JP2015155379A - Inhalation powder and production method thereof - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide inhalation powder of benz [d] [1,3] oxazine-derivative maleate which is excellent in inhalation characteristics.

SOLUTION: The invention provides a formulation for inhalation containing benz [d] [1,3] oxazine-derivative maleate, where the active ingredient concerned is a crystal which has a characteristic peak of 8.4° as an angle of diffraction (2θ±0.5°) in X-ray power diffraction, the crystal having a characteristic peak of 7.7° is an active ingredient which is not contained substantially, and a 10% accumulation particle diameter of the carrier particles concerned is 20 μm or more.

COPYRIGHT: (C)2015,JPO&INPIT

Description

The present invention relates to an inhalable powder of benz [d] [1,3] oxazine derivative maleate and a method for producing the same.

Human neutrophil elastase is a type of serine hydrolase released from neutrophil granules that appear in the case of infectious or inflammatory diseases. Neutrophil elastase is an enzyme that hydrolyzes elastin, collagen, proteoglycan, fibronectin or other proteins that make up the interstitium of connective tissue in vivo such as lung, cartilage, blood vessel wall or skin.

In vivo, serine hydrolases such as neutrophil elastase maintain the homeostasis of the organism. The activity of serine hydrolase is also controlled by endogenous proteinaceous inhibitors such as α1-protease inhibitors, α2-macroglobulins or secretory leukocyte protease inhibitors. However, if the equilibrium between neutrophil elastase and the endogenous inhibitor is lost by excessive release of neutrophil elastase at the site of inflammation or a decrease in inhibitor levels, it may maintain control of neutrophil elastase activity. It cannot be done and the organization is damaged.

A benz [d] [1,3] oxazine derivative is known as an excellent serine hydrolase inhibitor (Patent Document 1), and its maleate is excellent in drug substance stability, solubility and crystallinity. It is known (Patent Document 2).
Diseases involving serine hydrolase include emphysema, acute respiratory distress syndrome, adult respiratory distress syndrome (ARDS), idiopathic interstitial pneumonia (IIP), cystic pulmonary fibrosis, chronic interstitial pneumonia, chronic bronchitis, Chronic respiratory tract infections, diffuse panbronchiolitis, bronchiectasis, asthma, etc. can be mentioned, and inhalants are expected as dosage forms that can deliver active ingredients directly to the lower respiratory tract which is the target site of these diseases It was.

Nebulizers, pressurized metered dose inhalers (MDI) and inhaled powders (Dry Powder Inhaler, DPI) can be mentioned as dosage forms of inhalants. A nebulizer is a dosage form in which a liquid active ingredient is atomized and inhaled under the spontaneous breathing of a patient, but is generally expensive and inconvenient to carry. Pressurized metered dose spray inhaler is a dosage form that is sprayed by strongly pushing a can filled with active ingredients, but it is necessary to synchronize spray and inhalation, and inhalation technology is required It becomes. In addition, chlorofluorocarbons that cause destruction of the ozone layer and global warming are used as the propellant, which is undesirable in terms of the global environment. On the other hand, the inhalable powder is a dosage form in which a powdered active ingredient is inhaled under the patient's spontaneous breathing and can be inhaled at a suitable timing of the patient. Moreover, it can be manufactured at a lower cost than a nebulizer and is easy to carry.

Inhaled powders use fine particles of active ingredients of about 0.5 to 5 μm in order to allow the active ingredients to reach the lower airways such as the trachea and bronchi (Non-Patent Documents 2 to 4, Patent Documents 3 to 7). However, when the active ingredient fine particles themselves are filled into the inhalation container, the adhesion and aggregation are high, so that the active ingredient fine particles are aggregated to form a large lump with a large particle diameter and adhere to the wall of the container. Fine particles are not released. As means for solving these problems, there are a granulation method and a carrier method. The granulation method is a method using a granulated product obtained by softly granulating active ingredient fine particles. When the granulated product is inhaled from inside the container, the constituent active ingredient fine particles are separated from the granulated product and separated. Active ingredient fine particles reach the target site and show medicinal effects. On the other hand, the carrier method is a method using a mixture of active ingredient fine particles and carrier particles such as lactose (carrier). In the container, the active ingredient fine particles are attached to the carrier particles, but when inhaled by the patient, the active ingredient fine particles are separated from the carrier particles, and the separated active ingredient fine particles reach the target site and exhibit a medicinal effect. In general, the carrier method is easier to manufacture than the granulation method, and is highly versatile.

