WO2017078371A1

WO2017078371A1 - Dry powder composition for inhalation comprising tiotropium or pharmaceutically acceptable salt thereof

Info

Publication number: WO2017078371A1
Application number: PCT/KR2016/012466
Authority: WO
Inventors: Hyuk Jun Cho; Young Min Yoon; Ho Taek IM; Yong Il Kim; Jae Hyun Park; Jong Soo Woo
Original assignee: Hanmi Pharm. Co., Ltd.
Priority date: 2015-11-03
Filing date: 2016-11-01
Publication date: 2017-05-11
Also published as: KR101728116B1

Abstract

Provided is a dry power composition including tiotropium or a pharmaceutically acceptable salt thereof, and also including a micronized lactose and a non-micronized lactose as excipients in a specific weight ratio. When the dry powder composition is formulated as a capsule, the content of the active ingredient in each capsule may be uniform, and the delivered dose uniformity and stability of the active ingredient of tiotropium may be improved. Therefore, the dry powder composition may be effectively used to treat respiratory diseases.

Description

DRY POWDER COMPOSITION FOR INHALATION COMPRISING TIOTROPIUM OR PHARMACEUTICALLY ACCEPTABLE SALT THEREOF

The present disclosure relates to a dry powder composition for inhalation including tiotropium or a pharmaceutically acceptable salt thereof, and micronized lactose and non-micronized lactose in a specific weight ratio of amount as excipients.

Tiotropium bromide, which is disclosed in EP 0 418 716, is represented by the following formula:

Tiotropium is an effective long-acting muscarinic antagonist (LAMA), and is particularly widely used for the treatment of chronic obstructive pulmonary disease (COPD), and recently for the treatment of asthma.

Inhalation formulations are in wide use for the treatment of respiratory diseases such as chronic obstructive pulmonary disease or asthma. Due to the nature of inhalation formulations, active ingredients thereof are micronized to a particle size of, normally about 5 ㎛ or less, and have a large surface area. However, when such active ingredients having a large surface area are formulated for inhalation, it may be difficult to ensure stability of the active ingredients in an inhalation formulation, depending on an excipient or pharmaceutical additive used together in the inhalation formulation, or external environments. In a combination formulation including different active ingredients, generation of related compounds (impurities) may be further accelerated by interaction between the active ingredients. Accordingly, to develop a more effective formulation with fewer side effects, stability of the active ingredients needs to be carefully considered.

For an active ingredient in a dry powder composition for inhalation to be effectively delivered to and exhibit pharmaceutical activity in the lungs, the active ingredient is micronized to a particle size of about 5 ㎛ or less. However, such micronized particles have a relatively high surface-area-to-volume ratio, generate excess surface energy due to being thermodynamically unstable, and are consequently likely to agglomerate. Such agglomeration of the micronized particles may lead to the micronized particles being adhered to the inner wall of a capsule or inhalation device, thereby interrupting the release of the micronized powder upon inhalation. To address this drawback, the active ingredient may be administered mixed with an appropriate carrier, i.e., an excipient. As such, preparing a dry powder composition for inhalation by mixing an active ingredient and an excipient is known in the related art as a method of ensuring effective delivery of the active ingredient.

Commonly, an inhalation formulation is administered in the form of a capsule or blister filled with dry powder by inhalation with an inhalation device. The amount of dry powder for inhalation, including an active ingredient and an excipient, , filled in a capsule or blister is relatively small as compared with other commonly used capsule formulations, and may be, for example, about 5 ㎎ to 25 ㎎. Accordingly, filling of a capsule or blister with dry powder is a crucial factor in product quality, and is related to content uniformity in a capsule and a unit dosage amount delivered by an inhalation device.

In this regard, the inventors of the present disclosure found that when a dry powder composition for inhalation including tiotropium as an active ingredient and micro-sized lactose and non-micronized lactose at a particular ratio as excipients is formulated as a capsule, content uniformity in a capsule and stability of the active ingredient may be improved such that the dry powder composition in the capsule may be used to effectively treat respiratory diseases, thereby completing the present invention.

The present disclosure provides a dry powder composition including tiotropium or a pharmaceutically acceptable salt thereof, micronized lactose, and non-micronized lactose, a method of preparing the same, and a capsule formulation for inhalation including the same.

According to an aspect of the present disclosure, there is provided a dry powder composition including: tiotropium or a pharmaceutically acceptable salt thereof; a micronized lactose; and a non-micronized lactose, wherein a weight% ratio of the micronized lactose to the non-micronized lactose is about 1:1.5 to about 1:19.

