JP2001072586A - Powdery inhaling preparation and its production - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a powdery inhaling preparation having a good re-dispersing property while keeping a high medicine-discharging property, and an excellent powder fluidity and improving the medicine-attainability to the region of a disease. SOLUTION: This powdery inhaling preparation used by a dry powder inhaling tool contains (a) a fine particle mixture obtained by a method of mixing an azulene derivative having a thromboxane-antagonizing activity with an additive and then mixing and crushing it to a fine particle state and (b) a carrier particles of a saccharide, a sugar alcohol, an amino acid or the like. The method for production is simple, and in the case of inhaling by using a dry powder- inhaling tool, the discharging property from the inhaling tool is not damaged and it is possible to achieve a high lung attainability.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a powder preparation for inhalation of an azulene derivative having a thromboxane antagonism and a method for producing the same.

[0002]

2. Description of the Related Art Among drugs used for respiratory diseases,
Inhaled preparations have been rapidly developed in recent years because they have the advantages of being able to deliver drugs directly to the respiratory system, which is a diseased area, reducing the side effects because only a small amount of the drug is required, and having a rapid onset of action. . In particular steroidal compounds targeting a disease with lesions, such as asthma respiratory, beta ₂ stimulants,
It is widely used for the administration of antiallergic drugs.

[0003] Currently, the most widely used portable inhalation preparations are those using a pressurized metered dose sprayer (hereinafter sometimes abbreviated as "pMDI" in the present specification). In pMDI, a certain amount of a drug is released together with a Freon solvent as a dispersion medium, and after the Freon containing the drug is discharged, the Freon volatilizes, and the drug is released in the oral cavity and upper respiratory tract.
Mass Median Aerodynamic Diameter of ~ 5 μm
an Aerodynamic Diameter; M
(MAD) and exhibit efficient lung reach. However, since the use of CFCs is inconvenient in terms of environmental protection, as an alternative, an inhalation preparation using a dry powder inhaler (hereinafter, this inhalation preparation may be referred to as an “inhalation powder preparation”). ) Is drawing attention. This powder formulation for inhalation is characterized in that the powder formulation is discharged from an inhalation container and inhaled as fine particles having a particle size that reaches the airway.

However, in the case of a powder preparation for inhalation composed of only a fine powder, a sufficient amount of drug is not discharged from the inhaler, and the dose is often uncertain. In addition, when the powder formulation for inhalation is inhaled from an inhaler, it takes 1 to 1 minute for the fine drug powder to reach the diseased lesions, such as the airways, small airways and alveoli.
It must have a MMAD of about 5 μm,
Since the particles are very easy to aggregate, 1
Even if it has a particle size of about 5 μm, most of the fine particles are aggregated, and the aggregates are not redispersed in the oral cavity and the upper respiratory tract. As a result, MMAD becomes large and the lung reach is low. turn into.

[0005] Therefore, a technique has been adopted in which a fine powder of a drug is attached to the surface of large particles to suppress aggregation of the fine powder, improve the fluidity of the powder, and improve the drug delivery to the lungs. However, in such an inhalation powder formulation, since a large amount of the carrier particles is used relative to the amount of the fine particles of the drug, most of the drug fine particles are strongly adhered to the surface of the carrier particles, and the drug fine particles are detached from the carrier particles. Requires a large external force (dispersion force). For this reason, there is a problem that the drug cannot efficiently reach the airways, small airways, and alveoli as primary fine particles. The amount of pulmonary drug delivered (pulmonary delivery rate) to the amount of drug excreted in a general inhalable powder formulation is 10%
However, the performance is not satisfactory as a formulation for inhalation for the purpose of efficiently delivering a drug to a target disease site (airway, small airway, alveoli).