In the carrier method for inhaled powders, it is important that the active ingredient fine particles adhere to the carrier particles to form a stable mixture during production and storage in a container. However, on the other hand, during inhalation, the active ingredient fine particles need to be easily separated from the carrier particles and released. If the active ingredient fine particles are not separated, the active ingredient fine particles remain attached to the carrier particles and deposit in the oral cavity, throat, etc. before reaching the lower airway, which is the target site, and the rate of reaching the lungs decreases. Result.

In the carrier method for inhaled powders, active ingredient fine particles molded with a sphericity of 0.9 or more are used as a method for improving the inhalation characteristics and efficiently delivering the active ingredient to the target site, and between the active ingredient fine particles and the carrier particles. (Patent Document 3), a method of adding micronized lactose (Patent Documents 4 to 6, Non-Patent Documents 1 to 3), a method of adding stearate (Patent Documents 7 to 9, Non-Patent Documents 3 to 4), a method of adding amino acids and polypeptides (Patent Document 10), a method of coating carrier particles with an antistatic agent such as sorbitan fatty acid ester (Patent Document 11), a method of processing the surface of carrier particles (Patent Document 12) is known.

WO2008 / 036379 WO2011 / 036895 JP-A-11-171760 WO2001 / 026630 JP2001-7258 Special table flat 8-501056 Special table 2007-509124 Special table 2007-5151502 Special table 2003-530425 Special table 10-513174 Special table flat 8-500109 Special table hei 9-507049

Journal of Pharmaceutical Technology Research Group, 2008, vol. 17, no. 3,249-254. International Journal of Pharmaceuticals, 1999, 182, 133-144. International Journal of Pharmaceuticals, 1998, 176, 99-110. PHARM TECH JAPAN, 2004, vol. 20, no. 6, 17-25 (1045-1053).

An object of the present invention is to provide an inhalation powder having excellent inhalation characteristics, comprising a benz [d] [1,3] oxazine derivative maleate as an active ingredient. Conventionally, there is a known method for improving the deposition efficiency on the trachea, bronchus, and lungs by optimizing the aggregation of the active ingredient fine particles and the adhesion between the active ingredient fine particles and the carrier particles by molding the active ingredient into a spherical shape. However, in order to form the active ingredient into a spherical shape, a complicated process such as granulation is required. An object of the present invention is to provide an inhalable powder having excellent inhalation characteristics by a simpler and less expensive method.

As a result of intensive studies to achieve the above object, the inventors of the present invention are excellent by using a pulverized product of a specific crystal among benz [d] [1,3] oxazine derivative maleate. The present inventors have found that an inhalation powder having inhalation characteristics can be obtained.
That is, the gist of the present invention is as follows: [1] Formula (1)

A preparation for inhalation containing an active ingredient and carrier particles represented by
The active ingredient is a crystal having a characteristic peak at 8.4 ° as a diffraction angle (2θ ± 0.5 °) in powder X-ray diffraction, and a crystal having a characteristic peak at 7.7 ° Is an active ingredient substantially free of
An inhalable powder, wherein the carrier particles have a cumulative 10% particle size of 20 μm or more.
[2] 2- {2-((S) -3-dimethylaminopyrrolidin-1-yl) pyridine-3, wherein the active ingredient has the same powder X-ray diffraction pattern as the powder X-ray diffraction pattern shown in FIG. The inhalable powder according to [1], which is -yl} -5-ethyl-7-methoxy-4H-benz [d] [1,3] oxazin-4-one.1 maleate.
[3] The inhalable powder according to [1] or [2], wherein the particle frequency of the active ingredient in the range of 0.5 to 5.0 μm is 65% or more.
[4] The inhalable powder according to any one of [1] to [3], wherein a cumulative 50% particle size of the active ingredient is 3 μm or less.
[5] The inhalable powder according to any one of [1] to [4], further containing finely divided saccharides.
[6] The inhalable powder according to [5], wherein a cumulative 50% particle size of the micronized saccharide is 5 μm or less.
[7] The inhalable powder according to [5] or [6], wherein the micronized saccharide is lactose.
[8] The inhalable powder according to any one of [1] to [7], wherein the carrier particles are lactose.

According to the present invention, it is possible to provide an inhalable powder of a benz [d] [1,3] oxazine derivative maleate having excellent inhalation characteristics and suitable for a content uniformity test.

3 shows a powder X-ray diffraction pattern of the crystal (Intact product A) obtained in Reference Example 1. The vertical axis represents intensity [cps], and the horizontal axis represents diffraction angle (2θ) [°]. 3 shows a powder X-ray diffraction pattern of the crystal (Intact product B) obtained in Reference Example 3. The vertical axis represents intensity [cps], and the horizontal axis represents diffraction angle (2θ) [°]. It is a SEM observation result of the crystal (Intact product A) obtained in Reference Example 1. It is a SEM observation result of the ground material (Mill product A) obtained in Reference Example 2. It is a SEM observation result of the crystal (Intact product B) obtained in Reference Example 3. It is a SEM observation result of the ground material (Mill product B) obtained in Reference Example 4.