According to another aspect of the present disclosure, there is provided a method of preparing the dry powder composition, the method including: i) obtaining a mixture of a micronized lactose with tiotropium or a pharmaceutically acceptable salt thereof by triturating, sieving, and mixing them; and ii) sieving a non-micronized lactose, adding the sieved non-micronized lactose to the mixture of step i) to satisfy a weight ratio of about 1:1.5 to about 1:19, and mixing a resulting mixture.

According to another aspect of the present disclosure, there is provided a capsule formulation for inhalation including the above-described dry powder composition.

According to the one or more embodiments of the present disclosure, a capsule formulation for inhalation prepared using a dry power composition according to any of the above-described embodiments may have improved delivered dose uniformity and improved stability of tiotropium included as an active ingredient, the active ingredient content may be uniform in each capsule, and the dry powder composition may be used to effectively treat respiratory diseases, and in particular, chronic obstructive pulmonary diseases or asthma.

FIG. 1 is a graph illustrating results of a content uniformity test of an active ingredient in capsule formulations for inhalation of Examples 1 to 5 and Comparative Examples 1 and 2.

FIG. 2 is a graph illustrating results of a delivered dose uniformity test of the capsule formulations for inhalation of Examples 1 to 5 and Comparative Examples 1 and 2.

FIG. 3 is a graph illustrating results of measuring the amount of BIIH27SE as a tiotropium-originating impurity over time in an accelerated storage test using the capsule formulations for inhalation of Examples 1 and 3 and Comparative Examples 1 and 2.

FIG. 4 is a graph illustrating results of measuring the amount of BIIH27SE as a tiotropium-originating impurity over time in an accelerated storage test using the capsule formulations for inhalation of Examples 3 to 5.

Unless otherwise defined, all terms (including technical and scientific terms) used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although example methods or materials are listed herein, other similar or equivalent ones are also within the scope of the present invention. All publications disclosed as references herein are incorporated in their entirety by reference.

According to an aspect of the present disclosure, a dry powder composition includes: tiotropium or a pharmaceutically acceptable salt thereof as an active ingredient; and micronized lactose and non-micronized lactose as excipients.

In some embodiments, tiotropium, also known as (1α, 2β, 4β, 7β-7-[(hydroxydi-2-thienylacetyl)oxy]-9,9-dimethyl-3-oxa-9-azoniatricyclo[3.3.1.0^2,4] nonane, may have a structure represented by the following formula.

Tiotropium may be used to treat respiratory diseases, and in particular, to treat chronic obstructive pulmonary diseases (COPD) or asthma which may be alleviated by controlling bronchoconstriction, bronchial infection, and mucous secretion of the airways.

In some embodiments, the tiotropium may be in the form of a pharmaceutically acceptable salt, for example, an acid addition salt of a pharmaceutically acceptable non-toxic organic or inorganic acid, such as acetic acid, citric acid, maleic acid, succinic acid, ascorbic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, or phosphoric acid; or a metal salt (for example, a sodium salt or potassium salt), an ammonium salt, an amine salt, or an amino acid salt thereof.

In addition to the pharmaceutically acceptable salt of tiotropium, other equivalents having the same or similar activity may be used. Non-limiting examples of available equivalents are a solvate, a hydrate, an anhydride, an enantiomer, a derivative, a polymorph, and a drug precursor.

In some embodiments, the pharmaceutically acceptable salt of tiotropium may be tiotropium bromide.

The amount of the tiotropium or the pharmaceutically acceptable salt thereof may be about 0.018 wt% to about 0.90 wt%, and in some embodiments, about 0.164 wt% to about 0.437 wt%, and in some other embodiments, about 0.395 wt%, based on a total weight of the composition. 0.395 wt% of tiotropium bromide is equivalent to 0.327 wt% of tiotropium. However, the amount of tiotropium bromide as an active ingredient may be varied depending on a variety of factors, such as a subject prescribed with the dry powder composition, a disease condition, and the like.

In some embodiments, the dry powder composition may use a mixture of the micronized lactose and the non-micronized lactose in a specific weight ratio as excipients, wherein the non-micronized lactose may include a medium-sized fine lactose and a large-sized fine lactose.

In general, an active ingredient used in a dry powder composition may have a small particle size of about 1 ㎛ to about 5 ㎛, and is more likely to agglomerate. Accordingly, it is difficult to fill a capsule or blister with an accurate amount of the active ingredient, and a delivery rate to the lungs upon inhalation may be reduced. Thus, by administering the micronized active ingredient as a mixture with an excipient having a particle size of about 50 ㎛ to about 250 ㎛, release of the active ingredient from the excipient particles in the airway may be facilitated. In some embodiments, the dry powder composition may include lactose as an excipient.

