JP2005298347A - Inhalation preparation and method for producing the same - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a preparation, exhibiting its efficacy effectively by administering it even in a small amount, showing less adverse effect, and especially useful for the treatment of allergy, asthma, rhinitis or the like. <P>SOLUTION: This inhalation preparation contains a compound expressed by formula I or its pharmaceutically acceptable salt, and preferably the compound of formula I has a form of nanoparticle having 250-400 nm mean particle diameter. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  The present invention relates to an inhalation preparation containing a known piperidine compound and a method for producing the same. More specifically, the present invention relates to an inhalation preparation wherein the compound of formula (I) is a nanoparticle.

の化合物又はその薬学的に許容される塩は公知であり、喘息等の治療に有用であることが知られている（例えば、特開平０４−３６４１５６号公報）。 The following formula (I) used in the present invention:

Or a pharmaceutically acceptable salt thereof is known and is known to be useful for the treatment of asthma and the like (for example, JP-A No. 04-364156).

  Traditionally, compounds of formula (I) have been administered orally. However, in the case of oral administration, there is a problem that a sufficient concentration of the drug does not transfer to the affected area and the therapeutic effect is low, or it takes time until the drug effect is exhibited.

  Although these problems can be solved to some extent by administering a large amount of the drug, the transfer of the drug to the affected area is still insufficient, and the large dose of the drug involves the risk of developing side effects.

Japanese Patent Laid-Open No. 04-364156 JP 08-157391 A

  An object of the present invention is to provide a preparation that exhibits a medicinal effect effectively even when administered in a small amount and has few side effects, particularly a preparation useful for treating allergies, asthma, rhinitis, and the like.

As a result of intensive studies to solve the above problems, the present inventors contain a known piperidine compound or a pharmaceutically acceptable salt thereof (hereinafter referred to as “SOA-132” in this specification) as an active ingredient. It was found that the inhalation preparation to be absorbed is effectively absorbed even in a small dose and shows a very high therapeutic effect, and side effects can be reduced, and the present invention has been completed.
That is, the present invention includes the following inventions.

の化合物又はその薬学的に許容される塩を含有する吸入製剤。 (1) The following formula I:

Or an pharmaceutically acceptable salt thereof.

(2) The inhalation preparation according to the above (1), wherein the compound of formula I is a nanoparticle having an average particle size of 250 to 400 nm.
(3) The compound of formula I is:
a) dissolving the starting compound of formula I in a good solvent and then mixing this solution with a poor solvent in which the water-soluble polymer is dissolved to obtain a suspension of the compound of formula I;
b) obtaining a powder of the compound of formula I by freeze-drying or spray-drying said suspension;
The inhalation preparation according to (1) or (2) above, which is a nanoparticle obtained by a process comprising

(4) The inhalation preparation according to any one of (1) to (3), comprising a compound of formula I and a pharmaceutically acceptable carrier, wherein the compound of formula I is attached to the surface of the carrier .
(5) The inhalation preparation according to any one of (1) to (4), which is used for treating allergy, asthma or rhinitis.

の化合物又はその薬学的に許容される塩を含有する吸入製剤の製造方法であって、原料の式Ｉの化合物を機械粉砕して粉末とし、得られた粉末を薬学的に許容される賦形剤又は担体と混合することを含む前記製造方法。 (6) Formula I below:

A method for producing an inhalation preparation comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the raw material compound of formula I is mechanically pulverized into a powder, and the resulting powder is a pharmaceutically acceptable excipient. The said manufacturing method including mixing with an agent or a support | carrier.

(7) The production method according to (6), wherein the mechanical pulverization is performed using a jet mill, a nanomizer, a ball mill, or a rod mill.

の化合物又はその薬学的に許容される塩を含有する吸入製剤の製造方法であって、以下の工程：
ａ）原料の式Ｉの化合物を良溶媒に溶解し、次いでこの溶液を水溶性高分子が溶解した貧溶媒と混合して式Ｉの化合物の懸濁液を得る工程；
ｂ）前記懸濁液を凍結乾燥又は噴霧乾燥することにより式Ｉの化合物の粉末を得る工程；
を含む前記製造方法。 (8) The following formula I:

A method for producing an inhalation preparation containing the compound or a pharmaceutically acceptable salt thereof, comprising the following steps:
a) dissolving the starting compound of formula I in a good solvent and then mixing this solution with a poor solvent in which the water-soluble polymer is dissolved to obtain a suspension of the compound of formula I;
b) obtaining a powder of the compound of formula I by freeze-drying or spray-drying said suspension;
The said manufacturing method containing.

