JP2001151673A - Method for producing powder formulation for inhalation - Google Patents

Abstract

(57) Abstract: A method for producing a powder formulation for inhalation used in a dry powder inhaler, comprising: (a) mixing a drug (excluding an azulene derivative having thromboxane antagonism) with an auxiliary substance After that, for example, a step of mixing and grinding into fine particles in a high-speed air stream to obtain a fine particle mixture, and (b) a step of mixing the fine particle mixture with carrier particles such as saccharides, sugar alcohols, or amino acids . Effect: It is possible to easily produce a powder preparation for inhalation having a high lung reach rate and good dischargeability from an inhaler when inhaling with a dry powder inhaler.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a method for producing a powder preparation for inhalation containing an active ingredient such as an antiallergic agent.

[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 method for producing a powder preparation for inhalation used in a dry powder inhaler. It is an object of the present invention to provide a method for producing a powder formulation for inhalation, which has good redispersibility, has excellent powder flowability, and has an increased drug delivery rate to a disease site.

[0008]

Means for Solving the Problems The present inventors have conducted various studies to solve the above problems, and as a result, prepared a fine particle mixture by mixing and pulverizing auxiliary substances such as lactose and a drug. It has been found that a powder formulation for inhalation having the above characteristics can be efficiently produced by mixing with carrier particles, and the present invention has been completed.

That is, the present invention relates to a method for producing a powder preparation for inhalation used in a dry powder inhaler,
(a) mixing a drug (excluding an azulene derivative having thromboxane antagonism) and an auxiliary substance, and then mixing and pulverizing the mixture into fine particles to obtain a fine particle mixture, and (b) mixing the fine particle mixture and carrier particles. A method comprising the step of mixing.

According to a preferred embodiment of the present invention, the above method of mixing and pulverizing in a high-speed air stream; the above method of mixing the fine particles mixture with the carrier particles while breaking the aggregate; the auxiliary substance is a saccharide, a sugar alcohol, Wherein the auxiliary substance is lactose; the above method, wherein the auxiliary substance is lactose; the above method, wherein the fine particle mixture has a particle size of 1 to 5 μm; And the above method, wherein the carrier particles are particles containing lactose; and the carrier particles are lactose-containing particles.
0 to 125 μm; the above method including 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 method as described above comprising in the range of 14.

[0011] In a further preferred embodiment, the method the drug is a drug showing efficacy by absorption from the lung胞部position; drug; drug antiallergic agents, beta ₂ stimulants, steroid compounds, or the method is a anticholinergics Is cromolyn, salbutamol sulfate, or beclomethasone propionate.

[0012]

BEST MODE FOR CARRYING OUT THE INVENTION The type of drug contained in the powder preparation for inhalation produced by the method of the present invention is not particularly limited, but, for example, a drug showing a medicinal effect by absorption from an alveolus site is preferable. Such drugs, for example, antiallergic agents, beta ₂ agonists, steroidal compounds,
Anticholinergic drugs and compounds having a phosphodiesterase IV inhibitory action (JP-A-10-120665, 10-5
No. 9950, No. 10-72415, No. 11-
189577, International Publication WO98 / 04534
No.), compounds having a lipoxygenase inhibitory action and a thromboxane synthase inhibitory action (WO 96/23)
772), compounds having a PAF antagonistic action and a thromboxane synthase inhibitory action (JP-A-11-71378), and the like, but are not limited thereto. Representative examples of preferred drugs include cromolyn,
Salbutamol sulfate or beclomethasone propionate, or 6-phenyltetrahydro-1,3-oxazine-2- described in WO 98/04534.
On-derivatives such as 6- [3- (2-indanyloxy) -4-methoxyphenyl] -6-methyl-3,
4,5,6-tetrahydro-2H-1,3-oxazin-2-one, 6- (3-cyclopropylmethyloxy-
4-methoxyphenyl) -3-methyl-3,4,5,6
-Tetrahydro-2H-1,3-oxazin-2-one, 6- [3- (2-indanyloxy) -4-methoxyphenyl] -3-methyl-3,4,5,6-tetrahydro-2H- 1,3-oxazin-2-one, 6- [3
-(2-Indanyloxy) -4-methoxyphenyl]
-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one, 6- (3-cyclopropylmethyloxy-4-methoxyphenyl) -6-methyl-3,4,
5,6-tetrahydro-2H-1,3-oxazine-2
-One, 6- (3-cyclopentylmethyloxy-4-
Methoxyphenyl) -6-methyl-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one. In the present invention, a mixture containing two or more kinds of drugs can also be produced. In addition, azulene derivatives having a thromboxane antagonism are excluded from the range of drugs used in the method of the present invention.

