JP2014105171A - Production method of powder for inhalation - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a production method of a powder for inhalation, allowing uniform distribution of an active ingredient and excellent dispersibility.SOLUTION: The present invention relates to a production method of a powder for inhalation, comprising: an anticholinergic agent-mixing step of stirring an anticholinergic agent and a carrier in the presence of a grinding medium and shredding the anticholinergic agent while mixing with the carrier to obtain a mixture of the carrier and the anticholinergic agent; and a granule powder-mixing step of adding a granule powder to the mixture obtained in the anticholinergic agent-mixing step and stir-mixing in the presence of the grinding medium.

Description

  The present invention relates to a method for producing a powder for inhalation. More specifically, the present invention suppresses the aggregation of the active ingredient by mixing and stirring the finely divided powder after stirring and mixing the active ingredient and the carrier having high agglomeration in the production of the powder for inhalation. The active ingredient can be uniformly distributed, and an inhalable powder with excellent dispersibility can be obtained.

  JP 2010-533697 A (Patent Document 1) discloses a dry powder medicine and a method for producing the same. In this production method, after powders of plural kinds of active ingredients are fractionated, they are mixed with a carrier, and the plural kinds of active ingredients mixed with the carrier are further blended (paragraph [0021] of Patent Document 1, FIG. 1).

  JP-T-2006-515830 (Patent Document 2) discloses a method for producing a dry powder inhalation composition. This method produces a dry powder inhalation composition by mixing a carrier and a first granular inhalation pharmaceutical ingredient, followed by a second granular inhalation pharmaceutical ingredient. In Patent Document 2, salmeterol is regarded as the second granular inhaled pharmaceutical ingredient.

  Japanese Unexamined Patent Publication No. 2004-507343 (Patent Document 3) discloses finely pulverized particles. Patent Document 3 discloses a method of pulverizing using a bead while mixing a solid substrate and a plurality of small particles.

  Japanese Patent Application Publication No. 2009-519972 (Patent Document 4) discloses a method for producing a pharmaceutical agent for transpulmonary or nasal administration of a particle base. In this method, a drug is produced by mixing the particles of the preparation and the excipient fine particle material and pulverizing the mixture with a ball mill.

  Tiotropium bromide is an active ingredient of a therapeutic agent for COPD (chronic obstructive pulmonary disease) known as Spiriva (registered trademark). Tiotropium bromide is an anticholinergic agent with bronchodilation. Tiotropium bromide is a known compound as disclosed in, for example, Japanese Patent No. 3009924 and Japanese Patent No. 4331619.

Special table 2010-533697 gazette JP-T-2006-515830 JP-T-2004-507343 JP-T 2009-519972 Japanese Patent No. 3009924 Japanese Patent No. 4331619

  When a dry powder inhalation composition is produced based on the methods disclosed in Patent Documents 1 to 4, there is a problem that the distribution of the active ingredient is biased and the resulting composition is not excellent in dispersibility.

  Therefore, an object of the present invention is to provide a method for producing a powder for inhalation having a small distribution and excellent dispersibility.

  In particular, the present invention relates to a method for producing an inhalable powder containing an anticholinergic agent (for example, tiotropium bromide) having a small distribution and excellent dispersibility, bronchodilator or COPD (chronic obstructive pulmonary disease) treatment. It aims at providing the manufacturing method of an agent.

  In the production of inhalable powders containing one or more active ingredients, the present invention is obtained by stirring and mixing an anticholinergic agent and a carrier to obtain a mixture, and then mixing and stirring the fine powder in the mixture. This is based on the knowledge that anti-cholinergic agent aggregation can be suppressed, the active ingredient can be uniformly distributed, and an inhalable powder with excellent dispersibility can be obtained.

  The 1st side surface of this invention is related with the manufacturing method of the powder for inhalation which contains an anticholinergic agent as an active ingredient. This manufacturing method includes an anticholinergic agent mixing step and a fine powder mixing step. The anticholinergic agent mixing step is a step of stirring the anticholinergic agent and the carrier in the presence of a grinding medium and mixing the anticholinergic agent with the carrier while crushing. By this step, a mixture of an anticholinergic agent and a carrier can be obtained. The fine powder mixing step is a step of adding fine powder to the mixture obtained in the anticholinergic agent mixing step and stirring and mixing in the presence of a grinding medium.

  After stirring and mixing the anticholinergic agent and the carrier in this way to obtain a mixture, mixing the finely divided powder into the mixture and stirring to suppress the aggregation of the anticholinergic agent and distribute the active ingredient uniformly Inhalable powder with excellent dispersibility can be obtained.

  As will be described later, the carrier in the anticholinergic agent mixing step may be in a state of being mixed with an active ingredient. In that case, for example, there may be a step of mixing another active ingredient (for example, β2 stimulant) and the carrier before the anticholinergic agent mixing step. Furthermore, in the anticholinergic agent mixing step, a mixture containing an active ingredient other than the anticholinergic agent (for example, a β2 stimulant or a cortisol derivative) may be stirred and mixed.

  In a preferred embodiment of the first aspect of the present invention, the anticholinergic agent is that of tiotropium bromide or tiotropium bromide hydrate.

  A preferred embodiment of the first aspect of the present invention further includes a β2 stimulant mixing step before the anticholinergic agent mixing step. The β2 stimulant mixing step is a step for obtaining a mixture of the β2 stimulant and the carrier by stirring the carrier and the β2 stimulant in the presence of the grinding medium and mixing with the carrier while crushing the β2 stimulant. is there.

  In this embodiment, the anticholinergic mixing step is performed by adding the anticholinergic agent to the mixture of β2 stimulating agent and carrier obtained in the β2 stimulating agent mixing step, stirring the mixture in the presence of a grinding medium, and releasing the anticholinergic agent. It can be said to be a step of obtaining a mixture of β2 stimulant, anticholinergic agent and carrier by crushing and mixing with carrier. In this case, it is preferable that the β2 stimulating agent has a higher aggregation property than the anticholinergic agent. An example of a β2 stimulant is formoterol fumarate.

