus is 0.5 to 10 µm. The fine particles according to claim 1 or 2, wherein the length of the needle-like crystal is 2 to 30 µm. The method for producing fluticasone propionate fine particles according to any one of claims 1 to 3, wherein a suspension containing fluticasone propionate crystal nuclei is added to a homogeneous solution containing fluticasone propionate in a crystallization solvent. And adding water to the resulting suspension and stirring. The process according to claim 4, wherein the crystallization solvent is ethanol. A nasal drop comprising an aqueous suspension of fluticasone propionate microparticles according to any one of claims 1 to 3. A powdery inhaler for pulmonary administration comprising the fluticasone propionate microparticles according to any one of claims 1 to 3.