As used herein, the term "lactose" refers to a disaccharide consisting of 1 mole of glucose and 1 mole of galactose, which has two isomeric forms, i.e., α- and β-lactose, and a molecular formula of C₁₂H₂₂O₁₁. According to the present disclosure, the dry powder composition may include a micronized lactose and a non-micronized lactose.

The non-micronized lactose may have an average particle size of about 45 ㎛ to about 130㎛, and in some embodiments, about 50 ㎛ to about 125 ㎛. The non-micronized lactose may include medium-sized fine lactose and large-sized fine lactose. The medium-sized fine lactose may have an average particle size of about 45 ㎛ to about 70 ㎛, and in some embodiments, about 53 ㎛ to about 65 ㎛. The large-sized fine lactose may have an average particle size of about 90 ㎛ to about 130 ㎛, and in some embodiments, about 95 ㎛ to about 125 ㎛. The medium-sized fine lactose and the large-sized fine lactose may be in a weight ratio of about 9:1 to 1:9, and in some embodiments, about 5:1 to about 1:5, and in some other embodiments, about 2:1 to about 1:2. In some embodiments, the medium-sized fine lactose and the large-sized fine lactose may be in a weight ratio of about 1:1.

The micronized lactose, as a product of micronization of lactose, may have an average particle size of about 2 ㎛ to about 45 ㎛, and in some embodiments, about 10 ㎛ to about 30 ㎛, and in some other embodiments, about 15 ㎛ to about 20 ㎛, and in still other embodiments, about 17 ㎛. The micronized lactose having an average particle size within these ranges may be of about 10% to about 70%, and in some embodiments, about 20% to about 60%, and in some other embodiments, about 30% to about 50% of a total amount of the micronized lactose. In some embodiments, the micronized lactose having an average particle size of about 10 ㎛ to about 30 ㎛ may be of about 40% of the total micronized lactose.

As used herein, the term "average particle size (X₅₀)" refers to a particle size corresponding to 50% in a cumulative particle size distribution graph, which means that 50% of a total number of particles is smaller than X₅₀ and the remaining 50% is larger than X₅₀.

When using a mixture of an excipient and micronized particles such as the micronized lactose, the release of the active ingredient from the excipient in the airways may be facilitated. This is attributed to a lowered and uniform overall surface energy of the excipient resulting primarily from adhering of a small amount of micronized particles of the excipient to a high-surface energy region of an irregular particle surface of the excipient, which thereby lowers the surface energy of the excipient particles. The amount of the micronized excipient used may be used in a range that does not affect flowability of the dry powder composition.

Accordingly, in some embodiments, the dry powder composition may include the micronized lactose and the non-micronized lactose in a weight ratio of about 1:1.5 to about 1:19, and in some embodiments, about 1:2 to about 1:15, and in some other embodiments, about 1:2 to about 1:10 by weight. In some other embodiments, the dry powder composition may include the micronized lactose and the non-micronized lactose in a weight ratio of about 1:2.3 to about 1:9, for example, about 1:2.3, 1:4, or 1:9 by weight. When the weight ratio of the micronized lactose and the non-micronized lactose is less than 1:1.5, this may fail to lead to content uniformity of the active ingredient among capsule formulations including the dry powder composition for inhalation, may also fail to lead to uniform release of an amount of the active ingredient upon inhalation, and may also increase generation of impurities of the active ingredient when the capsule formulation is stored under an accelerated condition.

In some embodiments, the excipient in the dry powder composition may be about 0.1 wt% to about 98.0 wt%, and in some embodiments, about 50 wt% to about 98.0 wt%, and in some other embodiments, about 90.0 wt% to about 98.0 wt% of a total weight of the dry powder composition. For example, the excipient may be about 96.0% of the total weight of the dry powder composition. When the amount of the excipient is too high, a patient may be reluctant to receive the inhalation formulation due to an unpleasant feeling occurring during inhalation, and also the excipient may act as an irritant in the bronchi. On the other hand, when the amount of the excipient is too small, it may be difficult to ensure uniformity of the excipient and the active ingredient, and to fill a unit dose of the dry powder into a capsule. When the amount of the excipient is within the above-mentioned ranges, the excipient may be filled into a capsule by using a general production method, and the dry powder formulation for inhalation may be prepared using general pharmaceutical production facilities without a need for specific equipment for producing the inhalation formulation.