  In a preferred embodiment of the first aspect of the present invention, the anticholinergic agent mixing step comprises stirring the powder containing not only the anticholinergic agent and the carrier but also a β2 stimulant in the presence of a grinding medium, And a β2 stimulant is mixed with a carrier while crushing. In this case, in the anticholinergic agent mixing step, a mixture of β2 stimulant, anticholinergic agent and carrier is obtained.

  In a preferred embodiment of the first aspect of the present invention, in the fine powder mixing step, not only the mixture and fine powder obtained in the anticholinergic agent mixing step, but also a cortisol derivative added thereto in the presence of a grinding medium. And stirring and mixing. An example of a cortisol derivative is fluticasone propionate.

  The preferred embodiment of the first aspect of the present invention further includes a cortisol derivative mixing step before the fine powder mixing step. In this case, the powder for inhalation is obtained through the following steps: (β2 stimulant mixing step), anticholinergic agent mixing step, cortisol derivative mixing step, and fine powder mixing step. In addition, in the middle of these, processes other than these may be included. In this case, it is preferable that the anticholinergic agent has a higher aggregation property than the cortisol derivative. An example of a cortisol derivative is fluticasone propionate.

  In this case, the fine powder mixing step is a step of adding the fine powder to the mixture obtained in the cortisol derivative mixing step and stirring and mixing in the presence of the grinding medium.

  In a preferred embodiment of the first aspect of the present invention, the average particle size of the fine powder is from 1/50 to 1/5 of the average particle size of the carrier.

  In a preferred embodiment of the first aspect of the present invention, the composition of the carrier and the fine powder may be the same or different, and is a saccharide or a sugar alcohol.

  In a preferred embodiment of the first aspect of the present invention, the grinding medium is a bead.

  A preferred embodiment of the first aspect of the present invention is a method for producing a bronchodilator using the above-described method for producing a powder for inhalation. That is, the above inhalable powder contains an anticholinergic agent as an active ingredient, and the resulting inhalable powder can be effectively used as a bronchodilator.

  A preferred embodiment of the first aspect of the present invention is a method for producing a therapeutic agent for chronic obstructive pulmonary disease using the above-described method for producing a powder for inhalation. That is, the above inhalable powder contains an anticholinergic agent as an active ingredient, and the resulting inhalable powder can be effectively used as a therapeutic agent for chronic obstructive pulmonary disease.

  ADVANTAGE OF THE INVENTION According to this invention, the manufacturing method of the powder for inhalation | distribution with little distribution unevenness and excellent dispersibility can be provided.

  In particular, the present invention provides a method for producing a powder for inhalation containing an anticholinergic agent having a small distribution and excellent dispersibility, and a method for producing a bronchodilator or a therapeutic agent for COPD (chronic obstructive pulmonary disease). it can.

FIG. 1 is an SEM photograph replacing the drawing of the powder for inhalation obtained in Reference Example 1. FIG. 2 is an SEM photograph replacing a drawing of a commercially available powder for inhalation.

  Hereinafter, embodiments for carrying out the present invention will be described. The present invention relates to a method for producing a powder for inhalation. Inhalable powder is an inhalable drug. The powder for inhalation is a drug administered to a patient using an inhaler, as disclosed in JP-T-2011-503058. Inhalers are used for the treatment of respiratory diseases including asthma, bronchitis, chronic obstructive pulmonary disease (COPD), emphysema and rhinitis. Inhalers are also used for oral or nasal administration of medications containing analgesics and hormones. Examples of inhalers are dry powder inhalers (DPI), pressurized metered dose inhalers (pMDI) and nebulizers. A preferred inhaler in the present invention is a dry powder inhaler. Examples of inhalation powders are inhaler dry powder and dry powder.

  This manufacturing method includes an anticholinergic agent mixing step (step 101) and a fine powder mixing step (step 102).

  The anticholinergic agent mixing step is a step of stirring the anticholinergic agent and the carrier in the presence of a grinding medium and mixing the anticholinergic agent with the carrier while crushing. By this step, a mixture of a carrier and an anticholinergic agent can be obtained. By this step, the anticholinergic agent can be adhered to the carrier surface while being crushed. The anticholinergic agent mixing step may include a known pharmaceutically used agent in addition to the anticholinergic agent and the carrier. Examples of such pharmaceutically used agents are additives, lubricants, acidity modifiers, pigments, refreshing agents, taste blockers, sweeteners, antistatic agents, absorption enhancers and excipients. These agents may be added in the fine powder mixing step, or may be added in a step after the fine powder mixing step. In the anticholinergic agent mixing step, the second active ingredient may be added, or in the fine powder mixing step, the second active ingredient may be added. Furthermore, a third or subsequent active ingredient may be added in the first or fine powder mixing step.

  In the anticholinergic agent mixing step, a second active ingredient other than the anticholinergic agent may be added. In this case, for example, the second active ingredient may be mixed after mixing the anticholinergic agent and the carrier. In this case, for example, after the anticholinergic agent and the carrier are stirred and mixed, the second active ingredient may be added and further stirred and mixed. When the second active ingredient is added in the anti-cholinergic agent mixing step, for example, the anti-cholinergic agent may be mixed after the second active ingredient and the carrier are mixed. In this case, for example, after the second active ingredient and the carrier are stirred and mixed, an anticholinergic agent may be added and further stirred and mixed. A process including two or more steps is also an anticholinergic mixing process.

  Examples of anticholinergic compounds are ipratropium, tiotropium, oxitropium, tolterodine, acridinium, and glycopyrronium. These agents may be pharmaceutically acceptable salts, pharmaceutically acceptable solvates, or pharmaceutically acceptable derivatives. Examples of pharmaceutically acceptable salts are acid salts and halides (eg, chloride, bromide, and fluoride). A preferred anticholinergic agent is tiotropium bromide or tiotropium bromide hydrate. The anticholinergic agent is preferably tiotropium bromide. However, the anticholinergic agent may be a mixture of tiotropium bromide and tiotropium bromide hydrate. The particle size of the anticholinergic agent contained in the inhalable powder is, for example, from 0.1 μm to 10 μm, from 0.5 μm to 5 μm, or from 1 μm to 4 μm. The particle diameter of the second active ingredient used as the raw material for the first step is, for example, 0.1 μm or more and 20 μm or less, 1 μm or more and 10 μm or less, or 2 μm or more and 4 μm or less.

