KR101728116B1 - Dry powder composition for inhalation comprising tiotropium or pharmaceutically acceptable salt thereof - Google Patents

Abstract

The present invention relates to a dry powder composition which contains, at a specific content ratio, tiotropium or a pharmaceutical acceptable salt thereof, finely powdered lactose as a diluting agent, and lactose rather than finely powdered lactose. When the dry powder composition processed into capsules, the content of active components in a capsule is even, and content uniformity per unit delivery rate for tiotropium used as the active component and stability increase. Accordingly, the dry powder composition can be useful for treating respiratory diseases.

Description

TECHNICAL FIELD The present invention relates to a dry powder composition for inhalation containing tiotropium or a pharmaceutically acceptable salt thereof,

The present invention relates to a dry powder composition for inhalation which contains tiotropium or a pharmaceutically acceptable salt thereof and lactose which is not a lactose and a lactose but a lactose as an excipient.

The tiotropium bromide is known from European Patent No. 0418716, the formula of which is as follows:

Thiotropium is one of the long-acting, long-acting muscarinic antagonists (LAMA), which is a long-lasting drug. In particular, it is widely used for the treatment of chronic obstructive pulmonary disease (COPD), and recently it has also been used for asthma treatment.

For the treatment of respiratory diseases such as chronic obstructive pulmonary disease or asthma, many inhalation preparations are used. Inhalation formulations have a large surface area because of the nature of the formulation, the particle size of the active ingredient is generally undifferentiated to 5 탆 or less in general. However, when an active ingredient having a large surface area is prepared as an inhalation preparation, there is a problem that it is difficult to ensure the stability of the active ingredient in the inhalation preparation due to the effects of excipients, pharmaceutical additives, or the external environment contained therein. In addition, in the case of a complex containing a plurality of drugs, the generation of an impurity due to interaction between the active ingredients can be further accelerated. Therefore, in order to develop a formulation with less side effects and better efficacy, the stability of the active ingredient should be taken into account.

The active ingredient contained in the dry powder composition for inhalation is effectively transferred to the lungs to exhibit pharmacological activity, and its particle size is extremely undifferentiated to about 5 탆 or less. However, the undifferentiated particles are thermodynamically unstable due to their large surface area relative to the volume ratio, and excessive surface energy is generated, and the particles tend to proceed to the agglomerated state. When the particles are agglomerated in this way, they 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, that is, an excipient. Thus, it has been known in the art to prepare an inhalable dry powder composition by mixing an active ingredient with an excipient for effective delivery of the active ingredient.

Conventional inhalation preparations are filled with a dry powder in a capsule or cyst, which is administered by inhalation using an inhaler. The amount of the dry powder for inhalation containing the active ingredient and the excipient to be filled in the capsule or the cyst is much smaller than that of conventional capsules and is usually filled in an amount of about 5 to 25 mg. Therefore, the uniform filling of the dry powder has a very important effect on the quality of the product, which is highly related to the uniformity of the content in the capsule and the unit transfer amount injected through the inhalation device.

Thus, when the dry powdered composition for inhalation containing thiotropium as the active ingredient and having a certain ratio of lactose rather than lactose and lactose as an excipient is prepared into a capsule, the content of the active ingredient in the capsule is Uniformity and excellent stability, and thus it can be usefully used for the treatment of respiratory diseases, thereby completing the present invention.

European Patent No. 0418716

Accordingly, the present invention provides a dry powder composition containing tiotropium or a pharmaceutically acceptable salt thereof, lactose rather than lactose, and a method for preparing the same, and a capsule for inhalation containing the lactose composition .

In order to achieve the above object, the present invention provides a pharmaceutical composition comprising a compound selected from the group consisting of tiotropium or a pharmaceutically acceptable salt thereof, lactose, which is not a lactose, and a lactose which is not lactose, 1: 1.5 to 1: 19. ≪ / RTI >

In addition, the present invention relates to a method for preparing a pharmaceutical composition comprising the steps of: blending and sieving fine powdered lactose, and thiotropium or a pharmaceutically acceptable salt thereof; And mixing the resulting mixture obtained in step 1) with lactose in a ratio of 1 part by weight of lactose rather than 1 part by weight to 1 part by weight of lactose rather than lactose. To provide a method of making the dry powder composition.