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 produced by the method of the present invention, the probability that the drug fine particles strongly adhere to the carrier particle surface is reduced by increasing the relative amount of the fine particles to the carrier particles by adding an auxiliary substance, preferably crystalline fine particles, to the drug fine particles. Thus, the drug microparticles are easily redispersed after administration, and the drug can be efficiently delivered to the target site.

The type of the auxiliary substance used in the method of the present invention is not particularly limited, and any auxiliary substance may 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. 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. Further, the auxiliary substance and the carrier particles may be either the same substance or different substances, but it is desirable to use the same substance. As the auxiliary substance, for example, a crystalline substance can be used, and sugars (glucose, lactose, sucrose, maltose, trehalose, dextran, etc.), sugar alcohols (mannitol, xylitol, erythritol, etc.), or amino acids such as leucine And the like can be suitably used. Among these, it is preferable to use lactose which is a crystalline saccharide or erythritol which is a crystalline sugar alcohol. Two or more of these substances may be used in combination. Of these,
Preferably, lactose is used. Although the mixing ratio of the drug and the auxiliary substance is not particularly limited, it is usually 1: 1 to 1: 199.
It is about.

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, in the method of the present invention, the drug and the auxiliary substance are mixed in the state of a powder (particle diameter: about 5 to 1000 μm) (large particles) before being pulverized into fine particles, and are further mixed and pulverized to be uniformly mixed. It is characterized in that a fine particle mixture of 1 to 5 μm is obtained. 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, nitrogen gas, in order to prevent the crystallinity of the fine particles from being impaired by the mixed 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 method of the present invention, it is desirable to use a sufficient amount of the fine particle mixture 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 drug contained in the powder formulation for inhalation produced by the method of the present invention,
It can be appropriately selected according to the type and efficacy of the drug, and is usually 0.1 to 10% by weight, preferably 0.2 to 10% by weight.
~ 2% by weight. One or more pharmaceutical additives may be added to the mixture of the fine particle mixture and the carrier particles produced as described above to produce a pharmaceutical preparation for inhalation. Pharmaceutical additives suitable for inhalation preparations can be appropriately selected by those skilled in the art.

The powder preparation for inhalation produced by the method of the present invention has a suitable flowability when inhaled using a dry powder inhaler, and has a discharge rate of 80% to 100% from an inhalation container. Can be discharged. Also, after being discharged from the dry powder inhaler, the drug fine particles are easily re-dispersed into primary particles in the oral cavity and the upper respiratory tract, and about 2%.
Airways, small airways, which are target sites with high efficiency of 0% to 30%,
Reach the alveoli.

[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 Salbutamol sulfate which is a β ₂ agonist was used as a drug, the content of salbutamol sulfate per 20 mg of the preparation was fixed at 100 μg, and a fine particle mixture obtained by mixing and grinding salbutamol sulfate and lactose, and lactose used as carrier particles (Carrier lactose) at 4:16, 8:12
Was prepared according to the following method. For comparison,
A formulation containing no lactose microparticles and having a ratio of salbutamol sulfate to carrier lactose of 0.1: 19.9 was also prepared.

Salbutamol sulfate (crystal, average particle size:
(3.7 μm) 1.0 g each and 39 g and 79 g each of lactose were 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 .1g
The mixture was pulverized at / sec to obtain two kinds of fine particle mixtures having an average particle size of 1.6 μm. Salbutamol sulfate microparticles without lactose microparticles were similarly prepared for the manufacture of comparative formulations.

To 1.0 g of the above-mentioned salbutamol sulfate fine particles (for comparison) and 40 g and 80 g of the fine particle mixture, 199 g, 160 g and 120 g of lactose (carrier lactose) were mixed until uniform in a metal container. . 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 Salbutamol sulfate was used as a drug, erythritol was used as an auxiliary substance, lactose under crystal sieving (average particle diameter 65 μm) was used as carrier particles, and a 20% fine particle mixture based on the weight of the preparation was prepared according to the method of Example 1. A formulation for inhalation was obtained.

Example 3 As a drug, a steroid compound, beclomethasone dipropionate (hereinafter sometimes abbreviated as "BDP").
20% by weight of the formulation according to the method of Example 1
The inhalation preparation containing the fine particle mixture in the ratio of was obtained.

Example 4 As a drug, sodium cromoglycate (hereinafter referred to as "DSC
G ". ), The content of DSCG per formulation 20 mg (single dose) is 1 mg, 2 mg,
And 4 mg of the preparation were produced by the method shown below. Jet mill (Co-Jet: Seishin Enterprise) using DSCG bulk powder and lactose (carrier lactose) in the same amount as DSCG bulk powder
, P pressure (indentation pressure): 5.0 kg / cm ² , G pressure (grind pressure): 4.0 kg / cm ² , powder feed rate:
Mix and grind at 0.1 g / sec, average particle size 2.5μ
m was obtained. 20 g of this fine particle mixture, 4
180 g, 160 g for 0 g and 80 g, respectively
g and 120 g of lactose (carrier lactose) were mixed in a metal container 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.

