KR20160038767A - Dry powder for inhalation formulation with improved stability of combined active ingredients - Google Patents

Abstract

Provided in the present invention is a dry powder for inhalation formulation comprising two or more composite active ingredients selected from the group consisting of salmeterol or a pharmaceutically acceptable salt thereof; tiotropium or a pharmaceutically acceptable salt thereof; and fluticasone or a pharmaceutically acceptable salt thereof, and a diluent, wherein the diluent includes 0.1-50 wt% of fine powder having the average particle diameter (X50) of 30 μm or less with respect to total diluent, and improves stability of at least one among the active ingredients compared with a diluent containing 50% or more of the fine powder with respect to the total diluent. Also, an inhalation formulation comprising the dry powder is provided.

Description

Technical Field [0001] The present invention relates to a dry powder for inhaler formulations having improved stability of a composite active ingredient,

The present invention relates to a dry powder for inhalation mold comprising two or more complex active ingredients selected from salmeterol, tiotropium, fluticasone, and pharmaceutically acceptable salts thereof, More particularly, the present invention relates to a dry powder for an inhaler for improved in stability of an active ingredient which may be deteriorated when the active ingredient to be used in an undifferentiated form in a dry powder for inhalation form is used in combination, and a dry powder for the inhalant form Lt; / RTI >

Inhalants for a variety of drugs are on the market for the treatment of respiratory diseases, such as asthma and chronic obstructive pulmonary disease (COPD). Drugs such as short acting beta agonist (SABA), long acting beta agonist (LABA), inhaled corticosteroid (ICS), or long acting muscarinic antagonist (LAMA) are widely used for the prevention and treatment of respiratory diseases such as asthma or COPD do. The SABA, LABA, and LAMA are characterized by the bronchodilating effect of each drug mechanism, and the ICS has FEV1 (Forced expiratory volume in 1 second) through alleviation of inflammation, which is a factor of asthma And reduces symptoms of respiratory distress and COPD exacerbation. Commonly used drugs include Salbutamol, Terbutaline as SABA, Salmeterol, Formoterol, Indacaterol as LABA, Fluticasone as ICS, Fluticasone, Budesonide, TiROtium as LAMA, and Glycopyrronium.

The COPD treatment guideline of the global COPD mechanism (GOLD) includes the use of a combination that can simultaneously inhale drugs with different or complementary mechanisms of action. For example, LABA-based drugs are used predominantly in patients with an FEV1 of less than 80%, and ICS is used in severe patients with a FEV1 of less than 50% or acute exacerbations. In addition, the improved therapeutic effect expected by simultaneous inhalation of a drug having a complementary mechanism of action has already been demonstrated through a number of studies (Non-Patent Documents 1 and 2).

The combination of the two drugs mentioned above is already widely used clinically. Typical examples are seretayideu ^® that contains salmeterol and fluticasone. Seretide has an effective therapeutic effect by simultaneous inhalation of LABA and ICS to provide airway dilation and inflammation treatment simultaneously. However, Salmeterol is a LABA-based drug, and has a half-life of about 5.5 hours.

LABA, ICS, and LAMA have been reported to have improved therapeutic effects at the same time, and studies on triple combination drugs have been conducted based on this research (Non-Patent Document 3). As an example thereof, Patent Document 1 discloses an inhalation formulation for treating respiratory diseases, including salmeterol or a phosphate salt (LABA), fluticasone propionate (ICS), and thiotrope bromide (LAMA). Patent Document 1 discloses that the above-mentioned three active components are sufficiently transferred to the target site and the content uniformity is excellent. In addition, in order to reduce the variation of the dynamic particle distribution according to the flow velocity change, the average particle size of the particles is 30-120 [ Discloses a dry powder for an inhalation mold. However, Patent Document 1 does not mention the development of a formulation for increasing the stability of the compounded active ingredient.