Formula (1)

2- {2-((S) -3-dimethylaminopyrrolidin-1-yl) pyridin-3-yl} -5-ethyl-7-methoxy-4H-benz [d] [1,3] Oxazin-4-one-1 maleate (hereinafter referred to as Compound 1) has a crystal having a characteristic peak in the vicinity of 14.8 ° as a diffraction angle (2θ ± 0.5 °) in powder X-ray diffraction; A crystal having a characteristic peak around 10.8 ° is known (Patent Document 2, WO2011 / 036895).

A crystal having a characteristic peak around 14.8 ° has a characteristic peak around 8.4 ° in addition to the peak. A powder X-ray diffraction pattern is shown in FIG. A crystal having a characteristic peak around 10.8 ° has a characteristic peak around 7.7 ° in addition to the peak. Since the former crystal has a higher melting point than the latter crystal, the former crystal is referred to as a high melting point crystal and the latter crystal is referred to as a low melting point crystal.
When Compound 1 is a mixture of a high melting point crystal and a low melting point crystal, a powder X-ray diffraction pattern of the mixture is measured, and a peak intensity of 7.7 ° with respect to a peak intensity of 8.4 ° (derived from a high melting point crystal) It is possible to determine how much low melting point crystals are contained by the ratio of (from low melting point crystals).

The active ingredient used in the present invention uses the above-mentioned high melting point crystal and does not substantially contain the low melting point crystal. In other words, the active ingredient represented by the formula (1) uses a crystal having a characteristic peak at 8.4 ° as a diffraction angle (2θ ± 0.5 °) in powder X-ray diffraction. The active ingredient which does not substantially contain crystals having a characteristic peak at 7 ° is used.

In the present specification, “active ingredient substantially free of crystals having a characteristic peak at 7.7 °” means 7.7 ° when the powder X-ray diffraction pattern of the active ingredient used is measured. This means that the peak intensity is 0.25 or less with respect to the peak intensity of 8.4 °.

From the viewpoint of improving inhalation characteristics, it is preferable that the content ratio of crystals having a characteristic peak at 8.4 ° (high melting point crystals) is high. More preferably, the peak intensity at 7.7 ° (derived from the low melting point crystal) is 0.15 or less, more preferably 0.05 or less, particularly preferably relative to the peak intensity at 8.4 ° (derived from the high melting point crystal). Is 0.01 or less.

In order to efficiently deliver the active ingredient to the target site with high inhalation characteristics, the active ingredient used in the present invention should have a particle frequency in the range of 0.5 to 5.0 μm of 65% or more. preferable. More preferably, it is 75% or more and 100% or less. When a high melting point crystal is used, a particle frequency of 0.5 to 5.0 μm has a particle frequency of 65% or more by simple operations such as milling such as jet milling, bead milling, ball milling, hammer milling, etc. An active ingredient can be obtained. Among milling, jet milling is preferable.

Similarly, in order to deliver the active ingredient efficiently to the target site with high inhalation characteristics, the cumulative 50% particle size of the active ingredient used in the present invention is preferably 3 μm or less. More preferably, the particle diameter is 3 μm or less and 0.5 μm or more, more preferably 2.5 μm or less and 0.5 μm or more. When a high melting point crystal is used, an active ingredient having a cumulative 50% particle size of 2.5 μm or less can be obtained by a simple operation such as jet milling, bead milling, ball milling, hammer milling, or the like. Among milling, jet milling is preferable.

In the present specification, carrier particles mean core particles to which an active ingredient is attached, for example, sugar such as lactose, glucose, sucrose, maltose, trehalose, dextran, or sugar alcohol such as mannitol, xylitol, erythritol. Among them, one or two or more kinds of carrier particles can be arbitrarily selected. Preferably, sugars such as lactose, glucose, sucrose, maltose, trehalose and dextran are used, and lactose is more preferable.

In the present invention, when a carrier particle having a cumulative 10% particle diameter of 20 μm or more is used as the carrier particle, a preparation suitable for the content uniformity test can be obtained. Among them, more preferably, a carrier having a cumulative 10% particle size of 20 μm or more and a cumulative 50% particle size of 150 μm or less, more preferably a cumulative 10% particle size of 20 μm or more and a cumulative 50% particle size of 120 μm or less. There are certain carrier particles, particularly preferably carrier particles having a cumulative 10% particle size of 25 μm or more and a cumulative 50% particle size of 70 μm or less.