On the other hand, a powder formulation for inhalation for the purpose of improving the pulmonary delivery rate of a drug is a formulation for inhalation comprising a finely divided active substance and an auxiliary substance, wherein the auxiliary substance is about 20 μm.
A formulation comprising a coarse fraction having an average particle diameter of at least m and a fine fraction having an average particle diameter of about 10 μm or less (Japanese Patent Application Laid-Open No. 8-501056) to improve the redispersibility of drug fine particles. For this purpose, there is a method in which the surface of carrier particles is processed to improve the lung accessibility (Japanese Patent Application Laid-Open No. 9-507049). However, the method described in Japanese Patent Application Laid-Open No. H8-501056 involves mixing two or more kinds of finely divided powders uniformly when mixing an active substance and an auxiliary substance which have been pulverized to a predetermined particle size in advance. In addition, there is a disadvantage that the fine particles are partially agglomerated and agglomerated at the time of mixing, which is not always satisfactory. Further, in the method described in Japanese Patent Application Laid-Open No. 9-507049, carrier particles having a predetermined particle size are preliminarily pulverized by a ball mill or the like, and finely divided from the surface of the carrier particles without substantially changing the particle size of the carrier particles. Since the carrier particles obtained by removing the powder are used, the processing operation is large and complicated.

[0007]

SUMMARY OF THE INVENTION An object of the present invention is to provide a powder preparation for inhalation used in a dry powder inhaler. It is an object of the present invention to provide a powder formulation for inhalation which has dispersibility, has excellent powder fluidity, and has an increased drug reach to a disease site. It is also an object of the present invention to provide a powder preparation for inhalation having the above characteristics and which can be produced by a simple process.

[0008]

Means for Solving the Problems The present inventors have conducted various studies to solve the above-mentioned problems, and as a result, prepared an auxiliary substance such as lactose and a drug as a fine particle mixture, and further mixed with a carrier particle. As a result, they have found that a powder formulation for inhalation having the above characteristics can be provided, and have completed the present invention.

That is, the present invention relates to a powder preparation for inhalation used in a dry powder inhaler, comprising: (a) a fine particle mixture containing an azulene derivative having thromboxane antagonism and an auxiliary substance; and (b) carrier particles. The present invention provides a preparation comprising a mixture of According to a preferred embodiment of the present invention, the above-mentioned preparation, wherein the fine particle mixture is a fine particle mixture obtained by mixing an azulene derivative having a thromboxane antagonism and an auxiliary substance, and then mixing and pulverizing into fine particles. The above-mentioned preparation is provided, wherein the azulene derivative is sodium 3- [4- (4-chlorobenzenesulfonylamino) butyl] -6-isopropyl-1-azulenesulfonate.

According to a further preferred embodiment, the above-mentioned preparation, wherein the auxiliary substance is one or more substances selected from the group consisting of sugars, sugar alcohols and amino acids; the above-mentioned preparation, wherein the auxiliary substance is lactose; The above-mentioned preparation, wherein the particle diameter of the fine particle mixture is 1 to 5 μm; the above-mentioned preparation, wherein the carrier particles are carrier particles containing one or more substances selected from the group consisting of sugars and sugar alcohols; The above-mentioned preparation, wherein the particles are lactose-containing particles;
The above formulation having a particle size of 0 to 125 μm; the above formulation comprising the fine particle mixture and the carrier particles in a weight ratio of 1:19 to 10:10; the fine particle mixture and the carrier particles being 3:17 to 6: 14. A formulation as described above comprising the range of 14.

[0011] In another aspect, there is provided a method for producing the above-mentioned inhalable powder preparation for use in a dry powder inhaler,
The following steps: (a) mixing an azulene derivative having thromboxane antagonism and an auxiliary substance, and then mixing and pulverizing the resulting mixture to obtain a fine particle mixture; and (b) the fine particle mixture and carrier particles. Are provided. According to a preferred aspect of the present invention, there are provided the above method of performing the mixing and pulverization in a high-speed air stream, and the above method including a step of mixing with a carrier particle while destroying an aggregate of a fine particle mixture.