In some embodiments, the dry powder composition may be a dry powder composition for inhalation. In a dry powder composition for inhalation, surface characteristics of excipient particles may be a significant factor affecting the release of the active ingredient from an inhalation device or the active ingredient reaching a target site. In order for the active ingredient to be easily released from the inhalation device with good flowability, the active ingredient needs to be supported with sufficient adhesion to the excipient supporting the active ingredient in the inhalation device. However, there also is a need for the active ingredient to be easily released from the surface of the excipient within the airways so that a target site can be reached from the inhalation device. Accordingly, there is difficulty in maintaining the adhesion between the surface of the excipient and the active ingredient at an appropriate level. According to the present disclosure, the active ingredient may be adhered to the surface of the excipient with an appropriate level of adhesion through a mixing process of the active ingredient and the excipient.

According to another aspect of the present disclosure, a method of preparing a dry powder composition according to any of the above-described embodiments includes: i) obtaining a mixture of a micronized lactose with tiotropium or a pharmaceutically acceptable salt thereof by triturating, sieving, and mixing them; and ii) sieving a non-micronized lactose, adding the sieved non-micronized lactose to the mixture of step i) to satisfy a weight ratio of about 1:1.5 to about 1:19, and mixing a resulting mixture.

In some embodiments of the dry powder composition preparation method, in the sieving of the micronized lactose as well as tiotropium or the pharmaceutically acceptable salt thereof in step i), a sieve mesh size may be about 50 ㎛ to about 250 ㎛, and in some embodiments, about 100 ㎛ to about 200 ㎛, and in some other embodiments, about 120 ㎛ to about 180 ㎛, and in still some other embodiments, about 145 ㎛ to about 155 ㎛. In the sieving of the non-micronized lactose in the step ii), a sieve mesh size may be about 280 ㎛ to about 700 ㎛, and in some embodiments, about 300 ㎛ to about 550 ㎛, and in some other embodiments, about 350 ㎛ to about 500 ㎛, and in still some other embodiments, about 405 ㎛ to about 445 ㎛.

According to another aspect of the present disclosure, a formulation includes a dry powder composition for inhalation according to any of the above-described embodiments in a capsule or cartridge, such as a capsule or cartridge made of gelatin or hypromellose, or a blister such as a blister made of aluminum thin layers for use in inhalation device. For example, the formulation may be a capsule formulation. Capsules used for capsule formulations have different sizes, each having a unique capsule number, and internal capacities which vary according to the capsule number. Known capsules include, for example, a No. 0 capsule having an internal capacity of about 0.68 ㎖, a No. 1 capsule having an internal capacity of about 0.47 ㎖, a No. 2 capsule having an internal capacity of about 0.37 ㎖, a No. 3 capsule having an internal capacity of about 0.27 ㎖, and a No. 4 capsule having an internal capacity of about 0.20 ㎖. The capsule size available for the capsule formulation according to an embodiment may be small enough for a patient to receive easily. However, according to a mass limit of content to be filled in a capsule, the capsule size of a formulation according to an embodiment may be No. 0, No. 1, No. 2, No. 3, or No. 4. For example, the capsule size of the formulation may be No. 3.

The dry powder formulation in capsule formulation according to any of the embodiments may include about 0.001 ㎎ to about 0.05 ㎎, and in some embodiments, about 0.009 ㎎ to about 0.024 ㎎, and in some other embodiments, about 0.0217 ㎎ of tiotropium or the pharmaceutically acceptable salt thereof per unit dose as the active ingredient. About 0.0217 ㎎ of tiotropium bromide is equivalent to about 0.018 ㎎ of tiotropium.

When a dry powder composition for inhalation according to any of the above-described embodiments is prepared as a capsule formulation, advantageously there is no need for a specific device for filling a capsule with the dry power composition. In some embodiments, a capsule to be filled with the dry powder composition for inhalation may be transparent. Using a transparent capsule may allow patients to see immediately after inhalation whether the dry powder active ingredient in the capsule was inhaled and to visually inspect deterioration in stability or product defects, such as agglomeration or discoloration, of the dry powder in the capsule before inhalation.

A capsule formulation for inhalation according to any of the embodiments may be administered to a patient by using any known inhalation device for dry powder. For example, the inhalation device may include a device which breaks or punches the capsules, or uses any other method to open the capsule to allow delivery of weighed dry powder in the capsule to the lungs of the patient. The inhalation device may further include an air inlet which creates an air flow to supply air into the device, an air outlet via which the active ingredient is discharged upon the patient's inhalation of the inhalation formulation, and a filter for filtering out any impurities. Examples of such devices currently available in the market are ROTAHALER^® (available from GSK), HANDIHALER^® (available from Boehringer Ingelheim), and AEROLIZER^® (available from PLASTIAPE). The HANDIHALER^® and AEROLIZER^® include a hole in a cap thereof to receive a capsule, wherein pins come out from opposite sides of the hole to punch the capsule when a button is pressed. The device is small and portable.