In the present specification, micronized saccharide means saccharide pulverized to a cumulative 50% particle size of 10 μm or less. Among them, saccharides having a cumulative 50% particle size of 5 μm or less, more preferably 3 μm or less, and particularly preferably 3 μm or less and 0.5 μm or more are exemplified. The micronized saccharide is not particularly limited as long as it can adjust the adhesion between the carrier particles and the active ingredient. For example, sugars such as lactose, glucose, sucrose, maltose, trehalose, dextran, or sugar alcohols such as mannitol, xylitol, erythritol, etc., among which one or more micronized saccharides are arbitrarily selected can do. Among these, Preferably, sugars, such as lactose, glucose, sucrose, maltose, trehalose, and dextran, are mentioned, More preferably, lactose is mentioned. As the micronized saccharide, the same saccharide or sugar alcohol as that of the carrier particles can be used.

By adding micronized saccharide, the adhesive force of the active ingredient to the carrier particles is weakened. Therefore, when released from the inhaler, the active ingredient is easily separated from the carrier particles, and the separated active ingredient can reach the lower part of the airway, which is the target site, without being deposited in the oral cavity, throat, etc. it can.

In this specification, “cumulative 50% particle size” is assumed to be one powder group, its particle size distribution is determined by laser diffraction method, and the total volume of the powder group is 100% to determine a cumulative curve. Means the particle size at which the cumulative curve is 50%.

In this specification, “cumulative 10% particle size” is assumed to be one powder group, its particle size distribution is determined by laser diffraction method, and the total volume of the powder group is 100% to determine a cumulative curve. Means the particle diameter at which the cumulative curve becomes 10%.

In the present specification, “cumulative 50% particle diameter of active ingredient” and “cumulative 10% particle diameter of active ingredient” are based on the particle diameter measurement method by laser diffraction listed in the 16th revised Japanese Pharmacopoeia, It means a measured value (measuring instrument: particle size distribution meter, manufactured by Nikkiso, Microtrac MT3300EX).
In this specification, “cumulative 50% particle size of carrier particles”, “cumulative particle size of 10% of carrier particles”, “cumulative particle size of pulverized saccharides 50%” and “cumulative particle size of pulverized saccharides 10%” Means a value measured by a laser diffraction method (Sympatec Laser Diffraction).

In this specification, “the particle frequency in the range of 0.5 to 5.0 μm” is obtained by calculating the frequency (%) by the particle size measurement method by laser diffraction included in the 16th revised Japanese Pharmacopoeia. This is the sum of frequencies (%) in the range of 0.5 to 5.0 μm in diameter category. (Measuring instrument: Particle size distribution meter, Nikkiso, Microtrac MT3300EX).
(Example)
EXAMPLES Hereinafter, although an Example demonstrates this invention in detail, this invention is not limited by these Examples.

In the following examples, powder X-rays were measured under the following conditions.
The sample was filled in the filling part of the silicon non-reflective sample plate. Subsequently, the powder X-ray diffraction of the sample was measured using a Rigaku Denki RINT2200 type powder X-ray diffractometer. The sample used for the measurement used what was grind | pulverized with the agate mortar about the unground product. For the pulverized product, pulverization in an agate mortar was not performed, and measurement was performed as it was in the state of the pulverized product.

Tube current: 40 mA
Tube voltage: 40 kV
Scanning speed: 2 ° / min
X-ray: CuKα
Divergent slit: 1 / 2deg
Receiving slit: 0.15 mm
Scattering slit: 1 / 2deg
Counter cathode: Copper scanning range: 5-40
(Reference Example 1)
Manufacture of a mixed product of a low-melting crystal and a high-melting crystal of Compound 1 (hereinafter referred to as Intact product A) 2- {2-((S) -3-dimethylaminopyrrolidin-1-yl) pyridin-3-yl} -5- A solution of ethyl-7-methoxy-4H-benz [d] [1,3] oxazin-4-one (10.0 g) in acetone (180 mL) was stirred at an external temperature of 30 ° C. At an internal temperature of 30 ° C., 3.09 g of maleic acid was added, and the container was washed with 20 mL of acetone. While stirring, the reaction product (1 maleate) was crystallized. After stirring the mixed solution for 10 minutes, t-butyl methyl ether (200 mL) was added to the mixed solution, and the mixture was further heated and stirred at an internal temperature of 45 to 50 ° C. for 1 hour. The mixture was stirred while cooling, and further stirred for 10 minutes at an internal temperature of 15 ° C. or less (up to an internal temperature of 6 ° C.). The precipitated crystals were collected by filtration and washed with t-butyl methyl ether (50 mL). The wet crystals were blown dry at 50 ° C. to give white flocculent 2- {2-((S) -3-dimethylaminopyrrolidin-1-yl) pyridin-3-yl} -5-ethyl-7-methoxy- 11.7 g (yield 91%) of 4H-benz [d] [1,3] oxazin-4-one.1 maleate was obtained.