The present invention also provides a capsule for inhalation comprising the dry powder composition according to the present invention.

The inhalation capsules made of the dry powder composition according to the present invention increase the uniformity and stability of the content of thiotoluium per unit transfer amount of the active ingredient and uniformly fill the content of the active ingredient in the capsules, For example, as a dry powder composition for the treatment of chronic obstructive pulmonary disease or asthma.

FIG. 1 is a graph showing the results of checking the uniformity of contents of active ingredients in capsules using the inhalation capsules of Examples 1 to 5 and Comparative Examples 1 and 2. FIG.
FIG. 2 is a graph showing the results of confirming the uniformity of contents per unit transfer amount using the inhalation capsules of Examples 1 to 5 and Comparative Examples 1 and 2. FIG.
3 is a graph showing the results of measurement of the amount of BIIH27SE as a flexible substance derived from tiotropium in the acceleration experiments using the inhalation capsules of Examples 1 and 3 and Comparative Examples 1 and 2 over time .
4 is a graph showing the results of measurement of the amount of BIIH27SE as a flexible substance derived from tiotropium in the acceleration experiment using the inhalation capsules of Examples 3 to 5 over time.

Hereinafter, the present invention will be described in detail.

The present invention provides a dry powder composition comprising tiotropium or a pharmaceutically acceptable salt thereof as an active ingredient and lactose which is not lactose and lactose lactose as an excipient.

The thiotropium according to the present invention can be obtained by reacting (1?, 2?, 4?, 7? -7 - [(hydroxydi-2-thienylacetyl) oxy] -9,9-dimethyl- Nitrotricyclo [3.3.1.0 ^2,4 ] nonane, the structure of which is as follows:

.

.

The thiotropium may be used for the treatment of chronic obstructive pulmonary disease (COPD) or asthma, which can be treated through the control of respiratory diseases, particularly bronchoconstriction, inflammation and intracranial mucus secretion.

The thiotropium according to the present invention may be in the form of a pharmaceutically acceptable salt and examples include pharmaceutically acceptable salts such as acetic acid, citric acid, maleic acid, succinic acid, ascorbic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, (For example, sodium or potassium salts), ammonium salts, amine salts, amino acid salts, and the like.

In addition to the pharmaceutically acceptable salts, equivalents having the same or similar activity can be used. Examples of usable equivalents include solvates, hydrates, anhydrides, enantiomers, derivatives, But is not limited thereto.

According to one embodiment of the present invention, the pharmaceutically acceptable salt of thiotropium is tiotropium bromide.

The thiotropium or a pharmaceutically acceptable salt thereof may be contained in an amount of 0.018 to 0.90% by weight, specifically 0.164 to 0.437% by weight based on the total weight of the composition. According to one embodiment of the present invention, 0.395% by weight. The 0.395% by weight thiotropium bromide corresponds to about 0.327% by weight of thiotropium. However, the content of thiotropium bromide, which is an active ingredient, may vary depending on various factors such as the subject to be prescribed and the disease state.

The dry powdery composition according to the present invention is mixed with a certain amount of lactose rather than lactose and lactose as an excipient. The lactose, which is not the lactose, is characterized by containing neutralized lactose and high lactose.

In general, the active ingredients used in the dry powder composition tend to agglomerate because the particle size is very small, about 1 to 5 mu m. Therefore, it is difficult to fill capsules or cysts at an accurate dosage, and the delivery rate to the lungs at the time of inhalation is lowered. Thus, by mixing and dispensing an excipient having a size of about 50 to 250 占 퐉 into the micronised active ingredient, release of the active ingredient from the excipient particles in the airways can be facilitated. Therefore, the present invention includes lactose as an excipient.

As used herein, the term " lactose "is a disaccharide consisting of 1 mole of glucose and 1 mole of galactose. There are two types of disaccharides, alpha and beta, and the molecular formula is C ₁₂ H ₂₂ O ₁₁ . The dry powder composition according to the present invention comprises lactose rather than lactose and lactose.