In examples of the present disclosure, the inventors of the present disclosure prepared capsule formulations from various dry powder compositions for inhalation each including tiotropium as an active ingredient, a micronized lactose and a non-micronized lactose in a weight ratio of about 1:2.3 to 1:9 as excipients, and the non-micronized lactose including a medium-sized fine lactose and a large-size fine lactose in an weight ratio of 1:1 (see Table 1).

As a result of measuring the content of the active ingredient in each of the prepared capsule formulations for inhalation, the capsule formulations for inhalation including the dry powder compositions for inhalation according to embodiments were found to have uniform content distribution of the active ingredient among the capsule formulations, and the dry powder compositions were found to have good flowability during a capsule filling process (see Table 3 and FIG. 1).

When each of the capsule formulations for inhalation including one of the dry powder compositions for inhalation according to embodiments were inhaled using an inhalation device, an average content of active ingredient per unit delivery dose was about 100% in each of the capsule formulations, similar to a target delivery dose, with all the capsule formulations according to the embodiments complying with the levels required by the U.S. Pharmacopoeia (USP) (see Table 4 and FIG. 2).

As a result of an accelerated storage stability test using the capsule formulations for inhalation which include the dry powder compositions for inhalation according to embodiments, the capsule formulations including the dry powder compositions for inhalation according to the embodiments were found to include a significantly reduced amount of tiotropium-originating related compounds (see FIGS. 3 and 4).

As a result of measuring a fine particle mass of particles delivered to the lungs from the capsule formulation for inhalation including the dry powder compositions for inhalation according to embodiments, the capsules formulations including the dry powder compositions according to the embodiments were found each time to have a uniform delivered dose of the active ingredient, and in particular, the capsule formulations for inhalation including a micronized lactose, a medium-sized fine lactose, and a large-sized fine lactose in a specific weight ratio were found to have a more uniform delivery dose of the active ingredient (see Table 6).

Therefore, a dry power composition according to any of the above-described embodiments may have improved delivered dose uniformity and stability of tiotropium included as the active ingredient, may ensure uniform content of the active ingredient in each capsule when formulated as a capsule formulation, and may effectively treat respiratory diseases, and in particular, chronic obstructive pulmonary diseases or asthma.

One or more embodiments of the present disclosure will now be described in detail with reference to the following examples. However, these examples are only for illustrative purposes and are not intended to limit the scope of the one or more embodiments of the present disclosure.

Examples 1 to 5: Preparation of capsule formulation for inhalation including tiotropium , and micronized lactose and non- micronized lactose in different weight ratios

First, tiotropium bromide [Sicor S.R.L.(TEVA)] as an active ingredient, a micronized lactose having an average particle size of about 17 ㎛ (Respitose ML006, available from DFE Pharma), a medium-sized fine lactose having an average particle size of about 60 ㎛ (Respitose SV003, available from DFE Pharma), and a large-sized fine lactose having an average particle size of about 105 ㎛ (Respitose SV010, available from DFE Pharma) were weighed according to the compositions of Table 1. The weighed tiotropium bromide and micronized lactose were triturated, sieved through a 100-mesh sieve, and then mixed with the medium-sized fine lactose and the large-sized fine lactose, which were previously sieved through a 40-mesh sieve, in a mixer for about 30 minutes. The resulting mixture was filled into a transparent No. 3 capsule using a capsule filler (GKF 702, available from Bosch).

(unit: ㎎)		Example 1	Example 2	Example 3	Example 4	Example 5
Tiotropium bromide(Amount of tiotropium)		0.0217(0.018)	0.0217(0.018)	0.0217(0.018)	0.0217(0.018)	0.0217(0.018)
Micronized lactose		0.55	1.10	1.65	1.65	1.65
Non-micronized lactose	Medium-sized fine lactose(SV003)	2.46	2.19	1.91	3.83	0
Non-micronized lactose	Large-sized fine lactose(SV010)	2.47	2.19	1.92	0	3.83
Ratio of micronized lactose and non-micronized lactose		1:9	1:4	1:2.3	1:2.3	1:2.3
Total weight		5.50	5.50	5.50	5.50	5.50

Comparative Examples 1 and 2: Preparation of capsule formulations for inhalation including tiotropium , and micronized lactose and non- micronized lactose in a ratio of 1:0.4 or1:1

Capsule formulations for inhalation were prepared in the same manner as in Example 1, except that an amount ratio of micronized lactose, medium-sized fine lactose, and large-sized fine lactose was varied according to the compositions of Table 2.