Inhalation formulations are generally undifferentiated in that the particle size of the active ingredient is generally below about 5 microns due to the nature of the formulation. Thus, the active ingredient contained in the inhalation formulation is difficult to ensure the stability of the active ingredient against the effects of the diluent and / or the external environment contained together, since the particles have a large surface area due to undifferentiation. In addition, since the unit dose of the active ingredient contained in the inhalation dosage form is very low, the stability of the active ingredient is very important for the quality control of the medicines. Moreover, in the case of inhalation formulations comprising two or more complex active ingredients as mentioned above, the interaction between the active ingredients having a large surface area can accelerate the production of impurities, It becomes more problematic. Therefore, inhalation formulations of respiratory diseases containing two or more complex active ingredients are of particular importance in pharmaceutical studies to ensure the stability of each active ingredient.

1. Korean application publication 2013-0140358

1. Aaron, Shawn D., et al., Annals of internal medicine 146.8 (2007): 545-555; 2. Hand Delay, et al., Tuberculosis and Respiratory Diseases 67.6 (2009): 536-544; Hanania, Nicola A., et al., CHEST Journal 124.3 (2003): 834-843). 3. Singh, Dave, et al., Thorax 63.7 (2008): 592-598

It is an object of the present invention to provide a dry powder for inhaler formulations containing two or more complex respiratory disease active ingredients with improved stability of the active ingredient.

Another object of the present invention is to provide an inhalation dosage form comprising the dry powder for the inhalant form.

It is still another object of the present invention to provide a pharmaceutical method for producing a dry powder for an inhalation mold having improved stability of an active ingredient.

One aspect of the present invention is

Salmeterol or a pharmaceutically acceptable salt thereof;

Tiotropium or a pharmaceutically acceptable salt thereof; And

Two or more complex active ingredients selected from the group consisting of fluticasone or a pharmaceutically acceptable salt thereof, and

Comprising a diluent,

Wherein the diluent comprises 0.1 to 50% by weight of the total diluent, wherein the fineness with an average particle size (X ₅₀ ) of 30 탆 or less is at least one of the stability of at least one of the active ingredients Wherein the dry powder for inhalation mold is improved.

In another aspect of the present invention,

Salmeterol or a pharmaceutically acceptable salt thereof;

Tiotropium or a pharmaceutically acceptable salt thereof; And

At least two complex active ingredients selected from the group consisting of fluticasone, and

In order to prepare a dry powder for inhaler form containing a diluent and having improved stability of at least one of the complex active ingredients,

And a fine powder of a diluent having an average particle size (X ₅₀ ) of 30 m or less is used in an amount of 0.1 to 50% by weight of the total diluent.

Yet another aspect of the present invention provides an inhalation dosage form comprising the dry powder for inhalation formulations according to the present invention.

The inhalation formulation comprising the dry powder for inhalation form and the dry powder according to the present invention is characterized in that the fine powder having an average particle size (X ₅₀ ) of 30 탆 or less among the total diluents contained together with the complex active ingredient is in the range of about 0.1 to 50 wt% %, The stability of the active ingredient is remarkably excellent. Therefore, according to the present invention, it is possible to provide a dry powder inhalation formulation of a composite component having excellent stability with a very small amount of the active ingredient being produced even after a lapse of time.

FIG. 1 is a graph showing the results of measurement of the total amount of unknown substances of fluticasone propionate after storage for 0, 1, 3, and 6 months at 40 ° C. and RH 75% And the results are shown together with the corresponding results of the comparative example.
FIGS. 2 to 4 show results of measurement of GR97980X, a flexible material of salmeterol, after storage of the inhalation dosage form according to one embodiment of the present invention at 0, 1, 3, and 6 months at 40 DEG C and RH 75% Together with the corresponding results of the comparative example.
FIGS. 5 to 7 are graphs showing results of measurement of B IIH27SE, which is a substance of thiotropium, after storage of the inhalation formulations according to one embodiment of the present invention at 0 ° C, 75% relative humidity for 0, 1, 3 and 6 months Together with the corresponding results of the comparative example.

Hereinafter, the present invention will be described in more detail.

All technical terms used in the present invention are used in the sense that they are generally understood by those of ordinary skill in the relevant field of the present invention unless otherwise defined. In addition, preferred methods or samples are described in this specification, but similar or equivalent ones are also included in the scope of the present invention. The contents of all publications referred to in this specification are incorporated herein by reference in their entirety.