  The content of the anticholinergic agent only needs to include an effective amount of the anticholinergic agent. Examples of the content of the anticholinergic agent are 0.01% by weight or more and 10% by weight or less of the powder for inhalation, and may be 0.1% by weight or more and 5% by weight or less. Tiotropium bromide or tiotropium bromide hydrate may be administered, for example, at 1 μg or more and 1 g or less, or 10 μg or more and 100 mg or less per day.

The second active ingredient is an active ingredient administered by a dry powder inhaler. The second active ingredient includes, for example, therapeutic agents for respiratory diseases including asthma, bronchitis, chronic obstructive pulmonary disease (COPD), emphysema and rhinitis, or analgesics and hormones. Examples of the second active ingredient are steroids, β ₂ -agonists (β 2 -stimulants). The second active ingredient is preferably a β ₂ -agonist or an anticholine compound. An example of the second active ingredient is formoterol fumarate. Examples of β ₂ -agonists are salmeterol, formoterol, bambuterol, carmoterol, indacaterol, 3- (4-{[6-({(2R) -2- [3- (formylamino) -4-hydroxyphenyl] ] -2-hydroxyethyl} amino) hexyl] oxy} -butyl) -benzenesulfonamide, and 3- (4-{[6-({(2R) -2-hydroxy-2- [4-hydroxy-3- (Hydroxy-methyl) phenyl] ethyl} amino) -hexyl] oxy} butyl) benzenesulfonamide. These agents may be pharmaceutically acceptable salts, pharmaceutically acceptable solvates, or pharmaceutically acceptable derivatives. Examples of pharmaceutically acceptable salts are acid salts and halides (eg, chloride, bromide, and fluoride).

  The particle diameter of the second active ingredient contained in the powder for inhalation is, for example, from 0.1 μm to 10 μm, from 0.5 μm to 5 μm, and from 1 μm to 4 μm. The particle diameter of the second active ingredient used as the raw material for the first step is, for example, 0.1 μm or more and 20 μm or less, 1 μm or more and 10 μm or less, or 2 μm or more and 4 μm or less.

  When the inhalable powder of the present invention contains a β2-stimulant, the content of the β2-stimulant only needs to include an effective amount of the β2-stimulant. An example of the content of β2-stimulant is 0.01 wt% or more and 10 wt% or less of the powder for inhalation, and may be 0.1 wt% or more and 5 wt% or less.

  Examples of carriers are sugars, sugar alcohols, mixtures of sugars and sugar alcohols, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates, and their pharmaceutically acceptable derivatives. is there. Examples of sugars are glucose, galactose, D-mannose, arabinose, sorbose, lactose (lactose), maltose, sucrose and trehalose. Examples of sugar alcohols are mannitol, maltitol, xylitol, sorbitol, myo-inositol and erythritol. As described above, the saccharide may be any of monosaccharides, disaccharides, and polysaccharides. A preferred example of the carrier is lactose.

  The particle size of the carrier contained in the powder for inhalation is, for example, from 10 μm to 200 μm, from 50 μm to 150 μm, from 60 μm to 100 μm, and from 65 μm to 90 μm. The particle diameter of the carrier as a raw material in the first step is, for example, 15 μm or more and 300 μm or less.

  The amount of the carrier contained in the inhalable powder is from 50% to 99% by weight of the inhalable powder, from 60% to 99% by weight, or from 80% to 95% by weight.

  As the pulverizing medium, a known medium used in a pulverizing apparatus can be appropriately used. An example of a grinding media is beads. The type, shape, and size of the beads may be adjusted as appropriate. The grinding media may be removed after any step. In order to remove the beads, sieving may be performed using a finer sieve than the beads.

  The stirrer is a device that contains a component to be stirred and a pulverization medium, and stirs and mixes them. Since the stirrer is known, a known stirrer can be used as appropriate. A preferable example of the stirring device is a stirring device that does not generate a shearing force. An example of such a stirrer is a tumble blender (see, for example, JP 2009-215310 A). A specific example of the stirring device is a three-dimensional mixer (TURBULA MIXER). An example of a mixer is one in which a classifier is provided in the middle of a conveyance path for conveying a powder material to the mixer, as disclosed in JP-A-2009-279558. As the stirring device and the classification device, for example, those disclosed in the above-mentioned patent documents can be used as appropriate. The stirring and mixing in the present specification includes those in which a plurality of components are mixed by shaking.

  In the anti-cholinergic agent mixing step, for example, a raw material (for example, powder) containing an active ingredient and a carrier and a grinding medium such as beads are contained in a mixing container. The shaking time is, for example, not less than 10 seconds and not more than 10 minutes. Examples of the stirring speed are 5 rpm to 500 rpm, 5 rpm to 200 rpm, 20 rpm to 100 rpm, or 30 rpm to 80 rpm. Examples of the stirring time are 30 seconds to 6 hours, 1 minute to 6 hours, or 10 minutes to 2 hours.

  The method of the present invention may include an intermediate mixing step of appropriately mixing before the fine particle mixing step. The intermediate mixing step is a step of adding an active ingredient other than the anticholinergic agent (or anticholinergic agent and β2 stimulant) to the mixture obtained in the anticholinergic agent mixing step, and stirring and mixing in the presence of a grinding medium. is there. An example of such an intermediate mixing step is a cortisol derivative mixing step. In this case, the fine powder mixing step is a step of adding fine powder to the mixture obtained in the intermediate mixing step and stirring and mixing in the presence of the grinding medium. However, in the fine powder mixing step, stirring and mixing may be performed in a state where other components are further added. An example of a cortisol derivative is fluticasone propionate.

  The fine powder mixing step is a step of adding fine powder to the mixture obtained in the anticholinergic agent mixing step and stirring and mixing in the presence of a grinding medium. In the fine powder mixing step, an active ingredient different from the anticholinergic agent (and β2 stimulating agent) may be further added and stirred and mixed. As explained above, this active ingredient may be added at or after the anticholinergic mixing step. In either case, in the final mixing step, it is preferable to add the mixture and the fine powder and to stir and mix in the presence of the grinding medium.