(9) The production method according to (8), wherein the good solvent is a mixed solvent of a lower alcohol and water.
(10) The production method according to (8) or (9), wherein the water-soluble polymer is polyvinyl alcohol.
(11) Following step b), the following step c):
c) mixing and stirring the powder of the compound of formula I and a pharmaceutically acceptable carrier to adhere the powder of the compound of formula I to the surface of the carrier;
The manufacturing method in any one of said (8)-(10) which further contains.

  According to the present invention, an inhalation preparation is provided that has good absorbability after administration and rapidly exhibits a medicinal effect. In addition, since the inhalation preparation of the present invention effectively exhibits a medicinal effect even when administered in a small amount, the risk of side effects due to a large dose of the drug can be greatly reduced.

の化合物又はその薬学的に許容される塩を用いる。SOA-132は公知であり、以下のような理化学的性質を有する。 The present invention is described in detail below.
In the inhalation preparation of the present invention, the following formula (I):

Or a pharmaceutically acceptable salt thereof. SOA-132 is known and has the following physicochemical properties.

[Chemical name] 4-Benzylhydroxy-1- [2- (3-hydroxy-5-pyridylmethoxy-2-naphthoyl) -aminoethyl] piperidine [Molecular formula] C ₃₇ H ₃₇ N ₃ O ₄
[Molecular weight] 587.72
[Appearance / Property] Crystalline powder of slightly yellowish white to grayish white. Odorless.
[Solubility]
Solvent amount required to dissolve 1 g:
Dimethylformamide 2ml
Glacial acetic acid 2ml
Acetic anhydride 7ml
Chloroform 3ml
300 ml of methanol
Absolute ethanol 640ml
Acetonitrile 800ml
Diethyl ether 10000ml or more Water 10000ml or more First solution (pH1.2) 10000ml or more Acetic acid buffer solution (pH4.0) 10000ml or more Second solution (pH6.8) 10000ml or more
35% 10% lactic acid aqueous solution
[Melting point] Approx. 134 ° C
[Dissociation constant (pKa)] 4.4
[Distribution coefficient]
n-Octyl alcohol / Robinson Buffer (pH2) 3.0
n-octyl alcohol / phosphate buffer (pH 6.8) 999 or more
n-Octyl alcohol / Robinson Buffer (pH10) 999 or more [Hygroscopic] None [Stability] Airtight, light-shielded, stable for 12 months at room temperature. It is stable for 6 months under sealed, light-shielded, heated and humidified conditions (40 ℃, 75% RH). Stable for 2 months under white fluorescent light.

  Further, the pharmaceutically acceptable salt of SOA-132 is not particularly limited, and examples thereof include alkali metal salts (for example, sodium salts, potassium salts) and alkaline earth metal salts (for example, calcium salts, Metal salts such as magnesium salts), ammonium salts (for example, trimethylamine salts, triethylamine salts, etc.), organic base salts such as pyridine salts, picoline salts, dicyclohexylamine salts and N, N′-dibenzylethylenediamine salts, formate salts , Acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate and toluenesulfonate, and other organic acid salts, hydrochloride, hydrobromide, sulfate and phosphate Inorganic salts such as arginine, salts with amino acids such as arginine, aspartate and glutamate.

  In designing an inhalation preparation, in order to reach SOA-132, which is an active ingredient, to the bronchi, alveoli, etc., it is desirable to use a powder having a particle size within the predetermined range. Therefore, SOA-132 used as an active ingredient in the inhalation preparation of the present invention is preferably in the form of fine particles. Further, in order to improve inhalation characteristics, nanoparticles (hereinafter referred to as “NP”) which are submicron-sized particles are used. "). The particle diameter of the fine particles is not particularly limited as long as it does not interfere with inhalation, but for example, the average particle diameter is preferably 250 to 400 nm, more preferably 300 to 400 nm. . Moreover, it is preferable that 90% by weight or more of all the fine particles are in the range of particle size of 300 to 400 nm.

  Such fine particles (NP) of SOA-132 can be obtained, for example, by mechanically grinding SOA-132 bulk powder or by an underwater solvent diffusion method. Examples of the mechanical pulverization method include a method of forming fine particles using a jet mill, a nanomizer, a ball mill (vibrating ball mill), a rod mill, or the like.