Example 5 6- [3- (2-Indanyloxy) -4- as a drug
[Methoxyphenyl] -3-methyl-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one (hereinafter abbreviated as compound A), and the content of compound A per 20 mg of preparation was 2 mg. / Dose was prepared by changing the amount of fine lactose in the fine particle mixture as shown below. Compound A bulk powder alone, Compound A bulk powder 1 part by weight and lactose 1
1 part by weight of Compound A bulk powder and 2 parts by weight of lactose, and 1 part by weight of Compound A bulk powder and 3 parts by weight of lactose in a jet mill (Co-Jet: Seishin Enterprise), each having a P pressure of 5.
The mixture was pulverized at 0 kg / cm ² , G pressure: 5.0 kg / cm ² and powder feed rate: 0.1 g / sec (1.0 mg / sec) to obtain a fine particle mixture having an average particle size of 1.5 μm. .
Next, lactose was added to 90 parts by weight, 80 parts by weight to 80 parts by weight in the case of 10 parts by weight, 40 parts by weight in the case of
The parts by weight, 70 parts by weight, and 60 parts by weight were added to a metal container and mixed until uniform. Thereafter, a sieving step of extruding aggregates (aggregates) while crushing them on a 32 mesh sieve was repeated three times. Each powder obtained here was used as a powder formulation for inhalation. The lactose used had an average particle diameter of 65 μm.
Lactose under the crystalline sieve.

Test Example 1 Each of the three powder formulations for inhalation obtained in Example 1 was filled in a No. 3 capsule in an amount of 20 mg, and then dried with a dry powder inhaler (MIAT).
The ratio [discharge rate = (difference in capsule weight before and after discharge / 20) × 100] with respect to the amount of dry powder discharged from a single-dose inhaler manufactured by the company was 20 mg. When the ratio of the fine particle mixture and the carrier particles exceeded the ratio of 4:16, the emission rate tended to slightly decrease.

Andersen Cascade Impactor (C
OPLEY) at 88.3 L / min for 8 seconds and then measuring the amount of drug that has reached each stage,
Lung reach was examined. The lung reach was expressed as a percentage of the amount that salbutamol sulfate in the capsule reached stages 3 to 7 after inhalation (corresponding to the amount of salbutamol sulfate fine particles of 4.7 μm or less). The results are shown in FIG.

Test Example 2 Each of the four types of powder preparations for inhalation obtained in Example 5 filled in a No. 3 capsule in an amount of 20 mg was prepared using a dry powder inhaler (a single dose inhaler manufactured by MIAT). Discharged well. Furthermore, these capsule preparations were aspirated with a twin impinger (COPLEY) at 60.0 L / min for 4 seconds, and the amount of Compound A that reached each stage was measured to determine the lung reach. Table 1 shows the results.
Shows the lung arrival rate. In addition, the lung arrival rate was calculated based on the amount of compound A in the capsule after the suction reached the stage 2 (6.4 μm).
m or less).

[0031]

[Table 1]

[0032]

According to the method of the present invention, a powder preparation for inhalation having a high pulmonary penetration rate and having good dischargeability from an inhaler when inhaled with a dry powder inhaler can be easily produced. be able to.

[Brief description of the drawings]

FIG. 1 is a graph showing the lung reach of a powder formulation for inhalation produced by the method of the present invention (Example 1).

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61P 37/08 A61P 37/08

Claims (14)

[Claims] 1. A method for producing a powder preparation for inhalation used in a dry powder inhaler, comprising the steps of: (a) mixing a drug (excluding an azulene derivative having thromboxane antagonism) with an auxiliary substance; To obtain a fine particle mixture by mixing and pulverizing, and (b) mixing the fine particle mixture and carrier particles. 2. The method according to claim 1, wherein the mixing and grinding are performed in a high-speed air stream. 3. The method according to claim 1, wherein the fine particles are mixed with the carrier particles while breaking the aggregates of the fine particle mixture. 4. The method 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 method according to claim 4, wherein said auxiliary substance is lactose. 6. The method according to claim 1, wherein the fine particle mixture has a particle size of 1 to 5 μm. 7. The method 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 method 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 method according to any one of claims 1 to 8, wherein 10. The method according to claim 1, wherein the fine particle mixture and the carrier particles are contained in a weight ratio of 1:19 to 10:10. 11. The method according to claim 10, comprising the fine particle mixture and the carrier particles in a weight ratio of 3:17 to 6:14. 12. The method according to any one of claims 1 to 11, wherein the drug is a drug having a medicinal effect by absorption from an alveolus site. 13. drug antiallergic agents, beta ₂ stimulants,
13. The method according to claim 12, which is a steroid compound or an anticholinergic. 14. The method according to claim 13, wherein the drug is cromolyn, salbutamol sulfate, or beclomethasone propionate.