One aspect of the present invention is

Salmeterol or a pharmaceutically acceptable salt thereof;

Tiotropium or a pharmaceutically acceptable salt thereof; And

Two or more complex active ingredients selected from the group consisting of fluticasone or a pharmaceutically acceptable salt thereof, and

Comprising a diluent,

Wherein the diluent comprises 0.1 to 50% by weight of the total diluent, wherein the fineness with an average particle size (X ₅₀ ) of 30 탆 or less is at least one of the stability of at least one of the active ingredients Wherein the dry powder for inhalation mold is improved. Improving the stability of at least one of the active ingredients may mean a reduction in the amount of at least one of the active ingredients that is produced.

Particles in this specification, "average particle size (X _50)" is as meaning a particle size corresponding to 50% in the cumulative particle size distribution graph, smaller and 50% particles in the whole particles than X ₅₀ other 50% X ₅₀ Quot; means a larger particle size.

Generally, in the dry powder for inhalation agent form, the particle size of the active ingredient is extremely undifferentiated to about 5 mu m or less in order to effectively deliver the active ingredient to the lungs. However, such undifferentiated particles are thermodynamically unstable due to their large surface area relative to their volume ratios, and excessive surface energy is generated, and the particles tend to proceed to the agglomerated state. When the particles are agglomerated, the particles are attached to the inner wall of the capsule or the suction device, and the powder is not easily discharged at the time of inhalation. To solve this problem, the active ingredient is mixed with a suitable carrier, i.e. diluent particles, for administration. The particle size of the diluent may be about 30 to 120 [mu] m. In addition, it is possible to mix and use the undiluted diluent of about 30 탆 or less in the diluent particles. In this case, it is possible to uniformly adhere the active ingredient particles to the diluent particles and to facilitate the release of the active ingredient particles from the diluent particles in the airway It is known that there is an advantage that can be made. This is because a small amount of undifferentiated diluent particles are first attached to the surface of the irregular diluent particles in general, so that the undifferentiated diluent particles are preferentially adhered to a portion having a high surface energy to lower the surface energy, thereby lowering the overall surface energy of the diluent In addition, it has homogeneous surface energy. Thus, although it is conventionally known to prepare dry powders for inhalation form by the combination of a diluent and an undifferentiated diluent for effective delivery of the active ingredient, the stability of the active ingredient may be improved by controlling the ratio of the undifferentiated diluent There was no attempt to improve.

In the dry powder for inhalation mold according to the present invention, the fine powder having an average particle size (X ₅₀ ) of about 30 탆 or less among the total diluents together with the complex active ingredient has about 0.1 to 50% by weight of the total diluent, The stability of the active ingredient is markedly improved as compared with the case where it exceeds about 50% by weight.

Salmeterol or a pharmaceutically acceptable salt thereof, tiotropium or a pharmaceutically acceptable salt thereof; And fluticasone or a pharmaceutically acceptable salt thereof are known to produce a flexible substance over time due to the influence of the diluent and / or the external environment included in the formulation. As a result of the test, The dry powder for inhalation mold according to the present invention was found to significantly reduce the generation of the flexible material as compared with the case where the fine powder having an average particle size (X ₅₀ ) of 30 탆 or less exceeded about 50% by weight of the total diluent.

Specifically, the present inventors have found that when a diluent having a mean particle size of about 30 탆 or less and including a sulometrolate, a phosphate salt, thiotoluium bromide, and fluticasone propionate and a diluent is mixed with about 50 wt% % To prepare a capsule for a dry powder inhaler, and then subjected to a stability test under accelerated conditions at about 40 DEG C and 75% relative humidity. As a result, the amount of the substance produced is significantly lower than that in the case where the dry powder inhaler capsule containing about 50% by weight or less of the diluent having an average particle diameter of about 30 탆 or less is contained in an amount of about 50% And the lower the content of diluent having an average particle size of about 30 ㎛ or less, the lower the amount of the substance produced. In addition, it was confirmed that the production of the flexible substance was significantly lower than that of commercially available Seretide ( ^R) and Spiriva ( ^R ). (See Test Example 2).

In the dry powder for inhalation mold according to the present invention, the fine powder having an average particle size (X ₅₀ ) of 30 탆 or less is specifically about 10 to 35% by weight of the total diluent, more specifically about 10 to 20% %, And still more specifically about 13 to 18 wt%.