  Examples of active ingredients other than the anticholinergic agent and β2 stimulant added in any of the anticholinergic agent mixing step, the step between the anticholine agent mixing step and the fine particle mixing step, and the fine particle mixing step are dry Active ingredient administered by powder inhaler. This active ingredient includes, for example, therapeutic agents for respiratory diseases including asthma, bronchitis, chronic obstructive pulmonary disease (COPD), emphysema and rhinitis, or analgesics and hormones. An example of this active ingredient is a steroid, and a preferred example of a steroid is a cortisol derivative.

  Examples of active ingredients other than this anticholinergic agent and β2-stimulant are cortisol derivatives, and more specifically, budesonide, fluticasone (eg, propionate or furoate), mometasone (eg, furoate), Beclomethasone (eg 17-propionate or 17,21-dipropionate), ciclesonide, triamcinolone (eg acetonide), flunisolide, zoticasone, flumoxonide, rofleponide, loteprednol, etipredol (eg ipredol) Acetate), butyxocoat (eg propionate), prednisolone, prednisone, tipredane, 6α, 9α-difluoro-17α-[(2-furanylcarbonyl) oxy] -11β-hydroxy-16α- Tyl-3-oxo-androsta-1,4-diene-17β-carbothioic acid S-fluoromethyl ester, 6α, 9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxy-androsta 1,4-diene-17β-carbothioic acid- (2-oxo-tetrahydro-furan-3S-yl) ester, and 6α, 9α-difluoro-11β-hydroxy-16α-methyl-17α-[(4-methyl- 1,3-thiazole-5-carbonyl) oxy] -3-oxo-androst-1,4-diene-17β-carbothioic acid-fluoromethyl ester. An example of this active ingredient is a cortisol derivative, and a more preferred example is fluticasone propionate.

  The particle diameter of the active ingredient contained in the inhalable powder is, for example, from 0.1 μm to 10 μm, from 0.5 μm to 5 μm, or from 1 μm to 4 μm. The particle diameter of the third active ingredient used as the raw material for the second step is, for example, from 0.1 μm to 20 μm, from 1 μm to 10 μm, and from 2 μm to 4 μm.

  When the inhalable powder contains an active ingredient other than the above-described anticholinergic agent and β2 stimulant, an example of the content of the active ingredient other than the anticholinergic agent and β2 stimulant is 0.1% by weight of the inhalable powder. It is 20% by weight or less and may be 1% by weight or more and 10% by weight or less.

  The fine powder is usually a powder made of a compound other than the active ingredient (for example, a compound or composition having no or low physiological activity or not expected to have physiological activity). Examples of fine powders are sugars, sugar alcohols, mixtures of sugars and sugar alcohols, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates, and their pharmaceutically acceptable Is a derivative. The composition of the fine powder and the carrier may be the same or different. The average particle size of the fine powder is preferably from 1/50 to 1/5 of the average particle size of the carrier. The particle diameter of the fine powder is, for example, from 0.1 μm to 10 μm, from 0.5 μm to 5 μm, and from 1 μm to 4 μm. The particle size of the fine powder used as the raw material in the second step is, for example, 0.1 μm or more and 20 μm or less, 1 μm or more and 10 μm or less, or 2 μm or more and 4 μm or less.

  The fine powder mixing process can be performed under the same conditions using the same apparatus as the anticholinergic mixing process. Furthermore, each mixing process demonstrated in this specification can be performed on the same conditions using the apparatus similar to an anticholinergic agent mixing process.

  The powder for inhalation produced through the above process has a structure in which an aggregate of an anticholinergic agent (or anticholinergic agent, β2 stimulant and cortisol derivative) and fine powder adheres to the surface of the carrier particle, or a surface of the carrier particle. It takes a structure in which fine powder adheres and these active ingredients adhere through the fine powder. For this reason, the distribution of the active ingredient becomes extremely uniform and the dispersibility is extremely excellent.

  In addition to the above steps, the method for producing inhalable powder may appropriately include known steps in the ordinary method for producing inhalable powder. Examples other than the above two steps are a classification step, a drying step, and a commercialization step. The commercialization process is a process of filling the obtained powder for inhalation into an inhaler or the like under dry conditions. Inhalers include inhalers, cartridges for inhalers, blisters and capsules. In addition, between the anticholinergic agent mixing step (step 101) and the fine powder mixing step (step 102), the mixture obtained in the anticholinergic agent mixing step is wetted and then dried, and then finely divided powder You may make it perform a mixing process (step 102). In this way, the drug release time can be controlled. That is, since the anticholinergic agent adheres firmly to the carrier, the release rate of the anticholinergic agent in vivo can be slowed.

  For example, salmeterol xinafoate / fluticasone propionate is a combination drug used to treat childhood asthma, bronchial asthma, and chronic obstructive pulmonary disease (COPD). Japan is sold under the trade name “Adoair”, “Seretide” in the EU countries other than Germany, “Viani” in Germany, and “Advair” in the United States. Yes. This compounding agent contains 50 μg of salmeterol xinafoate and 50 μg to 500 μg of fluticasone propionate. The inhalable powder of the present invention can also be used in the same manner as Adair (registered trademark), for example.

  Inhalation powder containing tiotropium bromide as an active ingredient is known as a therapeutic agent for COPD (chronic obstructive pulmonary disease) known as Spiriva (registered trademark). For this reason, the powder for inhalation of the present invention can be used in the same manner as, for example, Spirever (registered trademark).

  The present invention also provides a method for bronchodilation of a patient and a method for treating chronic obstructive pulmonary disease, including the step of administering to the subject (patient) the inhalable powder obtained by the production method of the present invention.

[Reference Example 1]
Confirmation Experiment of Mixing Uniformity Prominence (registered trademark) manufactured by Shimadzu Corporation was used as HPLC (liquid high-performance chromatography). Detection wavelength is 228 nm, flow rate is 0.8
mL / min, CH ₃ CN: H ₂ O = 7: 1 was used as a mobile phase, and trans-stilbene 10 microg / ml was used as an internal standard. The sampling solution used was methanol: water: CH ₃ CN: H ₂ O = 10: 7: 3. As a column, TSKgel ODS-80Ts diameter 4.6 manufactured by Tosoh Corporation
One with a length of 150 mm was used.