(unit: ㎎)		Comparative Example 1	ComparativeExample 2
Tiotropium bromide(Amount of tiotropium)		0.0217(0.018)	0.0217(0.018)
Micronized lactose		2.75	3.85
Non-micronized lactose	Medium-sized fine lactose(SV003)	1.36	0.81
Non-micronized lactose	Large-sized fine lactose(SV010)	1.37	0.82
Ratio of micronized lactose and non-micronized lactose		1:1	1:0.4
Total weight		5.50	5.50

Test Example 1: Content uniformity test of active ingredient in capsule

A content uniformity test of tiotropium as an active ingredient filled in each of the capsule formulations for inhalation of Examples 1 to 5 and Comparative Examples 1 and 2 was performed as follows.

Column: Stainless steel column (having an inner diameter of about 4.0 ㎜ and a length of about 125 ㎜) packed with octylsilylated silica gel (liquid chromatography grade) having a particle diameter of about 5 ㎛ (LiChrospher ^®60 RP-select B, available from Merck Millipore)

Mobile phase: Solution obtained by dissolving 1.4 g of sodium octanesulfonate in 700 ㎖ of deionized water, adjusting pH to 3.2 with 0.05 mol/l of phosphoric acid, and adding 250 ㎖ of acetonitrile

Detector: UV absorbance detector (measurement wavelength: 237 ㎚)

Temperature: 30°C

Flow rate: 2.0 ㎖/min

Injection volume: 100 ㎕

The results of the content uniformity test of the active ingredient in each of 10 capsules of each of the capsule formulations for inhalation of Examples 1 to 5 and Comparative Examples 1 and 2 are shown in Table 3 and FIG. 1.

(unit: %)	Example 1	Example 2	Example 3	Example 4	Example 5	Comparative Example 1	Comparative Example 2
1	96.3	102.1	101.9	100.5	99.1	96.0	40.2
2	100.5	102.9	96.2	96.2	103.6	88.0	88.0
3	100.8	98.0	94.1	98.2	103.1	97.2	68.4
4	100.3	102.0	105.8	102.5	95.9	90.7	78.1
5	99.5	98.9	102.3	97.0	97.8	88.6	76.6
6	96.9	101.0	98.3	97.9	100.1	99.7	68.0
7	100.0	97.7	98.2	103.3	97.1	79.4	70.4
8	100.1	101.9	100.6	97.2	103.3	86.2	89.7
9	100.2	96.8	98.3	104.7	102.8	93.0	72.3
10	97.7	99.3	98.6	96.9	95.6	84.2	91.8
Average	99.2	100.1	99.1	99.4	99.8	90.3	74.3
Standard deviation	1.6	2.2	3.3	3.1	3.2	6.3	14.9

Referring to Table 3 and FIG. 1, the capsule formulations for inhalation of Examples 1 to 5 were found to have a high tiotropium content of about 94% to about 106% with a standard deviation (SD) of about 5.0 or less indicating good content uniformity. Smooth flow of the dry powder for inhalation (Examples 1 to 5) from a hopper to a dosing disc and vice versa was also observed during a capsule filling process. However, the capsule formulations of Comparative Examples 1 and 2 were found to include about 40% to about 99% of tiotropium in each capsule with an SD of above 5.0 indicating poor content uniformity of tiotropium in each capsule. In particular, for the capsule formulation of Comparative Example 2, the flowability of the dry powder for inhalation from the hopper to the dosing disc during a filling process was so poor that that content variations of the dry powder for inhalation that moved onto the dosing disc from the hopper were able to be visually identified.

Test Example 2: Delivered dose uniformity test

To identify uniformity of content emitted from an inhaler from each of the capsule formulations for inhalation of Examples 1 to 5 and Comparative Examples 1 and 2, delivered dose uniformity was evaluated using an inhaler (Capsuhaler^®, airflow resistance; 0.047

) and Apparatus B described in the U.S. Pharmacopoeia (USP). After inhalation at an inhalation flow rate of about 42 l/min for about 6.2 seconds, the interior and a filter of the inhaler was washed with deionized water, and the amount of tiotropium in the deionized water was analyzed.

Mobile phase: Solution obtained by dissolving 1.25 g of 1-sodium heptanesulfonate in 700 ㎖ of deionized water, adjusting pH to 3.2 with dilute phosphoric acid, and adding 330 ㎖ of acetonitrile.

Detector: UV absorbance detector (measurement wavelength: 240 ㎚)

Temperature: 25°C

Flow rate: 1.7 ㎖/min

Injection volume: 100 ㎕

The amount of tiotropium was analyzed using 10 capsules of each of the capsule formulations for inhalation of Examples 1 to 5 and Comparative Examples 1 and 2, and was represented as a percentage with respect to a target-delivered dose of 10.2 ㎍ in Table 4 and FIG. 2.