  The solvent diffusion method in water is a solution in which SOA-132 is dissolved in a good solvent (for example, a mixed solvent of an organic solvent and water), and this solution is dissolved in an aqueous polymer (SOA-132 is a poor solvent). And SOA-132 is precipitated by mixing and stirring. When a solution in which SOA-132 is dissolved and an aqueous solution in which a water-soluble polymer is dissolved are mixed and stirred, the good solvent rapidly diffuses and migrates into the aqueous phase, and the interface between the oil phase and the aqueous phase is disturbed to cause self-emulsification. A submicron-sized O / W emulsion is formed. At this time, the water-soluble polymer in the poor solvent is adsorbed on the emulsion surface to stabilize the dispersion of the emulsion droplets. Thereafter, when the good solvent is further diffused and transferred, submicron-sized SOA-132 fine particles are precipitated as the solubility decreases, and a suspension of SOA-132 is obtained. This underwater solvent diffusion method will be described in detail later. Then, if desired, the suspension of SOA-132 produced by the solvent diffusion method in water is freeze-dried or spray-dried to obtain NP of SOA-132.

  By the way, the above-mentioned fine particles may cause problems such as adhesion and agglomeration of the active ingredient fine particles, which may remain attached to the inhalation device or the inner wall of the capsule, or the handleability may deteriorate. In such a case, it is preferable to use a particle (composite particle) in which the above-mentioned SOA-132 fine particles are attached to the surface of coarse particles serving as carriers.

  As the material for the carrier particles, a solid carrier or excipient known in the pharmaceutical field can be used, and examples thereof include lactose, mannitol, glucose, sorbitol and the like. The particle size of the carrier particles is preferably 10 to 100 μm, and more preferably 40 to 70 μm. The weight ratio of carrier particles to SOA-132 is preferably 10: 0.5 to 10: 4, and more preferably 10: 1 to 10: 3.

  In addition to the active ingredient SOA-132, the inhalation preparation of the present invention optionally contains an isotonic agent (for example, sodium chloride), a buffer (for example, boric acid, sodium monohydrogen phosphate, dihydrogen phosphate). Sodium or the like), preservatives (for example, benzalkonium chloride, etc.), and thickeners (for example, carboxyvinyl polymer, etc.) may be used. The amount of SOA-132 contained in the inhalation preparation of the present invention is preferably 5 to 30% by weight, more preferably 10 to 25% by weight.

  The form of the inhalation preparation of the present invention is not particularly limited, and examples thereof include a powder inhalation preparation, a liquid (droplet) inhalation preparation, and an aerosol inhalation preparation. The liquid inhalation preparation can be administered using an inhalation device such as a nebulizer (registered trademark). Powdered inhalation preparations can be administered using an inhalation device such as Spin Heller (registered trademark).

  The inhalation preparation of the present invention is useful for administering SOA-132 to the lower respiratory tract such as the oral cavity, nasal cavity, trachea, bronchi, and alveoli. The lower respiratory tract here refers to the airway, trachea, bronchi, bronchiole, alveoli and the like. Since the inhalation preparation of the present invention can deliver SOA-132 directly to the above organs, it is useful for the treatment of diseases involving these organs (for example, allergy, asthma or rhinitis).

Next, the manufacturing method of the inhalation formulation of this invention is demonstrated.
As mentioned above, it is preferable to use NP of SOA-132 in the inhalation preparation of the present invention. Examples of the method for producing the NP of SOA-132 include a method of finely pulverizing SOA-132 by mechanical pulverization, a method by a solvent diffusion method in water, and the like.

  Examples of the method by mechanical pulverization include a method using a jet mill, a nanomizer, a ball mill (vibrating ball mill), a rod mill, or the like.

  As the SOA-132 used as a raw material, the SOA-132 crude product obtained by chemical synthesis may be used as it is without isolation or purification, or a normal method (for example, crystallization / filtration / filtration / What was refine | purified by drying etc. may be used.

  The solvent diffusion method in water is a method using a good solvent and a poor solvent of SOA-132 as described above. The general procedure of the solvent diffusion method in water is as follows. First, SOA-132 is dissolved in a good solvent, and then this solution is mixed and stirred with a poor solvent in which a water-soluble polymer is dissolved. After a while, SOA-132 begins to precipitate and the solution becomes cloudy. The white turbid suspension is dried to remove the solvent, thereby obtaining SOA-132 NP having a particle size of 250 to 400 nm.