Dispersibility confirmation experiment (cascade impact analysis)
A series 290 Marple personal cascade impactor manufactured by Tisch Environmental was used as the cascade impactor. The flow rate was 2 l / min, the sample amount was 5 to 10 times in terms of blister, and the above-described HPLC was used for quantitative analysis.

Self-aggregation confirmation method Three types of sieves (60, 100, 200 mesh) with different sieve openings are stacked in order, and a container is attached to the bottom. Supply 2g of powder (for example, 200 mesh or less) to the top (60 mesh) sieve and vibrate the sieve for a certain period of time.
The vibration time (T) is determined by the following equation.
T = 20 + (1.6−W) /0.016 [sec] (2)
Here, W is called dynamic apparent density and is calculated by the following formula.
W = {(P−A) C / 100} + A [g / cm ³ ] (3)
After the vibration is finished, measure the remaining screen amount X [g] for the upper stage (60 mesh), the remaining amount Y [g] for the middle stage (100 mesh), and the remaining amount Z [g] for the lower stage (200 mesh). The self-aggregation degree G is calculated from the equation.
G = (X / 2 + 3Y / 10 + Z / 10) x 100 (4)
It shows that self-aggregation property is so high that this G is high.

  Carrier lactose and β2-stimulant were added into the mixing vessel. Thereafter, beads corresponding to about half the volume of the powder added to the container were added to the container. The bead diameter was 3 mm. The mixing vessel was shaken for 1 minute. Mixing was performed for 30 minutes at a rotational speed of 46 rpm using a tumbler mixer. Fine lactose and cortisol derivatives were added into the mixing vessel. The mixing container was then shaken for 1 minute. Mixing was performed for 1 hour at a rotational speed of 46 rpm using a tumbler mixer. Thereafter, it was sieved using a sieve (aperture 250 μm). A dry powder composition was thus obtained. The weight ratio of the components in Reference Example 1 was 0.6% by weight for the β2-stimulant, 1.4% by weight for the cortisol derivative, 93% by weight for the carrier lactose and 5% by weight for the fine lactose.

  The particle size (D50) of the fine lactose was 5 μm or less, and the particle size (D50) of the carrier lactose was 60 μm. The β2-stimulant (salmeterol xinafoate (SX)) was manufactured by Melody and had a particle size (D50) of 1.5 μm. The cortisol derivative (fluticasone propionate (FP)) was manufactured by Shipra and had a particle size (D50) of 2.2 μm.

[Comparative Example 1]
Carrier lactose, β2-stimulant, fine lactose and cortisol derivative were added into the mixing vessel. The mixing container was then shaken for 1 minute. Mixing was performed for 1 hour at a rotational speed of 46 rpm using a tumbler mixer.

[Comparative Example 2]
A dry powder composition was obtained in the same manner as in Reference Example 1, except that the carrier lactose and fine lactose were mixed and stirred, and then the β2-stimulant and the cortisol derivative were mixed and stirred.

  The verification results of the mixing uniformity of Reference Example 1, Comparative Example 1 and Comparative Example 2 were as follows. Verification of mixing uniformity was performed using HPLC.

Reference example 1: Relative standard deviation 2.1%
Comparative Example 1: Relative standard deviation 10.5%
Comparative Example 2: Relative standard deviation 8.3%

  As described above, even when the same raw materials were used, the dry powder composition obtained by the production method of the present invention had a remarkable effect on mixing uniformity as compared with the comparative example.

  FIG. 1 is a SEM photograph of the powder for inhalation obtained in Reference Example 1. FIG. 2 is an SEM photograph of Adair (registered trademark), which is a commercially available powder for inhalation.

  From FIG. 1, it can be seen that the powder for inhalation obtained in Reference Example 1 has fine powder aggregates adhered to the entire carrier surface, powder adhered to the carrier surface, and powder further adhered thereto. . On the other hand, it can be seen from FIG. 2 that the commercially available powder for inhalation directly adheres to a part of the carrier surface.

Examination of dispersibility 1
[Reference Example 2]
In Reference Example 2, it was examined whether or not the present invention is effective when the active ingredient is changed. In Reference Example 1, instead of salmeterol xinafoate (SX), formoterol fumarate (FF) (particle size (D50) of 5 μm or less) manufactured by Teva API was used, and budesonide manufactured by Teva API was used instead of fluticasone propionate (FP). An inhalable powder was produced in the same manner as in Reference Example 1 except that (particle diameter (D50) was 5 μm or less) was used. And the FPF (Fine Particle Fraction) was evaluated using the cascade impactor about the dispersibility of the inhalation powder of Reference Example 1 and the inhalation powder of Reference Example 2.

  The inhalable powder of Reference Example 1 showed an FPF of 13.9% FP and 12.4% SX. The inhalable powder of Reference Example 2 showed an FPF with a BD of 21.0% and an FF of 14.8%. That is, it was shown that the method of the present invention is effective for various active ingredients.

[Reference Example 3]
Influence of excipient physical properties on dispersibility Reference Example 3-1. In Reference Example 1, except that rocket mannitol (particle size (D50) is 60 μm) was used instead of carrier lactose, and rocket mannitol (particle size (D50) was 5 μm or less) was used instead of fine lactose. Produced a powder for inhalation in the same manner as in Reference Example 1.

  Reference Example 3-2. In Reference Example 1, Asahi Kasei trehalose (particle size (D50) 60 μm) was used instead of carrier lactose, and Asahi Kasei trehalose (particle size (D50) 5 μm or less) was used instead of fine lactose Produced a powder for inhalation in the same manner as in Reference Example 1. About the dispersibility of the inhalation powder of Reference Example 3-1, and the inhalation powder of Reference Example 3-2, FPF (Fine Particle Fraction) was evaluated using a cascade impactor.

  The inhalable powder of Reference Example 3-1 showed an FPF of 14.7% FP and 14.5% SX. The inhalable powder of Reference Example 3-2 showed an FPF of 11.5% FP and 11.4% SX. Thus, it was shown that the present invention functions effectively when sugar or sugar alcohol is used as a carrier or fine powder.

[Reference Example 4]
Influence of fine powder on dispersibility Reference Example 4-1. In Reference Example 1, powder for inhalation was produced in the same manner as in Reference Example 1 except that mannitol (particle size (D50) of 5 μm or less) manufactured by Rocket Corporation was used instead of fine lactose.