The lactose which is not the fine lactose may be a lactose having an average particle size of 45 to 130 탆, specifically 50 to 125 탆. In addition, the lactose, which is not the lactose, may include the neutralized lactose and the high lactose. The neutralized lactose may have an average particle size of 45 to 70 탆, specifically 53 to 65 탆, and the high-fat lactose may have an average particle size of 90 to 130 탆, specifically 95 to 125 탆. At this time, the weight ratio of the neutralized milk powder and the high milk powdered sugar may be 9: 1 to 1: 9, specifically 5: 1 to 1: 5, more specifically 2: 1 to 1: 2. According to one embodiment of the present invention, the weight ratio of the neutralized milk powder and the high milk powder may be 1: 1.

The fine powdered sugar may be a fine powder of lactose and may have an average particle size of 2 to 45 mu m, specifically 10 to 30 mu m, more specifically 15 to 20 mu m. According to one embodiment of the present invention, Lt; RTI ID = 0.0 > 17 < / RTI > The fine powdered lactose having an average particle size as described above may be contained in an amount of 10 to 70%, specifically 20 to 60%, more specifically 30 to 50% of the total fine lactose. According to one embodiment of the present invention, the fine powdered milk having a particle size of 10 to 30 占 퐉 may be contained at about 40% of the total fine powdered lactose.

As used herein, the term "average particle size" refers to the particle size corresponding to 50% in the cumulative particle distribution graph, and may also be expressed as X ₅₀ . This means that 50% of the total particles are smaller than the size of X ₅₀ and the remaining 50% of the particles are larger than the size of X ₅₀ .

When mixed with micronized particles such as micronized lactose, the excipient has the advantage of facilitating the release of the active ingredient from the excipient particles in the airways. This is because, by first attaching a small amount of the excipient to the surface of the irregular excipient particles, the micronized excipient particles are preferentially adhered to the site having a high surface energy, thereby lowering the surface energy. As a result, the overall surface energy of the excipient is lowered, Surface energy. The finely divided excipients may also be used to such an extent that they do not affect the flowability of the dry powder composition.

Therefore, the dry powder composition according to the present invention is characterized in that the lactose, which is not the fine powdered milk and the fine powdered milk, is in the range of 1: 1.5 to 1:19, specifically 1: 2 to 1:15, more specifically 1: 2 to 1:10 And the weight ratio of the lactose rather than the lactose and the lactate may be 1: 2.3 to 1: 9, for example, 1: 2.3, 1: 4 or 1: 1: 9 weight ratio. When the weight ratio of the lactose to the lactose rather than the lactose is less than 1: 1.5, the content of the active ingredient is not uniform in each capsule when the capsule composition is prepared using the composition for inhalation, The content of the components is not uniform, and when the prepared capsules are stored in an accelerated state, there is a problem that the generation of the flexible substance of the active ingredient increases.

The excipient to be included in the dry powder composition according to the present invention may be 0.1 to 98.0% by weight, specifically 50 to 98.0% by weight, more specifically 90.0 to 98.0% by weight, and in accordance with an embodiment of the present invention 96.0% Lt; / RTI > If the amount of excipient is too large, the patient may feel uncomfortable due to excessive foreign body sensation at the time of inhalation, and stimuli within the bronchial tract may be caused by the excipient. On the other hand, if too small an amount of excipient is used, uniformity between the excipient and the active ingredient can not be ensured, and it may become very difficult to quantify the quantity to be inhaled once in the capsule. Since the excipient content in the above range can be filled into capsules according to the general production method, there is no need to install a special device for producing the inhalant, and it is advantageous that it can be manufactured in a general pharmaceutical production factory.

The dry powder composition according to the present invention may be a dry powder composition for inhalation. Such a dry powder composition for inhalation may be an important factor in the surface characteristics of the excipient particles in order for the active ingredient to be discharged from the suction device or reach the target site. In order for the active ingredient to have good fluidity and to be easily withdrawn from the inhalation device, it must be supported with sufficient adhesion to the excipient in the inhalation device. However, there is a difficulty in maintaining an appropriate value of adhesion between the excipient surface and the active ingredient, since it must be easy to leave the surface of the excipient in the airway to leave the suction device to reach the target site. In the present invention, the active ingredient is allowed to adhere to the surface of the excipient with a suitable adhesive force through a mixing process between the active ingredient and the excipient.