[0012]

DETAILED DESCRIPTION OF THE INVENTION As an azulene derivative having a thromboxane antagonism, for example, JP-A-3-1880
An azulene derivative described in JP-A No. 53 can be mentioned, and preferably, sodium 3- [4- (4-chlorobenzenesulfonylamino) butyl] -6-isopropyl-1-azulenesulfonate can be used. According to the publication, these compounds can be administered by any of oral and parenteral administration routes, but they are useful when these compounds are inhaled as a powder formulation for inhalation. There is no.

According to the study of the present inventors, when the drug particles adhere to the surface of the carrier particles, there are a drug particle that strongly adheres to the surface of the carrier particles and a drug particle that adheres weakly to the surface of the carrier particles. The drug microparticles are easily separated from the carrier particles when discharged from the inhaler, and can reach the target site as primary microparticles. However, when the amount of the drug particles is extremely small relative to the amount of the carrier particles, the drug particles preferentially adhere to the surface of the carrier particles, and the amount of the primary particles redispersed when discharged from the inhalation container is significantly reduced. I do. In the preparation of the present invention, by increasing the relative amount of the fine particles to the carrier particles by adding an auxiliary substance, preferably crystalline fine particles to the fine drug particles, the probability of the fine drug particles strongly adhering to the surface of the carrier particles is reduced. Later, the drug microparticles are easily redispersed, and the drug can be efficiently delivered to the target site.

The type of auxiliary substance used in the production of the preparation of the present invention is not particularly limited, and any substance can be used as long as it can prevent the drug from adhering to the carrier particles in the state of the fine particle mixture as described above. Good. In general, it is necessary to consider the degree of adhesion to the carrier particles, the chargeability, and the like, and to select a substance that is not expected to have a medicinal effect. Also, the auxiliary substance and the carrier particles may be either the same substance or different substances,
It is desirable to use the same substance. As the auxiliary substance, for example, a crystalline substance can be used, and saccharides (glucose, lactose, sucrose, maltose, trehalose,
Dextran, etc.), sugar alcohols (mannitol, xylitol, erythritol, etc.), or amino acids such as leucine can be suitably used. Two or more of these substances may be used in combination. Of these, lactose is preferably used. The mixing ratio of the azulene derivative and the auxiliary substance is not particularly limited, but is usually 1:
It is about 1-1: 199, preferably about 1: 4-1: 119.

Generally, it is technically difficult to obtain a fine particle mixture in which two or more types of fine particle powders having different properties are uniformly mixed as primary particles, because the fine particles have a property of easily aggregating with each other. It is. For this reason, the powder (particle size: 5 to 100) before the drug and the auxiliary substance are crushed into fine particles.
It is preferable to obtain a uniformly mixed fine particle mixture of 1 to 5 μm by mixing in a state of (about 0 μm) (large particles) and further mixing and pulverizing. Such mixing and pulverization is desirably performed in a high-speed airflow from the viewpoint of preventing aggregation of the same fine particles. Further, in some cases, it is preferable to perform (mixing) pulverization in a high-speed gas stream using a cooled gas, for example, a nitrogen gas, in order to suppress the crystallinity of the fine particles from being impaired by the mixing and pulverization. When the crystallinity of the fine particles is impaired by the mixing and grinding, aging (curing) may be performed under humidified conditions.

As the carrier particles, any carrier particles may be used as long as the above-mentioned fine particle mixture can be adhered to the surface to suppress aggregation of the fine particle mixture and maintain the fluidity of the powder. Various carrier particles are already used in the art for such purpose. For example, it is preferable to use the above sugars or sugar alcohols, and more preferably, the same sugars or sugar alcohols as the above auxiliary substances can be used. Two or more substances may be used in combination as carrier particles. Particularly preferably, lactose can be used. The carrier particles usually have a particle size of about 40 to 1
It is 50 μm, preferably about 50 to 80 μm.

The mixture of the carrier particles and the fine particle mixture is 28,
An extrusion mixing method using a screen of about 30 or 32 mesh is preferable. It is also preferable to use a high-speed rotation mixer. The particle mixture containing the drug particles is 1
Although they are uniformly mixed as secondary particles, they may be aggregated (aggregated) with a uniform composition due to the characteristics of the fine particles. In such a case, it is effective to redisperse the obtained fine particle mixture and uniformly disperse it on the surface of the carrier particles. For this purpose, it is preferable to adopt a step of mixing the fine particle mixture with the carrier particles while breaking the aggregates of the fine particle mixture. According to this step, the drug fine particles and the auxiliary substance fine particles can be attached to the surface of the carrier particles as primary particles of 1 to 5 μm.