The good solvent is not particularly limited, but a lower alcohol or a mixed solvent of lower alcohol and water is preferable. Examples of the lower alcohol include C _1-6 alcohols such as methanol, ethanol, propanol, and butanol. The mixing ratio (volume ratio) of the lower alcohol and water is preferably 100: 0 to 16: 5, and more preferably 16: 3 to 16: 5.

  As the poor solvent, water is preferable. Water-soluble polymers include polyvinyl alcohol (hereinafter also referred to as “PVA”) (for example, PVA205, PVA405, PVAL-8, etc.), hydroxypropylcellulose (for example, HPC-L manufactured by Shin-Etsu Chemical Co., Ltd.), dextran, and pluronic. (For example, PF-68 manufactured by Asahi Denka Kogyo Co., Ltd.) and the like, and PVA is particularly preferable. PVA preferably has a polymerization degree (or molecular weight) of 400 to 600, and a saponification degree of 71 to 88%.

  When PVA having a low degree of saponification (that is, PVA having a high hydrophobicity of a water-soluble polymer) is used, the particle size of the obtained SOA-132NP becomes small. In general, the particle size of the obtained SOA-132NP tends to increase as the polymer concentration in the polymer aqueous solution increases.

  Next, the NP powder of SOA-132 can be obtained by removing the solvent from the suspension of NP of SOA-132 produced as described above and drying.

  Examples of the method for drying the SOA-132 suspension include a freeze drying method and a spray drying method.

  The freeze-drying method is a drying method in which a suspension is frozen and highly decompressed, and water is sublimated in this state. Thus, the lyophilization method is suitable for pulverizing unstable drugs and drying biological samples because drying proceeds under relatively mild conditions.

  The spray drying method is a method of spray-drying a suspension using, for example, a nozzle-type spray dryer. By adjusting the spray pressure of the spray dryer, the nozzle diameter, and the concentration of the sample solution, the particle size of the NP can be adjusted. The spray drying method is suitable for industrial mass production because a large amount of processing can be performed at one time.

  A suspension of SOA-132 was obtained by the above-mentioned solvent diffusion method in water, and this was dried by freeze drying or spray drying, so that a water-soluble polymer (for example, PVA) was adsorbed on the surface of SOA-132. You can get SOA-132 NP. The SOA-132 content (drug content) in the NP of SOA-132 adsorbed with the water-soluble polymer is preferably about 75 to 99% by weight.

  It was also confirmed that SOA-132NP produced by freeze-drying or spray-drying after the underwater solvent diffusion method was amorphous. This is presumably because the drug was precipitated in solution at the time of NP preparation and the molecular arrangement became irregular and became amorphous. On the other hand, SOA-132NP particles prepared by mechanical pulverization with a nanomizer, jet mill or the like were observed to have crystal peaks by powder X-ray diffraction, and were confirmed to be crystals.

  SOA-132NP adsorbed with water-soluble polymer has improved surface “wetability (hydrophilicity)” and is easy to become familiar with water, so when administered into the body, SOA-132 dissolves quickly and quickly It is possible to develop a medicinal effect.

  The present inventors compared SOA-132NP prepared by mechanical pulverization, or SOA-132NP prepared by combining the solvent diffusion method in water with freeze-drying method or spray-drying method, compared with raw SOA-132 raw material powder. As a result, it was found that inhalation characteristics and absorption characteristics into the body are improved. As a result of examining the further improvement of the handling property and inhalation property of these SOA-132NP, the present inventors have made the composite particles by adsorbing SOA-132NP on the surface of the carrier particles, thereby improving the handling property and inhalation property. It was found that a superior SOA-132NP inhalation preparation can be provided. Hereinafter, a method for producing composite particles of SOA-132NP and carrier particles will be described.

  As SOA-132NP, SOA-132NP prepared by mechanical pulverization as described above, or SOA-132NP prepared by combining a solvent diffusion method in water with a freeze drying method or a spray drying method can be used. The carrier raw material is not particularly limited as long as it is an excipient or carrier solid material usually used in the pharmaceutical field, and examples thereof include lactose, mannitol, glucose, sorbitol and the like. The particle diameter of the carrier particles is preferably 10 to 100 μm, and more preferably 30 to 70 μm.