The diluent may be any diluent known to be used in the preparation of a dry powder for inhalation dosage forms for the treatment of respiratory diseases. The diluent may be, for example, a monosaccharide such as glucose or arabinose; Disaccharides such as lactose, maltose, or sucrose; Polysaccharides such as starch, dextrin, or dextran; Polyalcohols such as sorbitol, mannitol, or xylitol; And hydrates thereof, but are not limited thereto. In one embodiment of the present invention, the diluent may be a monosaccharide or a disaccharide, and in another embodiment, lactose may be used. The diluent may have an average particle size of about 30 to 120 [mu] m for delivery of the active ingredient in the inhaler formulation.

In one embodiment of the present invention, the active ingredient is at least two active ingredients selected from the group consisting of salmeterol, fosfate, thiotropium bromide, and fluticasone propionate, and in another embodiment the activity The component may comprise all three components: salmeterol, fosfate, thiotroum bromide, and fluticasone propionate.

In another aspect of the present invention,

Salmeterol or a pharmaceutically acceptable salt thereof;

Tiotropium or a pharmaceutically acceptable salt thereof; And

Two or more complex active ingredients selected from the group consisting of Fluticasone, and

In order to prepare a dry powder for inhaler form containing a diluent and having improved stability of at least one of the complex active ingredients,

And a fine powder of a diluent having an average particle size (X ₅₀ ) of 30 m or less is used in an amount of 0.1 to 50% by weight of the total diluent.

The method of using a fine powder of a diluent having an average particle size (X ₅₀ ) of 30 탆 or less may be applied to the dry powder for inhalation mold according to one aspect of the present invention.

In one embodiment of the method of using a fine powder of a diluent having an average particle size (X ₅₀ ) of 30 탆 or less according to the present invention, the fine powder of the diluent may be used in an amount of 10 to 35% by weight of the total diluent, To about 10 to 20% by weight of the total diluent, and in another embodiment about 13 to 18% by weight.

In one embodiment of the method of using a fine powder of a diluent having an average particle diameter (X ₅₀ ) of 30 탆 or less according to the present invention, the diluent may be a monosaccharide such as glucose or arabinose; Disaccharides such as lactose, maltose, or sucrose; Polysaccharides such as starch, dextrin, or dextran; Polyalcohols such as sorbitol, mannitol, or xylitol; And hydrates thereof, but are not limited thereto. In one embodiment, the diluent is a monosaccharide or a disaccharide, and in another embodiment, lactose may be used.

In another aspect of the present invention,

The present invention provides the inhalation formulation comprising the dry powder for inhalation mold according to the present invention.

One embodiment of the inhalation formulations according to the present invention may comprise about 5 to 25 mg of the diluent on a unit dose basis, and another embodiment may comprise about 15 to 25 mg of the diluent. If too much diluent is used, excessive foreign body sensation may be felt during inhalation, which may not only be inconvenient to the patient but also may cause asthma due to diluent which is an external substance. On the other hand, if too little diluent is used, uniformity between the diluent and the active ingredient can not be ensured, and it may become difficult to fill the capsule or blister cyst with the amount to be inhaled once. Since the amount of diluent in the above range can be filled into a capsule or a blister according to a general production method, it is not necessary to install a special device for the production of an inhaler, and a manufacturing process in a pharmaceutical production factory capable of producing a general capsule or blister There are advantages.

The inhalation formulations comprising the dry powder for inhalation formulations according to the present invention can be prepared using conventional methods of preparing conventional inhalation formulations. Concretely, a step of weighing a predetermined volume of the active ingredient, the diluent, and the diluent of the fine powder, mixing the mixture into a mixer after sieving, and mixing the mixture; Stabilizing the resulting mixture; And filling the formulation with a stabilized mixture into a capsule or the like. The step of stabilizing the obtained compound can be carried out, for example, by allowing the mixture to stand at room temperature for about 10 to 20 hours.

The inhalation formulation according to the present invention may be in the form of a capsule, a cartridge, or a blister containing the dry powder for the inhalation form, for example. Specifically, the dry powder for the inhalation mold is contained in a blister, such as a capsule or cartridge such as gelatin or hypromellose used in a dry powder inhaler (DPI), or a layered aluminum film, .