In the preparation of the present invention, it is desirable to use a fine particle mixture in an amount sufficient to cover the entire surface area of the carrier particles. By using such an amount of the fine particle mixture, it is possible to reduce the ratio of the drug fine particles that strongly adhere to the carrier surface. However, if the amount of the fine particle mixture greatly exceeds the amount required to sufficiently cover the surface of the carrier particles, the fine particles are aggregated, hindering redispersion into the primary particles, and the fluidity of the powder is reduced. At the same time, the powder dischargeability may decrease.

Generally, the amount of the fine particle mixture is about 5 to 50% by weight, preferably 15 to 30% by weight based on the total weight of the preparation.
It is. The ratio of the fine particle mixture to the carrier particles is in the range of 1:19 to 10:10 by weight, particularly 3:17 to 10:10.
It is preferably in the range of 6:14. The amount of the azulene derivative contained in the powder formulation for inhalation of the present invention is 0.1 to 1
0% by weight, preferably 0.2 to 2% by weight. The preparation of the present invention may be produced by further adding one or more pharmaceutical additives to the mixture of the fine particle mixture and the carrier particles produced as described above. Pharmaceutical additives suitable for inhalation preparations can be appropriately selected by those skilled in the art.

The powder formulation for inhalation of the present invention has a suitable flowability when inhaled using a dry powder inhaler, and can be discharged from the inhalation container at a discharge rate of 80% to 100%. . In addition, after being discharged from the dry powder inhaler, one or more drug microparticles are found in the oral cavity or upper respiratory tract.
It is easily redispersed into the secondary particles and reaches the target site, such as the airway, the small airway, the alveoli, etc. with high efficiency of about 20% to 30%.

[0021]

EXAMPLES Hereinafter, the present invention will be described more specifically with reference to Examples, but the scope of the present invention is not limited to these Examples. Example 1 3- having thromboxane A ₂ antagonism as a drug
Using [4- (4-chlorobenzenesulfonylamino) butyl] -6-isopropyl-1-azulenesulfonic acid sodium (hereinafter, abbreviated as "KTN-962" in the examples), KTN-9 per 20 mg of the preparation is used.
The content of 62 was fixed to 200 μg, and the ratio of the fine particle mixture obtained by mixing and grinding KTN-962 and lactose to lactose (carrier lactose) used as carrier particles was 2:18,
Formulations of 4:16, 8:12, 10:10 were prepared according to the following method. For comparison, the ratio of KTN-962 to the carrier lactose was 0.2: 19.8 without lactose microparticles.
Was also manufactured.

KTN-962 (crystal, average particle size: 10 μm)
m) 2.0 g each and lactose each 18 g, 38 g, 78 g, 98
g was placed in a metal container and mixed until uniform. Next, a sieving step of extruding the mixture while crushing aggregates (aggregates) on a 32 mesh sieve was repeated three times. The obtained mixture was jet-milled (Co-Jet: Seishin Enterprise), P pressure (indentation pressure): 5.0 kg / cm ² , G pressure (grind pressure): 4.0 kg / cm ² , powder feed rate: 0 The mixture was pulverized at a rate of 0.1 g / sec to give an average particle size of 3.
Four types of 0 μm fine particle mixtures were obtained. KTN-962 microparticles without lactose microparticles were similarly manufactured for the manufacture of comparative formulations.

The above KTN-962 fine particles (for comparison)
2.0 g, and each of the fine particle mixture 20 g, 40 g, 80
g, 100 g, 198 g, 180 g, 1
60 g, 120 g, and 100 g of lactose (carrier lactose) were placed in a metal container and mixed until uniform. Thereafter, a sieving step of extruding the mixture while crushing the aggregates on a 32 mesh sieve was repeated three times. Each powder obtained here was used as a powder formulation for inhalation. The lactose used in the examples is all lactose under the crystal sieve having an average particle diameter of 65 μm.