Acetone (200 mL) and water (10 mL) were added to the resulting maleate (10.0 g), and dissolved with stirring at an external temperature of 45 ° C. This solution was filtered while hot, and the filter was washed with a mixed solvent of acetone (30 mL) and water (1.5 mL). While stirring the filtrate at an external temperature of 45 ° C., t-butyl methyl ether (50 mL) was added to the filtrate and stirred while cooling to crystallize 1 maleate (crystallization start temperature: internal temperature). 27 ° C). The mixture containing the precipitated 1-maleate was stirred at an internal temperature of 23 to 27 ° C. for 30 minutes, and then stirred while heating. As a result, most of the precipitated crystals were dissolved in the mixed solution (internal temperature: 37 ° C.).

Next, the maleate was gradually crystallized by stirring the mixture while cooling. T-Butyl methyl ether (200 mL) was added dropwise to the mixture, followed by stirring while heating, and stirring at an internal temperature of 40 to 45 ° C. for 30 minutes. Subsequently, the mixture was gradually cooled and stirred at an internal temperature of 15 ° C. or lower for 30 minutes (up to an internal temperature of 7 ° C.), and the precipitated crystals were collected by filtration and washed with 50 mL of t-butyl methyl ether. The wet crystals were blown and dried at 40 to 50 ° C. to give 2- {2-((S) -3-dimethylaminopyrrolidin-1-yl) pyridin-3-yl} -5-ethyl-7- 8.36 g (Intact product A, yield 84%) of methoxy-4H-benz [d] [1,3] oxazin-4-one.1 maleate was obtained. The powder X-ray diffraction pattern is shown in FIG. In the powder X-ray diffraction pattern of Intact product A, the peak intensity at 7.7 ° is 3.0 with respect to the peak intensity at 8.4 °.
Melting point (hot plate method): 153-163 ° C. (melting)
(Reference Example 2)
Intact product A (10 g) obtained in Reference Example 1 was pulverized with a super jet mill (SJ-100GMP, manufactured by Nissin Engineering Co., Ltd.) to obtain 4.2 g of a pulverized product. Hereinafter, the pulverized material obtained here is referred to as Mill product A.

(Crushing conditions)
Crushing pressure (MPa): 0.44 to 0.46 MPa
Supply amount (g / hr): 6.45
(Reference Example 3)
Production of high-melting crystal of compound 1 (hereinafter referred to as Intact product B) Intact product A (12 g) obtained in Reference Example 1 was weighed into a brown bottle and set at 130 ° C. ) For 4 hours to obtain a high-melting crystal of Compound 1 (Intact product B). A powder X-ray diffraction pattern is shown in FIG.
(Reference Example 4)
Intact product B (10 g) obtained in Reference Example 3 was pulverized with a super jet mill (SJ-100GMP, manufactured by Nissin Engineering Co., Ltd.) to obtain 6.4 g of a pulverized product. Hereinafter, the pulverized material obtained here is referred to as Mill product B.

(Crushing conditions)
Crushing pressure (MPa): 0.44 to 0.46 MPa
Supply amount (g / hr): 10.00
Test Example 1 SEM Observation The crystals or pulverized products obtained in Reference Examples 1 to 4 were each observed with SEM (manufactured by KEYENCE, real surface view microscope). The observation results are shown in Table 1 and FIGS.

(Test Example 2) Particle size distribution measurement The particle size distribution of the pulverized product obtained in Reference Example 2 and Reference Example 4 was determined using a particle size distribution meter (manufactured by Nikkiso, Microtrac MT3300EX) under the following measurement conditions. The results are shown in Table 2.
Measurement condition Sample amount: 100mg
Measurement mode: Dry measurement Measurement time: 10 seconds Number of measurements: 1 Transmission: Refractive index of transmitted particles: 1.81
Shape: non-spherical compressor pressure: 15 psi
Dispersion pressure: 3

5000 mg of lactose (Repitose SV003, manufactured by DFE Pharm) was weighed into a brown bottle and stirred for 1 minute using a vortex mixer. Mill product B (50 mg) was weighed, added to the brown bottle, and mixed for 15 minutes using a vortex mixer.