One preferred embodiment of the inhalation formulation of the present invention may be in the form of a capsule. The size of the capsules may be, for example, 1 to 4 capsules, more specifically 3 capsules may be used. When the inhalation dosage form of the present invention is provided in the form of a capsule, there is an advantage that inhalation dosage form preparation is possible without a special filling device. Also, the capsule into which the composition of the present invention is filled may be transparent. When a transparent capsule is used, patients can directly confirm whether or not they have inhaled the powder after inhalation of the dry powder for inhalation mold of the present invention. In addition, there is an advantage that the stability of the dried powders such as agglomeration, discoloration and the like or product defects can be visually confirmed before the patients directly inhale.

The inhalation formulation according to the present invention can be administered by a patient using any conventional dry powder inhalation device (DPI). The dry powder inhaler includes means for rupturing the capsule, puncturing the capsule, or otherwise opening the capsule to deliver the dry powder in the form of a metered capsule to the patient's lungs. In addition, the dry powder inhaler may further include an inlet for introducing air to form a flow of air, a discharge port through which the patient sucks and sucks the active ingredient, and a sieve for filtering the foreign matter. One example of such a device is, of ROTAHALER ^® GSK on the market, of Boehringer Ingelheim HANDIHALER ^®, And PLASTIAPE AEROLIZER ^® , preferably AEROLIZER ^® . The AEROLIZER ^® device has a groove in which a capsule is inserted into a suction device cap. When the button is pressed, a pin is pulled out from both ends of the groove, and the hole is pierced in the capsule.

The content of the active ingredient per unit dosage form of the inhalation formulations according to the present invention may vary depending on the race, sex, age, weight, and severity of the respiratory disease of the patient in need of treatment. One embodiment of the present invention is a pharmaceutical composition comprising 25 to 100 占 퐂, 5 to 50 占 퐂, 5 to 50 占 퐂, Mu] g, and 25 to 500 [mu] g.

The inhalation formulations according to the present invention may be used for the treatment or amelioration of any respiratory diseases known to have the combined active ingredient effect. Specifically, the inhalation formulation can be used for respiratory diseases, because bronchoconstriction, inflammation, and airway mucus secretion can be controlled. One embodiment of the inhalation formulations of the present invention may be used for the treatment of asthma or chronic obstructive pulmonary disease.

Hereinafter, the present invention will be described in detail based on the following examples. However, the following examples are intended to illustrate the present invention, but the scope of the present invention is not limited thereto.

Example  1 to 3: Preparation of a diluted dry powder inhalation dosage form in which the ratio of the fine powdered sugar is about 10% by weight

(Respitose ^® ML006, manufactured by DMV) having an X ₅₀ of about 17 탆 was weighed and measured according to the composition shown in the following Table 1, After mixing, the mixture was mixed in a mixer for about 30 minutes. The mixture was stabilized for about 12 hours or longer and then filled into a clear 3 capsule using a capsule filling machine.

ingredient
(unit: mg ) Example  One Example  2 Example  3 Fluticasone
Propionate 0.2500 0.2500 0.2500 Salmetallo
Gonadate 0.0725
(0.05 as Salmeterol) 0.0725
(0.05 as Salmeterol) 0.0725
(0.05 as Salmeterol) Thiotropium
Bromide 0.0217
(As thiotropium
0.018) 0.0217
(0.018 as thiotropium) 0.0217
(0.018 as thiotropium) Lactose 18.0000 11.2500 4.7300 Differential milk sugar 2.000 1.250 0.5250 Gross weight 20.3442 12.5222 5.5992

Example  4 to 6: Preparation of a diluent-containing dry powder inhaler with a pulverulent lactose ratio of about 30% by weight

Dry powder inhaler formulations were prepared in the same manner as in the preparation of Examples 1 to 3 above, according to the compositions shown in Table 2 below.