Example 2 A powder formulation for inhalation was prepared according to the method of Example 1 using KTN-962 as a drug. 2.0 for KTN-962
g and lactose 39g on a 32 mesh sieve
Mix while extruding while destroying
Repeated times. The resulting mixture is jet milled (C
o-Jet: Seisin company) P pressure (indentation pressure):
5.0 kg / cm ² , G pressure (grind pressure): 4.0 k
The mixture was pulverized at g / cm ^{2 at} a powder feed rate of 0.1 g / sec to obtain a fine particle mixture having an average particle size of 3.0 μm.
Lactose (carrier lactose) 16 per 40 g of this fine particle mixture
0 g was mixed with a high-speed mixer. Mixing lower rotation 2,
2,000 rpm and lateral rotation of 500 rpm for 2 minutes. The resulting powder was used as a powder formulation for inhalation.

Example 3 KTN-962 (0.5 g) and lactose 39.5 g were placed in a metal container and mixed until uniform. Next, the sieving step of extruding the mixture while crushing aggregates (aggregates) on a 32 mesh sieve was repeated three times. The obtained mixture was jet-milled (Co-Jet: Seishin Enterprise), P pressure (indentation pressure): 5.0 kg / cm ² , G pressure (grind pressure): 4.0 kg / cm ² , powder feed rate: 0 .1g
/ Sec to obtain a fine particle mixture having an average particle size of 3.0 μm. For 40 g of this fine particle mixture, 16
0 g of lactose was placed in a metal container and mixed until uniform. Thereafter, a sieving step of extruding the mixture while crushing the aggregates on a 32 mesh sieve was repeated three times. The resulting powder was used as a powder formulation for inhalation.

Test Example 1 Five capsules for inhalation obtained in Example 1 were filled into No. 3 capsules in an amount of 20 mg each, and then dried with a dry powder inhaler (MIAT).
(A single-dose inhaler manufactured by the company) and the ratio (discharge rate) to the dry powder amount of 20 mg. 0.2:
The emission ratio was approximately 100% from 19.8 to 4:16, and the emission ratio tended to decrease slightly when the ratio of the fine particle mixture to the carrier particles exceeded the ratio of 4:16.

Andersen Cascade Impactor (C
After suctioning at 28.3 L / min for 8 seconds with OPLEY, the amount of KTN-962 that reached each stage was measured to determine the lung reach. The lung reach was expressed as a percentage of the amount that KTN-962 in the capsule reached stages 3 to 7 after aspiration (corresponding to the amount of KTN-962 microparticles of 4.7 μm or less). The results are shown in FIG. At around the ratio of the fine particle mixture and the carrier particles of more than 2:18, the pulmonary drug arrival rate was significantly increased, and a tendency was found to decrease as the excretion from the inhalation container decreased. Pulmonary coverage in formulations with a 4:16 and 8:12 ratio of particulate mixture to carrier particles was 28.4% and 25.5%, respectively.
Met. In consideration of the excretion rate and the lung arrival rate, it was considered that the weight ratio of the amount of the fine particle mixture to the amount of the carrier particles in the powder formulation for inhalation obtained in Example 1 was most preferably 2: 8.