5000 mg of lactose (Repitose SV010, manufactured by DFE Pharm) was weighed into a brown bottle and stirred for 1 minute using a vortex mixer. Mill product B (50 mg) was weighed, added to the brown bottle, and mixed for 15 minutes using a vortex mixer.

5000 mg of lactose (Repitose SV003, manufactured by DFE Pharm) was weighed into a brown bottle, and 500 mg of micronized lactose (Repitose MC001, manufactured by DFE Pharm) was added. Stir for 10 minutes using a vortex mixer. This lactose mixture (3000 mg) was weighed into a brown bottle, Mill product B (50 mg) was added, and the mixture was mixed for 15 minutes using a vortex mixer.
(Comparative Example 1)
In a brown bottle, 5000 mg of lactose (Repitose ML001, manufactured by DFE Pharm) was weighed and stirred for 1 minute using a vortex mixer. Mill product B (50 mg) was weighed, added to the brown bottle, and mixed for 15 minutes using a vortex mixer.
(Comparative Example 2)
In a brown bottle, 5000 mg of lactose (Repitose MC001, manufactured by DFE Pharm) was weighed and stirred for 1 minute using a vortex mixer. Mill product B (50 mg) was weighed, added to the brown bottle, and mixed for 15 minutes using a vortex mixer.
(Comparative Example 3)
To a brown bottle, 5000 mg of lactose (Repitose SV003, manufactured by DFE Pharm) was weighed, and 96 mg of magnesium stearate was added. Stir for 30 minutes using a vortex mixer. 3000 mg of this lactose mixture was weighed into a brown bottle, 31 mg of Mill product B was added, and the mixture was mixed for 15 minutes using a vortex mixer.
(Comparative Example 4)
5000 mg of lactose (Repitose SV003, manufactured by DFE Pharm) was weighed into a brown bottle and stirred for 1 minute using a vortex mixer. Mill product A 50 mg was weighed, added to the brown bottle, and mixed for 15 minutes using a vortex mixer.
(Test Example 3) Content uniformity test 0.01, 0.02, 0.10, 0.20, 1.00, 2.01, 5.02, 10.03, 20.06, and 24.07 μg / ml A series of standard solutions containing various active ingredient concentrations were prepared. The active ingredient was Mill product A, and the dilution solvent was a water / methanol mixture (4: 1) for liquid chromatography. Using these standard solutions, a calibration curve of the active ingredient concentration was prepared with respect to the peak area of the active ingredient, and the linearity was good in the range of 0.010 to 24 μg / ml.

HPLC measurement condition A:
Separation column: A stainless steel tube having an inner diameter of 4.6 mm and a length of 150 mm was filled with 5 μm of octadecylsilylated silica gel for liquid chromatography (manufactured by GL Sciences, Inertsil ODS-3V).
Column temperature: 35 ° C
Mobile phase: dilute phosphoric acid (1 → 1000) was added to 1.08 g of sodium 1-octanesulfonate to make 1000 mL. 200 mL of acetonitrile for liquid chromatography was added to 300 mL of the solution to obtain a mobile phase.
Flow rate: 0.9mL / min
Detector: UV absorptiometer (measurement wavelength: 240 nm)
Injection volume: 20 μL
Area measurement range: 8 minutes Retention time: 5 minutes

Six samples were randomly extracted from Examples 1 to 3 and Comparative Examples 1 to 4, respectively. Add 20 mL of water / liquid chromatography methanol mixture (4: 1) to 20 mg of sample and stir at room temperature for 10 minutes, then add water / liquid chromatography methanol mixture (4: 1) to 20 mL and centrifuge. Centrifugation was performed using a vessel (3000 rpm, 10 minutes). The obtained supernatant was subjected to HPLC measurement, and the amount of sample was measured (measured under HPLC measurement condition A). The relative standard deviation of the active ingredient content was used to evaluate the homogeneity of the mixture. In addition, it was judged that the content uniformity was obtained for a mixed product having an average content of 90 to 110% and a relative standard deviation of 15% or less. The results are shown in Table 3.

Examples 1 to 3 and Comparative Example 4 in which Receptose SV003 or Repitose SV010 was used as the carrier particles of the active ingredient met the content uniformity test. On the other hand, Comparative Example 1 using Repitose ML001 as carrier particles or Comparative Example 2 using Repitose MC001 was incompatible with the content uniformity test. Table 4 shows the particle size distribution of the carrier particles (lactose) used (Non-Patent Document 1). From the results in Table 3 and the data in Table 4, it is considered that if the cumulative 10% particle size of the carrier particles used is too small, the content uniformity test is not suitable. In the present invention, the cumulative 10% particle size of the carrier particles used is preferably 20 μm or more.