  Reference example 4-2. A powder for inhalation was produced in the same manner as in Reference Example 1 except that trehalose manufactured by Asahi Kasei Co., Ltd. (particle size (D50) is 5 μm or less) was used instead of fine lactose in Reference Example 1.

  [Comparative Example 3] An inhalable powder was produced in the same manner as in Reference Example 1 except that fine lactose was not used in Reference Example 1. About the dispersibility of the powder for inhalation of Reference Examples 4-1, 4-2 and Comparative Example 3, FPF (Fine Particle Fraction) was evaluated using a cascade impactor.

  The inhalable powder of Reference Example 4-1 showed an FPF of 16.0% FP and 16.8% SX. The inhalable powder of Reference Example 4-2 showed an FPF of 12.5% FP and 12.8% SX. The powder for inhalation of Comparative Example 3 showed an FPF with 4.2% FP and 5.3% SX. Thus, it was shown that the present invention functions effectively even if the carrier and the fine powder are not the same substance. On the other hand, in the fine powder mixing process, it was shown that the dispersibility was significantly reduced when no fine powder was added.

[Reference Example 5]
Carrier (lactose, D-mannitol, erythritol or trehalose) and β2-stimulant (salbutamol sulfate: SS) were added into the mixing vessel. Thereafter, beads corresponding to about half the volume of the powder added to the container were added to the container. The bead diameter was 3 mm. The mixing vessel was shaken for 1 minute. Mixing was performed for 5 minutes at a rotational speed of 46 rpm using a tumbler mixer. Fine granules (lactose, D-mannitol, erythritol or trehalose) and cortisol derivatives were added into the mixing vessel. The mixing container was then shaken for 1 minute. Mixing was performed for 30 minutes at a rotational speed of 46 rpm using a tumbler mixer. Thereafter, it was sieved using a sieve (aperture 250 μm). A dry powder composition was thus obtained. The weight ratio of the components in Reference Example 5 was 0.74% by weight of β2-stimulant, 92.70% by weight of carrier and 6.56% by weight of fine granules.

[Comparative Example 4]
A powder for inhalation was prepared in the same manner as in Reference Example 5 except that stirring was not performed.

  The particle size (D50) of the fine particles was 5 μm or less for any composition, and the particle size (D50) of the carrier was 60 μm for any composition. The β2-stimulant (salbutamol sulfate) was made by Melody and had a particle size (D50) of 2.2 μm or less.

Confirmation experiment of mixing uniformity The mixing uniformity in Reference Example 5 was performed as follows. Shimadzu Prominence (registered trademark) was used as HPLC (liquid high-performance chromatography). The detection wavelength is 235 nm, the flow rate is 0.8 mL / min, the mobile phase is CH ₃ CN: H ₂ O = 7: 1, and the internal standard is trans-stilbene 10 microg / ml. Was used. The sampling solution used was methanol: water: CH ₃ CN: H ₂ O = 10: 7: 3. As the column, TSKgel ODS-80Ts manufactured by Tosoh Corporation having a diameter of 4.6 mm and a length of 150 mm was used.

  Table 1 shows the mixing uniformity (% RSD: relative standard deviation SS) in Reference Example 5.

[Table 1]
Lactose: 2.8
Mannitol: 2.6
Erythritol: 2.9
Trehalose: 3.1

  Table 2 shows the mixing uniformity (% RSD: relative standard deviation) in Comparative Example 4.

[Table 2]
Lactose: 8.5
Mannitol: 7.7
Erythritol: 8.8
Trehalose: 10.1

  When Table 1 and Table 2 are compared, it can be seen that the mixing uniformity is remarkably increased by stirring (that is, the value of% RDS is reduced) even when the carrier and fine particles of any composition are used. This shows that the mixing uniformity is remarkably increased by employing the process of the present invention.

Dispersibility confirmation experiment (cascade impact analysis)
A series 290 Marple personal cascade impactor manufactured by Tisch Environmental was used as the cascade impactor. The flow rate was 2 l / min, the sample amount was 10 times in terms of blister, and the above-described HPLC was used for quantitative analysis.

  Table 3 shows the dispersibility (FPF) in Reference Example 5.

[Table 3]
Lactose: 20.5
Mannitol: 16.4
Erythritol: 15.6
Trehalose: 24.6

[Reference Example 6]
Carrier (lactose, D-mannitol, erythritol or trehalose) and macrolide (erythromycin stearate) were added into the mixing vessel. Thereafter, beads corresponding to about half the volume of the powder added to the container were added to the container. The bead diameter was 3 mm. The mixing vessel was shaken for 1 minute. Mixing was performed for 5 minutes at a rotational speed of 46 rpm using a tumbler mixer. Fine granules (lactose, D-mannitol, erythritol or trehalose) and cortisol derivatives were added into the mixing vessel. The mixing container was then shaken for 1 minute. Mixing was performed for 30 minutes at a rotational speed of 46 rpm using a tumbler mixer. Thereafter, it was sieved using a sieve (aperture 250 μm). A dry powder composition was thus obtained. The weight ratios of the components in Example 2 were 0.74% by weight for macrolide (eristomycin stearate), 92.70% by weight for the carrier, and 6.56% by weight for the fine granules.

[Comparative Example 4]
A powder for inhalation was prepared in the same manner as in Reference Example 6 except that stirring was not performed.

  The particle size (D50) of the fine particles was 5 μm or less for any composition, and the particle size (D50) of the carrier was 60 μm for any composition. β2-stimulant (salbutamol sulfate was manufactured by Melody and had a particle size (D50) of 2.2 μm or less.

Confirmation experiment of mixing uniformity The mixing uniformity in Reference Example 6 was performed as follows. Shimadzu Prominence (registered trademark) was used as HPLC (liquid high-performance chromatography). The detection wavelength is 235 nm, the flow rate is 0.8 mL / min, the mobile phase is CH ₃ CN: H ₂ O = 7: 1, and the internal standard is trans-stilbene 10 microg / ml. Was used. The sampling solution used was methanol: water: CH ₃ CN: H ₂ O = 10: 7: 3. As the column, TSKgel ODS-80Ts manufactured by Tosoh Corporation having a diameter of 4.6 mm and a length of 150 mm was used.