  The composite particles of the present invention can be obtained by mixing the above SOA-132NP and carrier particles. The weight ratio of carrier particles to be mixed with SOA-132NP is preferably 10: 0.5 to 10: 4, more preferably 10: 1 to 10: 3. Mixing can be performed by using a mixer such as a touch mixer, a theta composer, a V-type mixer, or a mechanofusion.

  In the inhalation preparation of the present invention, in addition to the SOA-132NP obtained as described above or the composite particles of SOA-132NP and a carrier, for example, excipients, carriers, isotonic agents (for example, sodium chloride, etc.) ), Buffers (for example, boric acid, sodium monohydrogen phosphate, sodium dihydrogen phosphate, etc.), preservatives (for example, benzalkonium chloride, etc.), thickeners (for example, carboxyvinyl polymer, etc.) You may formulate by mixing an additive.

  The amount of SOA-132 to be blended in the inhalation preparation of the present invention can be appropriately set depending on the symptoms of the patient to which this is applied, but generally it is preferably about 0.1 to 1000 mg per dosage unit.

  The daily dose of the inhalation preparation of the present invention is appropriately selected according to the patient's symptoms, body weight, age, sex, other conditions, etc., but is usually about 0.1 to 1000 mg / kg per day for an adult. Preferably, the dose may be about 1 to 100 mg / kg, which can be administered once or a plurality of times (for example, about 2 to 4 times) a day.

  EXAMPLES Hereinafter, the present invention will be described more specifically with reference to examples, but the present invention is not limited to these examples.

(Example 1) Preparation of SOA-132NP suspension by solvent diffusion method in water 8 ml of methanol and 2.5 ml of water were mixed, and 50 mg of SOA-132 raw material powder was dissolved therein to prepare a SOA-132 solution. Next, this SOA-132 aqueous solution is dropped at a rate of 2 or 8 ml / min into a solution in which water-soluble polymer (100 mg or 500 mg) is dissolved in 50 ml of purified water using a peristaltic pump (PERISTA, Atto Co., Ltd.). A suspension of SOA-132NP was prepared by adding and stirring. The results of measuring the particle size of SOA-132NP in this suspension with a Zetasizer 3000HS (Malvern) are shown in the following table.

  As shown in the above results, SOA-132NP used in the present invention has a nano-order particle size.

(Example 2) Preparation of SOA-132NP powder by freeze-drying method In order to remove the water-soluble polymer not adsorbed on SOA-132 in the SOA-132NP suspension obtained in Example 1, The suspension was centrifuged (20,000 rpm, 10 min, Kubota 7800). The formed pellet (precipitated NP) surface was washed with purified water. After washing, an appropriate amount of water was added, and NP was suspended by ultrasonic waves. This washing operation was repeated twice, and the final suspension obtained was freeze-dried (NEOCOOL, Yamato Kagaku, -90 ° C, 24 hours), and the SOA-132NP lyophilized powder adsorbed with water-soluble polymer (hereinafter referred to as “SOA-132NP”) , Also referred to as “FD-NP”).

Example 3 Preparation of SOA-132NP Powder by Spray Drying Method The SOA-132NP suspension obtained in Example 1 was subjected to the following conditions using a spray dryer (Pulvis mini spray GS31, Yamato). A spray-dried SOA-132NP spray-dried powder (hereinafter also referred to as “SD-NP”) on which the water-soluble polymer was adsorbed was obtained.
Spray drying conditions Inhalation temperature 150 ° C
Discharge temperature 80 ℃
Spray pressure 0.13 MPa
Supply speed 10ml / min
Nozzle diameter 406μm

(Example 4) Measurement of particle diameter and drug content of SOA-132NP powder Water was added to the FD-NP or SD-NP obtained in Examples 2 and 3, and ultrasonic waves were applied to disperse them. A 132NP suspension was prepared. The particle size of SOA-132NP was measured using a Zetasizer 3000HS (Malvern). The results are shown in the table below together with the drug content (measurement of absorbance (absorption wavelength 257 nm) by dissolving 5 mg of sample in methanol).

  As shown in the above results, it can be seen that even when the SOA-132NP powder obtained by the method of the present invention is redispersed in water, the SOA-132 particles are dispersed in nano order.

(Example 5) Crystallinity of SOA-132NP
SOA-132 bulk powder, SOA-132NP crushed by jet mill, SOA-132NP crushed by Nanomizer, FD-NP (PVA205 1wt%) and SD-NP (PVA205 1wt%), powder X-ray diffractometer (GElGERFLEX RAD -C, Rigaku). The result is shown in FIG. As shown in FIG. 1, a crystal peak was observed in the SOA-132 bulk powder, jet mill pulverized particles and nanomizer pulverized particles, but no crystal peak was observed in FD-NP and SD-NP, both of which were amorphous. It was confirmed that.