(unit: mg ) Example  4 Example  5 Example  6 Fluticasone
Propionate 0.2500 0.2500 0.2500 Salmetallo
Gonadate 0.0725
(0.05 as Salmeterol) 0.0725
(0.05 as Salmeterol) 0.0725
(0.05 as Salmeterol) Thiotropium
Bromide 0.0217
(0.018 as thiotropium) 0.0217
(0.018 as thiotropium) 0.0217
(0.018 as thiotropium) Lactose 13.3410 8.2560 3.5320 Differential milk sugar 6.3370 3.9220 1.6460 Gross weight 20.0222 12.5222 5.5222

Comparative Example  1 to 3: Preparation of a diluent-containing dry powder inhaler with a pulverulent lactose ratio of about 50% by weight

According to the compositions shown in the following Table 3, dry powder inhaler formulations were prepared in the same manner as in the production processes of Examples 1 to 3 above.

(unit: mg ) Comparative Example  One Comparative Example  2 Comparative Example  3 Fluticasone
Propionate 0.2500 0.2500 0.2500 Salmetallo
Gonadate 0.0725
(0.05 as Salmeterol) 0.0725
(0.05 as Salmeterol) 0.0725
(0.05 as Salmeterol) Thiotropium
Bromide 0.0217
(0.018 as thiotropium) 0.0217
(0.018 as thiotropium) 0.0217
(0.018 as thiotropium) Lactose 9.8390 6.0890 2.5890 Differential milk sugar 9.8390 6.0890 2.5890 Gross weight 20.0222 12.5222 5.5222

Comparative Example  4

As active ingredient salmeterol through port salt and fluticasone propionate containing, was used for current commercially available product seretayideu diseukeoseu ^®.

Comparative Example  5

Containing tiotropium bromide as active ingredients, it was used for current commercially available product seupiriba Handy Haller ^®.

Test Example  One : Particle size test

In the compositions of Examples 1 to 6 and Comparative Examples 1 to 3, the particle size distribution of a mixture of lactose and lactose other than the active ingredient was measured using a particle size analyzer (HELOS, Sympatec) Was measured. The results are shown in Tables 4 and 5 below.

- Measuring conditions -

Lens: R5

Dispersion pressure: 2.5 bar

Feed rate: 65%

Example  One Example  2 Example  3 Example  4 Example  5 Example  6 Less than 30 ㎛ in diluent
Percentage of derivative (%) 14.7 16.3 16.3 32.6 32.7 30.1

Comparative Example  One Comparative Example  2 Comparative Example  3 Less than 30 ㎛ in diluent
Percentage of derivative (%) 54.5 56.1 54.2

Test Example  2: Stability test

Each of the 30 inhalation formulations obtained in Examples 1 to 6 and Comparative Examples 1 to 5 was subjected to a stability test under the following conditions to determine the amount of the flexible substance of each component. Comparative Example seretayideu diseukeoseu ^® of 4 to 20 and Comparative Examples 5 seupiriba Handy Haller ^® in was measured using a 10. Each test was repeated three times and the average was measured.

- Storage conditions: Al-Al blister packaging condition at 40 ℃, 75% relative humidity

- Testing time: Initial, 1 month, 3 months, 6 months

- Analysis: Unknown suppositories from fluticasone propionate

            GR97980X due to Salmeterol

Biol H27SE due to thiotropium

- Unknown supersaturated material and GR97980X analysis method

Detector: Ultraviolet absorbance photometer (measuring wavelength: 228 nm)

Column: Inertsil ODS-2 (250 mm x 4.6 mm, 3.5 m)

Mobile phase A: 0.05 M aqueous ammonium dihydrogen phosphate solution adjusted to pH 2.9 with 10% (v / v) phosphoric acid

Mobile phase B: acetonitrile

Flow rate: about 1.0 mL / min

Injection volume: 50 μL

Column temperature: 35 ° C

- BIH27SE analysis method

Detector: Ultraviolet absorbance photometer (measuring wavelength: 240 nm)

Column: Propylsiyl silica gel for chromatography R

        (150 mm x 3.0 mm, 3.5 m)

Mobile phase A: Dissolve 1.0 g of sodium methanesulfonate and 5.0 g of potassium dihydrogenphosphate in 980 mL of purified water, adjust to pH 3.0 with diluted phosphoric acid, and adjust to 1000 mL.

Mobile phase B: Methanol: acetonitrile: mobile phase A

       = 10: 40: 50 (v / v / v)

Flow rate: 1.2 mL / min

Injection amount: 15 μL

Column temperature: 50 ° C

The test results are shown in Figs.