  Table 4 shows the mixing uniformity (% RSD: relative standard deviation) in Reference Example 6.

[Table 4]
Lactose: 2.8
Mannitol: 3.0
Erythritol: 3.2
Trehalose: 2.9

  Table 5 shows the mixing uniformity (% RSD: relative standard deviation) in Comparative Example 4.

[Table 5]
Lactose: 7.3
Mannitol: 7.0
Erythritol: 7.4
Trehalose: 8.1

  When Table 4 and Table 5 are compared, it can be seen that the mixing uniformity is remarkably increased by stirring (that is, the value of% RDS is reduced) even when the carrier and fine particles of any composition are used. This shows that the mixing uniformity is remarkably increased by employing the process of the present invention.

Dispersibility confirmation experiment (cascade impact analysis)
A series 290 Marple personal cascade impactor manufactured by Tisch Environmental was used as the cascade impactor. The flow rate was 2 l / min, the sample amount was 10 times in terms of blister, and the above-described HPLC was used for quantitative analysis.

  Table 6 shows the dispersibility in Reference Example 6.

[Table 6]
Lactose: 20.3
Mannitol: 26.4
Erythritol: 23.8
Trehalose: 19.3

  Carrier (lactose, D-mannitol, erythritol or trehalose) and β2-stimulant (formoterol phthalate: FF) were added into the mixing vessel. Thereafter, beads corresponding to about half the volume of the powder added to the container were added to the container. The bead diameter was 3 mm. The mixing vessel was shaken for 1 minute. Mixing was performed for 5 minutes at a rotational speed of 46 rpm using a tumbler mixer. An anticholinergic agent (or muscarinic receptor antagonist) tiotropium bromide (or tiotropium bromide hydrate) was added into the mixing vessel. The mixing vessel was shaken for 1 minute. Mixing was performed for 5 minutes at a rotational speed of 46 rpm using a tumbler mixer. Fine granules (lactose, D-mannitol, erythritol or trehalose) and cortisol derivatives were added into the mixing vessel. The mixing container was then shaken for 1 minute. Mixing was performed for 30 minutes at a rotational speed of 46 rpm using a tumbler mixer. Thereafter, it was sieved using a sieve (aperture 250 μm). A dry powder composition was thus obtained. The weight ratio of the components in Example 3 was as follows: 0.13% by weight of anticholinergic agent (or muscarinic receptor antagonist), 0.03% by weight of β2-stimulant, 1.85% by weight of cortisol derivative, and carrier It was 92.70 wt% and fine granules were 5.28 wt%.

[Comparative Example 4]
An inhalable powder was prepared in the same manner as in Example 1 except that stirring was not performed.

  The particle size (D50) of the fine particles was 5 μm or less for any composition, and the particle size (D50) of the carrier was 60 μm for any composition. Tiotropium bromide (or tiotropium bromide hydrate), which is an anticholinergic agent (or muscarinic receptor antagonist), was manufactured by AARTI and had a particle size (D50) of 2.3 μm. β2-stimulant (formoterol fumarate was manufactured by Teva API, and particle size (D50) was 5 μm or less. Cortisol derivative (fluticasone propionate (FP)) was manufactured by Shipra. The particle size (D50) was 2.2 μm.

Confirmation experiment of mixing uniformity The mixing uniformity in Example 1 was performed as follows. Shimadzu Prominence (registered trademark) was used as HPLC (liquid high-performance chromatography). The detection wavelength is 235 nm, the flow rate is 0.8 mL / min, the mobile phase is CH ₃ CN: H ₂ O = 7: 1, and the internal standard is trans-stilbene 10 microg / ml. Was used. The sampling solution used was methanol: water: CH ₃ CN: H ₂ O = 10: 7: 3. As the column, TSKgel ODS-80Ts manufactured by Tosoh Corporation having a diameter of 4.6 mm and a length of 150 mm was used.

  Table 7 shows the mixing uniformity (% RSD: relative standard deviation) in Example 1.

[Table 7]
FP FF TB
Lactose: 2.4 2.9 2.6
Mannitol: 1.5 1.2 2.1
Erythritol: 2.2 2.8 1.9
Trehalose: 2.5 2.9 2.8

  Table 8 shows the mixing uniformity (% RSD: relative standard deviation) in Comparative Example 4.

[Table 8]
FP FF TB
Lactose: 7.3 9.4 8.3
Mannitol: 4.6 3.5 8.1
Erythritol: 6.7 9.2 5.7
Trehalose: 7.0 8.5 8.1

  Comparing Tables 7 and 8, it can be seen that the mixing uniformity is remarkably increased (that is, the value of% RDS is reduced) by stirring even when the carrier and fine particles having any composition are used. This shows that the mixing uniformity is remarkably increased by employing the process of the present invention.

Dispersibility confirmation experiment (cascade impact analysis)
A series 290 Marple personal cascade impactor manufactured by Tisch Environmental was used as the cascade impactor. The flow rate was 2 l / min, the sample amount was 10 times in terms of blister, and the above-described HPLC was used for quantitative analysis.

  Table 9 shows the dispersibility in Example 1.

[Table 9]
FP FF TB
Lactose: 16.8 19.1 15.2
Mannitol: 18.7 13.9 13.1
Erythritol: 11.6 9.2 10.0
Trehalose: 15.8 17.6 14.1

  Carrier (lactose, D-mannitol, erythritol or trehalose) and β2-stimulant (formoterol fumarate) were added into the mixing vessel. Thereafter, beads corresponding to about half the volume of the powder added to the container were added to the container. The bead diameter was 3 mm. The mixing vessel was shaken for 1 minute. Mixing was performed for 5 minutes at a rotational speed of 46 rpm using a tumbler mixer. An anticholinergic agent (either or both of tiotropium bromide and tiotropium bromide hydrate) was added into the mixing vessel. The mixing vessel was shaken for 1 minute. Mixing was performed for 5 minutes at a rotational speed of 46 rpm using a tumbler mixer. Fine granules (lactose, D-mannitol, erythritol or trehalose) and a phosphodiesterase-4 (PDF4) inhibitor (Roflumislast: PDE) were added into the mixing vessel. The mixing container was then shaken for 1 minute. Mixing was performed for 30 minutes at a rotational speed of 46 rpm using a tumbler mixer. Thereafter, it was sieved using a sieve (aperture 250 μm). A dry powder composition was thus obtained. The weight ratio of the components in Example 1 was as follows: roflumislast 0.74 wt%, β2-stimulant (formoterol fumarate) 0.03% wt, muscarinic receptor antagonist 0.13% wt%, carrier 92 70% by weight and fines 6.4% by weight.