(unit: %)	Example 1	Example 2	Example 3	Example 4	Example 5	Comparative Example 1	Comparative Example 2
1	101.1	103.5	108.3	105.9	92.7	96.4	82.2
2	98.8	101.3	109.1	91.1	93.5	88.1	32.7
3	95.7	95.7	93.8	97.5	98.5	72.5	73.4
4	107.2	102.0	94.8	103.4	97.4	95.3	58.5
5	90.4	106.9	109.5	96.6	103.2	109.5	81.2
6	99.1	104.6	100.0	111.2	109.3	98.0	44.4
7	103.9	104.9	91.4	106.1	96.3	83.4	67.3
8	106.4	102.0	107.2	99.2	106.8	83.5	64.0
9	106.7	96.3	99.5	95.7	107.6	69.6	74.4
10	93.8	88.4	94.1	112.6	106.2	91.6	94.0
Average	100.3	100.6	100.8	101.9	101.2	88.8	67.2
Standard deviation	5.8	5.6	7.2	7.0	6.2	12.1	18.3

According to the USP Chapter <601>, entitled "Inhalation and Nasal Drug Products: Aerosols, Sprays, and Powders---Performance Quality Tests", delivered dose uniformity of a drug for inhalation is required to be within ±25% of a target-delivered dose for each of ten tests performed.

Referring to Table 4 and FIG. 2, the capsule formulations for inhalation of Examples 1 to 5 were found to have a delivered dose uniformity of about 100% on average, similar to the target-delivered dose, and all meet the USP criteria. However, the capsule formulations for inhalation of Comparative Examples 1 and 2 had a delivered dose uniformity of about 67% to about 89% on average, lower than the target-delivered dose, and a large deviation between capsules, failing to meet the USP criteria.

Test Example 3: Accelerated storage stability test of active ingredient

Stabilities of the capsule formulations for inhalation of Example 1, Examples 3 to 5, and Comparative Examples 1 and 2 were comparatively evaluated by measuring the amounts of related compounds of tiotropium after the capsule formulations were stored under the following accelerated conditions. The stability test was repeated three times using 10 capsules of each of the capsule formulations, and the test results are represented as an average thereof.

Storage conditions: stored in A1-A1 blister pack at about 40°C

Testing time: Initial, after 1 month, after 3 months, and after 6 months

Target analyte: Tiotropium-originating impurity BIIH27SE

Column: Stainless steel column (having an inner diameter of about 3.0 ㎜ and a length of about 150 ㎜) packed with propylsiyl silica gel (liquid chromatography grade) having a particle diameter of about 3.5 ㎛ (available from Merck, USA)

Mobile phase A: Solution obtained by dissolving 1.0 g of sodium methanesulfonate and 5.0 g of potassium dihydrogen phosphate in 980 ㎖ of deionized water, adjusting pH to 3.0 with dilute phosphoric acid, and adding water to make a total volume of 1,000 ㎖

Mobile phase B: Methanol, acetonitrile, and mobile phase A in a ratio of 10:40:50 (v/v/v)

Mobile phase gradient conditions as represented in Table 5.

Time (min)	A(%)	B(%)
0-3	90	10
3-17	90 → 80	10 → 20
17-28	80 → 25	20 → 75
28-30	25	75

Detector: UV absorbance detector (measurement wavelength: 240 ㎚)

Flow rate: 1.2 ㎖/min

Injection volume: 15 ㎕

Column temperature: 50°C

As a result, changes in amount of BIIH27SE as an impurity originating from tiotropium are represented in FIGS. 3 and 4.

Referring to FIGS. 3 and 4, the capsule formulations of Comparative Examples 1 and 2 were found to include a remarkably increased amount of the impurity over time. However, the capsule formulations of Examples 1 and 3 to 5 exhibited a small increase of the related compound, less than in the capsule formulations of Comparative Examples 1 and 2, indicating that the active ingredient may have improved stability in a capsule when the micronized lactose and the non-micronized lactose serving as excipients are added in a ratio of about 1:2.3 to 1:9.

Test Example 4: Fine particle mass test

A fine particle mass of tiotropium particles having a size of about 5 ㎛ or less absorbed by the lungs, from among tiotropium particles released from an inhaler upon inhalation of each of the capsule formulations of Examples 1 to 5 and Comparative Examples 1 and 2, was measured.

In particular, the fine particle mass of tiotropium particles absorbed by the lungs was measured using an inhaler (Capsuhaler^®, airflow resistance; 0.047

) and Apparatus 3 described in the USP. After inhalation at an inhalation flow rate of about 42 l/min for about 6.2 seconds, collected dose on Stages 2 to 7 were washed, and the amount of tiotropium was analyzed under the same conditions as described above in Test Example 2. Analysis of the fine particle mass of tiotropium particles was repeated three times using 6 capsules of each of the capsule formulations of Examples 1 to 5 and Comparative Examples 1 and 2, and the test results are represented as an average thereof in Table 6.