Further, even when Repitose SV003 having a cumulative 10% particle size of carrier particles of 20 μm or more is used, addition of magnesium stearate as an additive does not meet the content uniformity test (Comparative Example 3), but micronized lactose ( When Repitose MC001) is added, it complies with the content uniformity test (Example 3). Magnesium stearate and micronized lactose are added for the purpose of improving the inhalation characteristics, but it can be seen that micronized lactose is suitable for the content uniformity test.

(Test Example 4) Inhalation characteristics evaluation test An empty capsule was placed in a handy heller (manufactured by Nippon Boehringer Ingelheim), and a hole was made in the capsule with a needle attached to the handy heller. The handy heller was connected to the next generation impactor (NGI: next generation cascade impactor, manufactured by Copley) with an adapter, and the flow rate (40.8 L / min) at which the pressure loss was 4 kPa was determined.

From Examples 1 to 3 and Comparative Example 4, 20 mg was weighed and filled into hard capsules (size 3, gelatin capsule, manufactured by Capsugel Japan). Hard capsules were placed in Handy Heller (Nippon Boehringer Ingelheim).

A handy heller was connected to the NGI with an adapter, and a hole was made in the capsule with the needle attached to the handy heller. Suction was performed for 5.9 seconds at a flow rate of 40.8 L / min. Handy Heller, capsule, mouthpiece and NGI fractions (induction port, pre-separator, Stage 1-7, MOC) are washed with water / methanol mixture for liquid chromatography (4/1) and effective for each fraction. The component concentration was determined by HPLC measurement (using HPLC measurement condition A), and the deposition rate of the active ingredient was calculated. The amount of all active ingredients collected was calculated as an AD value, and the amount of active ingredient released from the capsule and the device was calculated as an ED value. The total amount of active ingredients distributed on the 0.5 to 5 μm stage was defined as FPD (Fine Particle Dose), and FPF _AD was calculated as the ratio of FPD to _AD value, and FPF _ED was calculated as the ratio of FPD to ED value. The results are shown in Tables 5 and 6.

The values of FPF _AD and FPF _ED of Examples 1 and 2 using Mill product B are more than double that of Comparative Example 4 using Mill product A, and the inhalation characteristics are significantly It turns out that it is improving. Mill product B has a nearly spherical shape compared to Mill product A (see FIG. 4 and FIG. 6), and the particle frequency in the range of 0.5 to 5.0 μm is high (see Table 2). It is thought that it had high inhalation characteristics. As shown in Reference Example 4, the Mill product B can be easily obtained by jet milling the Intact product B. Unlike the conventional method (Patent Document 3) in which the active ingredient fine particles are formed into a spherical shape by performing a spray drying method or the like, the step of forming into a spherical shape is unnecessary, and it is useful in that it can be easily and inexpensively manufactured. .

Furthermore, in Examples 1 and 2, the content in the pre-separator fraction is as high as about 50%. However, when pulverized lactose (Repitose MC001) is added and mixed, the content in the pre-separator fraction is up to 18.9%. (Example 3). A decrease in the content of the pre-separator fraction means that the amount of active ingredient deposited on the pre-target site organ is small. Here, the pre-target-site organ is an organ before reaching the lower airway, which is the target site, and means the oral cavity, the pharynx, or the like. By suppressing the active ingredient absorption from the organ in front of the target site, an inhalation preparation with few side effects becomes possible. Furthermore, since the amount of the active ingredient deposited on the pre-target site organ is small, the active ingredient reach to the target site is improved. The inhalation characteristics of Example 3 are as follows: FPF _{AD up} to 20.6%, FPF _ED Improved to 36.2%.
(Comparative Example 5)
The total amount of powder filled in 20 mg of Intal capsule for external use (Sanofi-Aventis Co., Ltd.) was filled into No. 3 gelatin capsule (manufactured by Capsugel Japan). The capsule was placed in a handy heller (manufactured by Nippon Boehringer Ingelheim).
(Comparative Example 6)
No. 3 gelatin capsule (manufactured by Capsugel Japan Co., Ltd.) was filled with the powder filled in Fulltide 200 Rotadisc (Glasso SmithKline Co., Ltd.). The capsule was placed in a handy heller (manufactured by Nippon Boehringer Ingelheim).
(Test Example 5) Inhalation characteristic evaluation test (30 mL / min)
Each handy spatula of Comparative Examples 5 and 6 was connected to NGI with an adapter, and a hole was made in the capsule with a needle attached to the handy spatula. Suction was performed for 8 seconds at a flow rate of 30 L / min. Handy Heller was washed with diluted phosphoric acid (1 → 1000), and capsules and NGI fractions (induction port, pre-separator, Stage 1-7, MOC) were mixed with acetonitrile / diluted phosphoric acid (1 → 1000) ( 1/1), the active ingredient concentration in each fraction was determined by HPLC measurement, and the deposition ratio of the active ingredient was calculated (Comparative Example 5 was HPLC measurement condition B, Comparative Example 6 was HPLC measurement condition C). It was used). The amount of active ingredient released from the capsule and device was calculated as the ED value. FPF _ED was calculated as the ratio of FPD with respect to ED value, with the cumulative amount of active ingredients distributed on the stage of 0.5-5 μm or less as FPD. The results are shown in Table 7.