[Comparative Example 5]
A powder for inhalation was prepared in the same manner as in Example 2 except that stirring was not performed.

  The particle size (D50) of the fine particles was 5 μm or less for any composition, and the particle size (D50) of the carrier was 60 μm for any composition. Roflumislast (PDE) was manufactured by AARTI, and the particle size (D50) was 5 μm or less. β2-stimulant (formoterol fumarate was made by Teva API, and the particle size (D50) was 5 μm or less. Anticholinergic agent (thiotropium bromide or tiotropium bromide hydrate (TB)) The product was manufactured by AARTI and had a particle size (D50) of 2.3 μm.

Confirmation experiment of mixing uniformity The mixing uniformity in Example 2 was performed as follows. Shimadzu Prominence (registered trademark) was used as HPLC (liquid high-performance chromatography). The detection wavelength is 228 nm, the flow rate is 0.8 mL / min, the mobile phase is CH ₃ CN: H ₂ O = 7: 1, and the internal standard is trans-stilbene 10 microg / ml. Was used. The sampling solution used was methanol: water: CH ₃ CN: H ₂ O = 10: 7: 3. As the column, TSKgel ODS-80Ts manufactured by Tosoh Corporation having a diameter of 4.6 mm and a length of 150 mm was used.

  Table 10 shows the mixing uniformity (% RSD: relative standard deviation) in Example 2.

[Table 10] FF TB PDE
Lactose: 2.7 2.4 2.5
Mannitol: 1.5 1.9 2.1
Erythritol: 2.6 2.7 2.0
Trehalose: 2.6 2.5 2.4

  Table 11 shows the mixing uniformity (% RSD: relative standard deviation) in Comparative Example 4.

[Table 11]
FF TB PDE
Lactose: 8.5 7.3 8.3
Mannitol: 4.5 5.5 7.3
Erythritol: 8.3 8.1 6.4
Trehalose: 8.5 7.6 7.3

  When Table 10 and Table 11 are compared, it can be seen that the mixing uniformity is remarkably increased by stirring (that is, the value of% RDS is reduced) even when the carrier and fine particles having any composition are used. This shows that the mixing uniformity is remarkably increased by employing the process of the present invention.

Dispersibility confirmation experiment (cascade impact analysis)
A series 290 Marple personal cascade impactor manufactured by Tisch Environmental was used as the cascade impactor. The flow rate was 2 l / min, the sample amount was 10 times in terms of blister, and the above-described HPLC was used for quantitative analysis.

  Table 12 shows the dispersibility in Example 2.

[Table 12]
FF TB PDE
Lactose: 17.0 15.6 14.0
Mannitol: 12.5 20.9 12.7
Erythritol: 8.5 10.2 8.8
Trehalose: 17.2 15.0 12.8

  The present invention can be utilized in the pharmaceutical industry.

Claims (14)

An anticholinergic agent mixing step of stirring the anticholinergic agent and the carrier in the presence of a grinding medium to obtain a mixture of the anticholinergic agent and the carrier by crushing the anticholinergic agent and mixing with the carrier;
A fine powder mixing step in which fine powder is added to the mixture obtained in the anticholinergic mixing step, and the mixture is stirred and mixed in the presence of a grinding medium;
including,
Method for producing inhalable powder. A method for producing the inhalable powder according to claim 1,
The anticholinergic agent is tiotropium bromide or tiotropium bromide hydrate,
Method for producing inhalable powder. A method for producing the inhalable powder according to claim 1,
Prior to the anticholinergic agent mixing step, the carrier and the β2 stimulant are agitated in the presence of a grinding medium, and the β2 stimulator is crushed and mixed with the carrier, thereby mixing the carrier and the β2 stimulant. Further comprising a β2 stimulator mixing step to obtain
Method for producing inhalable powder. A method for producing a powder for inhalation according to claim 3,
The β2-stimulant is formoterol fumarate,
Manufacturing method of powder for suction. A method for producing the inhalable powder according to claim 1,
In the anti-cholinergic agent mixing step, the anti-cholinergic agent and the carrier, and further containing a β2 stimulant are stirred in the presence of a grinding medium, and the anti-cholinergic agent and the β2 stimulant are crushed, Mixing with the carrier,
Method for producing inhalable powder. A method for producing the inhalable powder according to claim 1,
The fine powder mixing step is a step of further adding a cortisol derivative to the mixture obtained in the anticholinergic agent mixing step and the fine powder, and stirring and mixing in the presence of a grinding medium.
Method for producing inhalable powder. A method for producing a powder for inhalation according to claim 6,
The method for producing a powder for inhalation, wherein the cortisol derivative is fluticasone propionate. A method for producing the inhalable powder according to claim 1,
A cortisol derivative mixing step of adding a cortisol derivative to the mixture obtained in the anticholinergic agent mixing step and stirring and mixing in the presence of a grinding medium before the fine powder mixing step;
Method for producing inhalable powder. A method for producing an inhalable powder according to claim 8,
The method for producing a powder for inhalation, wherein the cortisol derivative is fluticasone propionate. A method for producing the inhalable powder according to claim 1,
The method for producing a powder for inhalation, wherein an average particle diameter of the fine powder is 1/50 or more and 1/5 or less of an average particle diameter of the carrier. A method for producing an inhalable powder according to claim 10,
A method for producing a powder for inhalation, wherein the composition of the carrier and the fine powder may be the same or different and is a saccharide or a sugar alcohol. A method for producing the inhalable powder according to claim 1,
The method for producing a powder for inhalation, wherein the grinding medium is beads.   A method for producing a bronchodilator using the method for producing an inhalable powder according to claim 1. A method for producing a therapeutic agent for chronic obstructive pulmonary disease using the method for producing a powder for inhalation according to claim 1.

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