(unit: ㎍)	Example 1	Example 2	Example 3	Example 4	Example 5	Comparative Example 1	Comparative Example 2
1	2.44	2.74	3.01	2.99	3.27	2.26	2.17
2	2.48	2.89	3.21	2.30	2.88	2.62	2.65
3	2.59	2.70	3.17	2.90	2.94	2.90	1.92
Average	2.50	2.78	3.13	3.06	3.03	2.59	2.25
Standard deviation	0.08	0.10	0.11	0.21	0.21	0.32	0.37
Relative standard deviation (%)	3.10	3.61	3.38	6.85	6.93	12.37	16.51

Referring to Table 6, the capsule formulations for inhalation of Examples 1 to 5 were found to have a fine tiotropium particle mass of about 2.5 ㎍ to about 3.1 ㎍, indicating the capsule formulations of Examples 1 to 5 may deliver a larger amount of tiotropium to the lungs as compared with the capsule formulations of Comparative Examples 1 and 2.

A relative standard deviation of fine particle mass of particles refers to a deviation in an amount of tiotropium delivered deep inside the lungs. Accordingly, the larger the relative standard deviation is, the larger a deviation in drug efficacy may likely become. The capsule formulations of Examples 1 to 5 had a relative standard deviation of about 3% to about 7% in a fine particle mass of tiotropium particles, whereas the capsule formulations of Comparative Examples 1 and 2 had a relative standard deviation of about 12% to about 16.5%. Accordingly, the capsule formulations of Examples 1 to 5 were found to deliver a uniform dose of the active ingredient to the lungs upon each inhalation and exhibit consistent efficacy. In particular, the capsule formulations for inhalation of Examples 1 to 3 were found to have a smaller relative standard deviation as compared with the capsule formulations of Examples 4 and 5, indicating that the active ingredient may be delivered with improved uniformity when a micronized lactose, a medium-sized fine lactose, and a large-sized fine lactose as excipients are used in a specific weight ratio.

While this invention has been particularly shown and described with reference to preferred embodiments thereof, 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. The disclosed embodiments should be considered in descriptive sense only and not for purposes of limitation. Therefore, the scope of the invention is defined not by the detailed description of the invention but by the appended claims, and all differences within the scope will be construed as being included in the present invention.

Claims

A dry powder composition comprising:

tiotropium or a pharmaceutically acceptable salt thereof;

a micronized lactose; and

a non-micronized lactose,

wherein a weight ratio between the micronized lactose and the non-micronized lactose is about 1:1.5 to about 1:19.
The dry powder composition of claim 1, wherein the pharmaceutically acceptable salt of tiotropium is tiotropium bromide.
The dry powder composition of claim 1, wherein an amount of the tiotropium or the pharmaceutically acceptable salt thereof is about 0.018 wt% to about 0.90 wt% based on a total weight of the dry powder composition.
The dry powder composition of claim 1, wherein the micronized lactose has an average particle size of about 10 ㎛ to about 30 ㎛.
The dry powder composition of claim 4, wherein the micronized lactose has an average particle size of about 15 ㎛ to about 20 ㎛.
The dry powder composition of claim 1, wherein the non-micronized lactose has an average particle size of about 45 ㎛ to about 130 ㎛.
The dry powder composition of claim 1, wherein the non-micronized lactose comprises medium-sized fine lactose and large-sized fine lactose, the medium-sized fine lactose and the large-sized fine lactose are satisfy a weight ratio of about 9:1 to about 1:9.
The dry powder composition of claim 7, wherein the medium-sized fine lactose has an average particle size of about 45㎛ to about 70 ㎛.
The dry powder composition of claim 7, wherein the large-sized fine lactose has an average particle size of about 90 ㎛ to about 130 ㎛.
A method of preparing a dry powder composition, the method comprising:

i) obtaining a mixture of a micronized lactose with tiotropium or a pharmaceutically acceptable salt thereof by triturating, sieving, and mixing them ; and

ii) sieving a non-micronized lactose, adding the sieved non-micronized lactose to the mixture of step i) to satisfy a weight ratio of about 1:1.5 to about 1:19, and mixing a resulting mixture.
The method of claim 10, wherein, in the sieving in the step i), a sieve mesh size is about 50 ㎛ to about 250 ㎛.
The method of claim 10, wherein in the sieving of the step ii), a sieve mesh size is about 280 ㎛ to about 700 ㎛.
A capsule formulation for inhalation filled with the dry powder composition of any one of claims 1 to 9.