HPLC measurement condition B:
Separation column: A stainless tube having an inner diameter of 4.6 mm and a length of 150 mm was filled with 5 μm of octadecylsilylated silica gel for liquid chromatography. (GL Sciences, Inertsil ODS-2)
Guard column: A stainless tube having an inner diameter of 4.6 mm and a length of 5 mm was filled with 3 μm of octadecylsilylated silica gel for liquid chromatography. (GL Sciences, Inertsil ODS-3)
Mobile phase: acetonitrile for liquid chromatography / diluted phosphoric acid (1 → 1000) mixture (7: 3)

Flow rate: 1.0 mL / min
Detector: UV absorptiometer (measurement wavelength: 327 nm)
Injection volume: 10 μL
Area measurement range: 5 minutes Retention time: 3.5 minutes

HPLC measurement condition C:
Separation column: A stainless tube having an inner diameter of 4.6 mm and a length of 150 mm was filled with 5 μm of octadecylsilylated silica gel for liquid chromatography. (GL Sciences, Inertsil ODS-2)
Guard column: A stainless tube having an inner diameter of 4.6 mm and a length of 5 mm was filled with 3 μm of octadecylsilylated silica gel for liquid chromatography. (GL Sciences, Inertsil ODS-3)
Mobile phase: acetonitrile for liquid chromatography / diluted phosphoric acid (1 → 1000) mixture (7: 3)

Flow rate: 1.0 mL / min
Detector: UV absorptiometer (measurement wavelength: 237 nm)
Injection volume: 100 μL
Area measurement range: 5 minutes Retention time: 3.4 minutes (Test Example 6) Inhalation characteristic evaluation test (60 mL / min)
The handy spallers of Comparative Example 5 and Comparative Example 6 were tested in the same manner as in Test Example 5 except that suction was performed at a flow rate of 60 L / min for 4 seconds. The results are shown in Table 7.

The FPF _ED of Example 3 is as high as 36.2%, and the highest comparative example 5 (flow rate 60 L / min, interle) among the inteles (Comparative Example 5) and fulltide (Comparative Example 6) distributed in the market. ), The value was 1.4 times higher. It can be seen that Example 3 is a useful inhalation powder with high inhalation characteristics.

According to the present invention, it is possible to provide an inhalable powder of a benz [d] [1,3] oxazine derivative maleate having excellent inhalation characteristics and suitable for a content uniformity test.

Claims (8)

Formula (1)
A preparation for inhalation containing an active ingredient and carrier particles represented by
The active ingredient is a crystal having a characteristic peak at 8.4 ° as a diffraction angle (2θ ± 0.5 °) in powder X-ray diffraction, and a crystal having a characteristic peak at 7.7 ° Is an active ingredient substantially free of
An inhalable powder, wherein the carrier particles have a cumulative 10% particle size of 20 μm or more. 2- {2-((S) -3-dimethylaminopyrrolidin-1-yl) pyridin-3-yl} having the same powder X-ray diffraction pattern as the active ingredient shown in FIG. The inhalable powder according to claim 1, which is -5-ethyl-7-methoxy-4H-benz [d] [1,3] oxazin-4-one.1 maleate. The inhalable powder according to claim 1 or 2, wherein the particle frequency of the active ingredient in the range of 0.5 to 5.0 µm is 65% or more. The inhalable powder according to any one of claims 1 to 3, wherein the active ingredient has a cumulative 50% particle size of 3 µm or less. Furthermore, the inhalation powder agent of any one of the Claims 1 thru | or 4 containing micronized saccharides. The inhalable powder preparation according to claim 5, wherein a cumulative 50% particle size of the micronized saccharide is 5 µm or less. The inhalable powder according to claim 5 or 6, wherein the micronized saccharide is lactose. The inhalable powder according to any one of claims 1 to 7, wherein the carrier particles are lactose.