FIG. 1 is a graph showing the results of measurement of the total amount of unknown substances of fluticasone propionate. As can be seen from FIG. 1, in the case of Comparative Examples 1 and 2, While Examples 1 to 6 showed no significant increase in the soft matter. Thus, it can be seen that the formulation according to the present invention is significantly superior in the stability of fluticasone propionate.

2 to 4 are graphs showing the results of measurement of GR97980X, a flexible material of salmeterol. According to the results shown in Figs. 2 to 4, the amount of the generation of the flexible material was significantly lower in Examples 1 to 6 as time passed between GNs than that of Comparative Example 1-3. In addition, the amount of the substance produced was significantly lower than that of Comparative Example 4, which is a commercially available product.

5 to 7 are graphs showing the results of measurement of B IIH27SE, which is a thiotropium suppository substance. According to the results shown in FIGS. 5 to 7, the amount of the flexible substance produced in Examples 1 to 6 was significantly lower over time than that of Comparative Example 1-3. In addition, the amount of the substance produced was significantly lower than that of Comparative Example 5, which is a commercially available product.

In view of the results shown in FIGS. 1 to 7, when the inhalation dosage form of the present invention contains less than 50% by weight of the microparticulate diluent smaller than 30% of the total diluent, And the stability was remarkably improved as compared with a commercial formulation.

The present invention has been described with reference to the preferred embodiments. It will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention as defined by the appended claims. Therefore, the above-described embodiments should be considered in an illustrative rather than a restrictive sense. The scope of the present invention is defined by the appended claims rather than by the foregoing description, and all differences within the scope of equivalents thereof should be construed as being included in the present invention.

Claims (13)

Salmeterol or a pharmaceutically acceptable salt thereof;
Tiotropium or a pharmaceutically acceptable salt thereof; And
Two or more complex active ingredients selected from the group consisting of fluticasone or a pharmaceutically acceptable salt thereof, and
Comprising a diluent,
Wherein the diluent comprises 0.1 to 50% by weight of the total diluent, wherein the fineness with an average particle size (X ₅₀ ) of 30 탆 or less is at least one of the stability of at least one of the active ingredients Lt; RTI ID = 0.0 > 1, < / RTI > The dry powder for a mold of claim 1, wherein the fine powder is from 10 to 35% by weight of the total diluent. The dry powder for inhaler according to claim 1, wherein the diluent is selected from the group consisting of monosaccharides, disaccharides, polysaccharides, polyalcohols, and hydrates thereof. The dry powder for inhaler according to claim 1, wherein the diluent is lactose. The dry powder of claim 1, wherein the two or more complex active ingredients are selected from the group consisting of salmeterol, fungicide, thiotropium bromide, and fluticasone propionate. Salmeterol or a pharmaceutically acceptable salt thereof;
Tiotropium or a pharmaceutically acceptable salt thereof; And
Two or more complex active ingredients selected from the group consisting of Fluticasone, and
In order to prepare a dry powder for inhaler form containing a diluent and having improved stability of at least one of the complex active ingredients,
Wherein the fine powder of the diluent having an average particle size (X ₅₀ ) of 30 탆 or less is used in an amount of 0.1 to 50% by weight of the total diluent. 7. The method of claim 6, wherein the fine of the diluent is used in an amount of 10 to 35% by weight of the total diluent. The method according to claim 6, wherein the diluent is selected from the group consisting of monosaccharides, disaccharides, polysaccharides, polyalcohols, and hydrates thereof 9. The method of claim 8, wherein the diluent is lactose. 7. The method of claim 6, wherein the two or more complex active ingredients are two or more active ingredients selected from the group consisting of salmeterol, fosfate, thiotropium bromide, and fluticasone propionate. 6. A suction formulation comprising the dry powder according to any one of claims 1 to 5. 12. The inhalation dosage form of claim 11 comprising from 5 to 25 mg of a diluent based on the unit dose. 12. The composition of claim 11, wherein the salmeterol phosphate, the phosphate salt, the thiotropium bromide, and the fluticasone propionate are present in an amount of from 25 to 100 μg, 5 to 50 μg, and 25 ≪ / RTI > to about 500 < RTI ID = 0.0 > pg. ≪ / RTI >

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