(Example 6) Solubility of SOA-132NP
Solubility of SOA-132 bulk powder, SOA-132NP crushed by jet mill, SOA-132NP crushed by Nanomizer, FD-NP (PVA205 1wt%) and SD-NP (PVA205 1wt%) as follows Was measured.

In 20 mL of Japanese Pharmacopoeia 14th revision 2nd solution (pH 6.8) added with 0.05% Tween 80, put 4 mg of sample powder and shake in a constant temperature water bath (TAIYO incubator M-100D, TAITEC) (37 ° C, 60 stroke / min). 1 mL was sampled over time and centrifuged (10,000 rpm, 7 min). The amount of drug dissolved was quantified by measuring the supernatant with a fluorometer (F-3010, Hitachi, Ltd.). The measurement conditions are as follows.
Fluorescence measurement conditions
EX wavelength: 262nm
EM wavelength: 496nm
Time average: 10 sec
EX band width: 3mm
EM band width: 5mm

  The results of solubility evaluation are shown in FIG. From FIG. 2, it was shown that SOA-132NP pulverized by a jet mill, SOA-132NP, FD-NP and SD-NP pulverized by a nanomizer have higher elution rates than the SOA-132 bulk powder. It can also be seen that the elution peak concentration is extremely high in the case of FD-NP and SD-NP. This is considered because FD-NP and SD-NP are amorphous.

(Example 7) Evaluation of deposition distribution in the lung of SOA-132NP using guinea pigs
Powdered bronchial administration (syringe method)
Administration to guinea pigs was performed by powder transbronchial administration (syringe method) shown below using the apparatus shown in FIG. Hartley male guinea pigs (5-6 weeks old, 325-390 g) were anesthetized with ethyl carbamate (1 g / Ml, 1.5 mL / kg, ip) to expose the trachea and insert a catheter. Sample powder (O.5 mg as drug) was filled in the tip connected to the catheter. In a syringe connected to the chip, 2 mL of air was compressed to O.2 mL, and the pressure was released with a three-way stopcock to perform transbronchial administration of the drug powder.

Intrapulmonary deposition distribution assessment
Hartley male guinea pig, SOA-132 bulk, SOA-132NP (D50, 4.1μm), FD-NP (PVA205 1wt%) and SD-NP (PVA205 1wt%) (0.5mg as drug) Was transbronchially administered by the syringe method described above. Ten minutes after administration, the guinea pigs were bled to death and the trachea and bronchi, bronchioles and alveoli were removed. In order to extract the drug deposited on each site, 2 mL of physiological saline was added and homogenized. To the obtained homogenate solution, 2 mL of dichloromethane was added and stirred with a touch mixer, and the drug was extracted into dichloromethane. The suspended tissue was centrifuged (5, OOO rpm, 10 min), and O.2 mL of dichloromethane phase was collected. This was dried under reduced pressure (50 ° C., 60 min) with a centrifugal evaporator (VEC-310, IWAKI), and the resulting residue was dissolved in O.8 mL of acetonitrile. Distilled water (1.2 mL) was added thereto, and passed through a pretreatment column (Sep Pak PS-1 vac 100 mg, Waters ™). The pretreatment column used was pretreated with 2 mL of acetonitrile and eluent (O.1% trifluoroacetic acid: acetonitrile = 4: 6) in advance. After the addition, the pretreatment column was washed with 2 mL of 40% acetonitrile and further eluted with 1 mL of eluent. This was dried under reduced pressure using a centrifugal evaporator, and the resulting residue was dissolved in 2 mL of 50% methanol and measured by HPLC under the conditions shown below.
HPLC measurement conditions Column: symmetry C8 4.6mm ID x 150mm (Waters (TM))
Column temperature: 40 ° C
Mobile phase: TFAaq. (PH 4.0) / methanol = 7/8
Flow rate: 1.0ml / min
Loop capacity: 20μL
Wavelength: 254nm

  The measurement result of the deposition distribution in the lung is shown in FIG. In addition, the ratio of the released drug to the amount of drug filled in the catheter and the rate of deposition (arrival) beyond the bronchiole to the amount of recovered drug are defined as OE value (%) and FPF value (%), respectively, and in vivo It was used as an index for evaluation of inhalation characteristics. The O.E. value (%) and FPF value (%) are shown in the following table.