Test Example 2 a) 20 mg of the powder formulation for inhalation obtained in Example 1 (having a weight ratio of the fine particle mixture amount to the carrier particle amount of 4:16) was filled in a No. 3 gelatin capsule. Using a inhalation container (single inhalation container manufactured by MIAT), the capsules were administered by inhalation to 6 healthy Caucasian persons, one capsule at a time. The inhalation of the powder formulation from the capsule was carried out by repeating inhalation for 4 seconds and holding breath for 3 seconds (Hold Breath) four times per capsule. After inhalation, 5, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours,
Blood was collected from each subject at 8 hours, 12 hours, and 24 hours later, and the KTN-962 concentration in the blood was measured using a high performance liquid chromatograph mass-mass spectrometer (LC / MS / MS). did. b) The test was carried out in the same manner as in a) above, except that the six same healthy capsules were inhaled by 6 healthy white persons. c) The powder formulation for inhalation obtained in Example 3 (having a weight ratio of the fine particle mixture amount to the carrier particle amount of 4:16) in 6 healthy Caucasians was placed in a No. 3 gelatin capsule by 2
0 mg was charged. The test was conducted in the same manner as in a) except that the obtained capsules were inhaled one by one. The blood concentration of KTN-962 obtained in the above test (average value of 6 subjects) is shown in FIG.

[0029]

EFFECTS OF THE INVENTION The powder preparation for inhalation of the present invention is characterized in that its production method is simple, and when inhaled with a dry powder inhaler, the exhalation property from the inhaler is not impaired, and high lung reach is achieved. There is.

[Brief description of the drawings]

FIG. 1 is a graph showing the lung reach of the preparation of the present invention.

FIG. 2. KT when the formulation of the present invention is inhaled by humans
It is a figure which showed the time-dependent change of the average blood concentration of N-962.

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁷ Identification code FI Theme coat ゛ (Reference) A61P 11/06 A61K 9/14 (72) Inventor Hideki Hakamada 1-346 Kitabukurocho, Omiya City, Saitama Prefecture NIKEN Inside the Omiya Research Laboratory of Chemical Co., Ltd. (72) Inventor Hiroshi Seki 1-346 Kitabukuro-cho, Omiya-shi, Saitama F-term (reference) 4C076 AA29 BB22 BB27 CC15 DD38 DD51 DD67 GG02 GG03 4C206 AA01 AA02 JA06 KA04 MA02 MA03 MA05 MA28 MA76 MA77 NA10 ZA59

Claims (14)

[Claims] 1. A powder preparation for inhalation used in a dry powder inhaler, comprising: (a) a fine particle mixture comprising an azulene derivative having thromboxane antagonism and an auxiliary substance;
And (b) a formulation comprising a mixture of carrier particles. 2. The preparation according to claim 1, wherein the fine particle mixture is a fine particle mixture obtained by mixing an azulene derivative having a thromboxane antagonism and an auxiliary substance and then mixing and pulverizing the mixture into fine particles. 3. The preparation according to claim 1, wherein the azulene derivative is sodium 3- [4- (4-chlorobenzenesulfonylamino) butyl] -6-isopropyl-1-azulenesulfonate. 4. The preparation according to claim 1, wherein the auxiliary substance is one or more substances selected from the group consisting of sugars, sugar alcohols, and amino acids. 5. The preparation according to claim 4, wherein the auxiliary substance is lactose. 6. The preparation according to claim 1, wherein the particle size of the fine particle mixture is 1 to 5 μm. 7. The preparation according to claim 1, wherein the carrier particles are carrier particles containing one or more substances selected from the group consisting of sugars and sugar alcohols. 8. The preparation according to claim 7, wherein the carrier particles are particles containing lactose. 9. The carrier particles have a particle size of 50 to 125 μm.
The preparation according to any one of claims 1 to 8, which is: 10. The preparation according to claim 1, comprising the fine particle mixture and the carrier particles in a weight ratio of 1:19 to 10:10. 11. The preparation according to claim 10, comprising the fine particle mixture and the carrier particles in a weight ratio of 3:17 to 6:14. 12. A method for producing a powder formulation for inhalation used in a dry powder inhaler according to any one of claims 1 to 11, comprising the following steps: (a) azulene having a thromboxane antagonism Mixing the derivative and the auxiliary substance, and then mixing and grinding the resulting mixture to obtain a fine particle mixture; and (b) mixing the fine particle mixture with carrier particles. 13. The method according to claim 1, wherein the mixing and grinding are performed in a high-speed air stream.
12. The method according to 12. 14. The method according to claim 12, comprising a step of mixing with the carrier particles while breaking up the aggregates of the fine particle mixture.