  As shown in the above table and FIG. 4, bronchioles and alveoli when SOA-132 NP of the present invention, particularly FD-NP (PVA205 1 wt%) and SD-NP (PVA205 1 wt%) are used, are used. It can be seen that it efficiently reaches the deep part of the lung.

(Example 8) Pharmacological effect by transbronchial administration of SOA-132NP A succinylcholine solution and a histamine solution were prepared by dissolving succinylcholine and histamine dihydrochloride in physiological saline so as to be 1.2 mg / mL and 9 μg / mL, respectively. did. The indomethacin solution was dissolved by adding 150 μL of 1N sodium hydroxide aqueous solution per 50 mg of indomethacin, and adjusted to 10 mL (5 mg / mL) with physiological saline. The pharmacological effect was measured according to the Kontzett-Rosler method. Hartley male guinea pigs (5-6 weeks old, 325-390 g) were anesthetized with ethyl carbamate (1 g / mL, 1.5 mL / kg, ip) to expose the trachea. After the exposure, the Yu cannula connected to the respirator was intubated and forced to breathe at a ventilation rate of 5 mL and 60 ventilations per minute. Immediately thereafter, succinylcholine solution (1 mL / kg, iv) and indomethacin solution (1 mL / kg, iv) were administered. Changes in airway resistance under forced ventilation were measured with a transducer (Bronchospasm Transducer 7020, Ugo Basil) connected to a tracheal cannula. 10 minutes after succinylcholine administration, histamine dihydrochloride solution (1 mL / kg, iv) was administered, and the height (mm) from the baseline to the maximum value of the airway contraction rate curve at this time was the airway resistance when no drug was administered Value.
Using the syringe shown in Fig. 3, SOA-132 bulk powder, SOA-132NP (D50, 4.1μm), FD-NP (PVA205 1wt%) and SD-NP (PVA205 1wt%) crushed by jet mill, respectively Transbronchial administration was performed so that the drug amount was 0.5 mg per guinea pig. After a predetermined time, histamine dihydrochloride solution (1 mL / kg, iv) was administered. The height (mm) from the base line of the airway contraction rate curve to the maximum value at this time was defined as the airway resistance value after drug administration. As shown in the following formula, the airway contraction inhibition rate was defined as the ratio of the airway resistance value after drug administration to the airway resistance value when no drug was administered.

The results of the pharmacological effect test are shown in FIG.
When antagonism against histamine was measured after transbronchial administration, as shown in FIG. 5, FD-NP and SD-NP showed a fast pharmacological effect and stronger antagonism than SOA-132 bulk powder. This is considered to be due to the improved solubility because FD-NP and SD-NP are amorphous and the wettability is improved by the water-soluble polymer present on the particle surface. In addition, when comparing the bulk powder and jet mill pulverized particles, the pulverized particles show a stronger inhibitory effect. Therefore, an increase in dissolution rate due to an increase in specific surface area is one factor that exhibits a high pharmacological effect. Conceivable.

(Example 9) Preparation of composite particles by SOA-132NP and carrier particles
FD-NP was used as SOA-132NP. Moreover, lactose (Pharmatose325M (trademark) (DMV)) was used as carrier particles.

  The composite particles were prepared by either the following method using a touch mixer or a method using a high-speed elliptic rotor type powder composite device.

Production method of composite particles by touch mixer 200 mg of lactose for inhalation (Pharmatose325MTM (DMV)) and 20 mg of FD-NP are placed in a bottle with a diameter of 25 mm and a height of 50 mm and placed in a touch mixer (MT-31, Yamato). For 10 minutes to prepare composite particles (hereinafter also referred to as “PM-NP”).

Production method of composite particles by high-speed elliptical rotor type powder compounding device 7g of lactose for inhalation (Pharmatose325M (TM) (DMV)) and FD-NP0.35g are combined with high-speed elliptical rotor type compounding device (Theta Composer THC-70 Lab) , Tokuju Seisakusho Co., Ltd.) and treated for 5 minutes under the conditions of a rotor speed of 1000 rpm, a vessel speed of 20 rpm, and a clearance of 0.5 mm. After the treatment, 0.35 g of FD-NP was further charged and the treatment was performed for 5 minutes to prepare composite particles (hereinafter also referred to as “θ-NP”).

(Example 10) Pharmacological effect of composite particles As a dosage-revenue preparation, drug bulk powder, jet mill pulverized particles (D50: 4.1 μm), Pharmatose 325M and jet mill pulverized particle pulverized particles (D50: 4.1 μm) using Theta Composer FD-NP (PVA205 1%) and PM-NP were used. Using these inhalation preparations, the pharmacological effect was measured in the same manner as in Example 8 above.
The result is shown in FIG. When the antagonistic action against histamine was measured after transbronchial administration, as shown in FIG. 6, PM-NP tended to have a faster rate of drug efficacy than FD-NP. When FD-NP and lactose are mixed to form composite particles, FD-NP aggregates are broken into fine aggregates in the composite process. For this reason, compared with the case where FD-NP is inhaled as it is, SOA-132 can reach deeper in the lung. In addition, it is considered that the specific surface area increased due to the refinement of the aggregates, the dissolution rate in the lung increased, and the rate at which the medicinal effect appeared was increased.

 Compared with the jet mill pulverized particles alone, the composite particles obtained by mixing 325M and jet mill pulverized particles with theta composer showed no difference in the speed at which the medicinal effect appeared. There was a tendency for the particles to appear stronger. This is thought to be because more drugs were deposited deep in the lung due to improved inhalation characteristics.

  The inhalation preparation of the present invention has excellent inhalation characteristics, or can efficiently deliver an active ingredient deep into the lung. The inhalation preparation of the present invention is useful for the treatment of allergies, asthma, rhinitis and the like. Compared with conventional oral preparations and the like, the inhalation preparation of the present invention can deliver an active ingredient efficiently to the affected area, and is excellent in absorbability into the body. Therefore, the risk of side effects due to large doses of drugs can be greatly reduced.

FIG. 1 is a diagram showing the results of powder X-ray diffraction. FIG. 2 is a diagram showing the results of a solubility test of SOA-132NP. FIG. 3 is a schematic view of an administration device used in powder transbronchial administration (syringe method) in the examples. FIG. 4 is a view showing the results of a lung-deposition distribution evaluation test for SOA-132NP using the guinea pig of Example 7. FIG. 5 shows the results of a pharmacological effect test by transbronchial administration of SOA-132NP of Example 8. 6 is a diagram showing the results of a pharmacological effect test of SOA-132 composite particles by transbronchial administration in Example 10. FIG.

Claims (11)

Formula I below:

Or an pharmaceutically acceptable salt thereof. The inhalation preparation according to claim 1, wherein the compound of formula I is a nanoparticle having an average particle size of 250 to 400 nm. The compound of formula I is:
a) dissolving the starting compound of formula I in a good solvent and then mixing this solution with a poor solvent in which the water-soluble polymer is dissolved to obtain a suspension of the compound of formula I;
b) obtaining a powder of the compound of formula I by freeze-drying or spray-drying said suspension;
The inhalable preparation according to claim 1, which is a nanoparticle obtained by a process comprising 4. An inhalation formulation according to any one of claims 1 to 3, comprising a compound of formula I and a pharmaceutically acceptable carrier, wherein the compound of formula I is attached to the surface of the carrier. The inhalation preparation according to any one of claims 1 to 4, which is used for treating allergy, asthma or rhinitis. Formula I below:

A method for producing an inhalation preparation comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the raw material compound of formula I is mechanically pulverized into a powder, and the resulting powder is a pharmaceutically acceptable excipient. The said manufacturing method including mixing with an agent or a support | carrier. The production method according to claim 6, wherein the mechanical pulverization is performed using a jet mill, a nanomizer, a ball mill or a rod mill. Formula I below:

A method for producing an inhalation preparation containing the compound or a pharmaceutically acceptable salt thereof, comprising the following steps:
a) dissolving the starting compound of formula I in a good solvent and then mixing this solution with a poor solvent in which the water-soluble polymer is dissolved to obtain a suspension of the compound of formula I;
b) obtaining a powder of the compound of formula I by freeze-drying or spray-drying said suspension;
The said manufacturing method containing. The production method according to claim 8, wherein the good solvent is a mixed solvent of a lower alcohol and water. The production method according to claim 8 or 9, wherein the water-soluble polymer is polyvinyl alcohol. Following step b), the following step c):
c) mixing and stirring the powder of the compound of formula I and a pharmaceutically acceptable carrier to adhere the powder of the compound of formula I to the surface of the carrier;
The method according to any one of claims 8 to 10, further comprising:

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