As described above, the present invention relates to a method for preparing a microcrystalline cellulose, which comprises: 1) blending and sieving and mixing fine powdered lactose and thiotropium or a pharmaceutically acceptable salt thereof; And 2) mixing the lactose, which is not the lactic acid powder, with the mixture obtained in the step 1) so that the weight ratio of lactic acid to lactic acid is 1: 1.5 to 1:19. There is provided a method for producing a dry powder composition according to the present invention.

In the preparation of the dry powder composition according to the present invention, the sieve size of the sieve for the fine powdered milk of the step 1) and thiourethmium or a pharmaceutically acceptable salt thereof is 50 to 250 탆, specifically 100 to 200 탆 Mu] m, more specifically 120 to 180 [mu] m, and may be 145 to 155 [mu] m according to a specific embodiment of the present invention. On the other hand, the sieve size of the sieve for the lactose rather than the lactose in step 2) may be 280 to 700 탆, specifically 300 to 550 탆, more specifically 350 to 500 탆, According to the embodiment, it may be 405 to 445 탆.

On the other hand, the present invention provides a formulation containing an inhalable dry powder composition according to the present invention in a blister such as capsules and cartridges such as gelatin or hymmelose used in a suction device, or a layered aluminum foil, Specifically, the formulation may be a capsule. The size of capsules usable as capsules of the present invention has various internal capacities depending on the lakes, for example, about 0.68 ml of No. 0 capsules, about 0.47 ml of No. 1 capsules, about 0.37 ml of No. 2 capsules, It is known that the capsule has an internal capacity of about 0.27 ml and the capsule No. 4 has an internal capacity of about 0.20 ml. The size of the capsule is preferably small considering the convenience of medication of the patient taking the formulation of the present invention. However, in the present invention, due to the mass limit of the contents to be filled in the capsule, the size of the capsule is preferably 0, 1, 2, 3 or 4 A call capsule may be used, and according to an embodiment of the present invention, a capsule No. 3 is used.

The dry powder composition according to the present invention contained in the capsules contains 0.001 to 0.05 mg, specifically 0.009 to 0.024 mg, more specifically 0.0217 mg, of the active ingredient per unit dosage form of thiotropium or a pharmaceutically acceptable salt thereof . 0.0217 mg of thiotoluium bromide corresponds to about 0.018 mg of thiotropium.

The advantage of being provided as a capsule is that the inhalation formulation of the present invention can be prepared without a special filling device. In addition, the capsule in which the dry powder composition for inhalation according to the present invention is filled is preferably transparent. The use of transparent capsules has the advantage of allowing the patient to visually confirm whether or not they have inhaled the dry powdered active ingredient in the capsule after inhaling the inhalant combination. In addition, it is possible to visually confirm that the stability of the capsule, such as cohesion, discoloration,

The inhalation capsules may be administered to a patient using any known dry powder inhaler. The dry powder inhaler includes means for rupturing the capsule, puncturing (puncturing), or otherwise opening the capsule to deliver the composition in the metered capsule to the patient's lungs. In addition, it may further include an inlet for introducing air to form a flow of air, a discharge port for discharging the active ingredient by sucking the patient's mouth, and a sieve for filtering the foreign substance. One example of such a device is a commercially available ROTAHALER ^® GlaxoSmithKline are, of Boehringer Ingelheim HANDIHALER ^® and flasks thiazol AEROLIZER ^® of Fe (Plastiape). The HANDIHALER ^® and AEROLIZER ^® have a groove in which a capsule is inserted into the cap of the suction device. When the button is pressed, the pin is pushed out to the life of the capsule, and the size is not so large.

In an embodiment of the present invention, the inventors of the present invention have found that when the active ingredient contains thiotropium, the content ratio of lactose rather than lactose and lactose is 1: 2.3 to 1: 9 as an excipient, (Table 1). The dry powdery composition for inhalation according to claim 1, wherein the ratio of the lactose to the lactose is 1: 1.

As a result of measuring the content of the active ingredient contained in the manufactured inhalation capsule, the content of the active ingredient in the inhalation capsule containing the inhalable dry powder composition of the present invention was uniformly distributed, It was confirmed that the flow of the dry powder composition was good (Table 4 and Fig. 1).

In addition, when the inhalation capsules containing the inhalable dry powder composition according to the present invention were inhaled using an inhaler, the average of the contents per unit volume was about 100%, which was similar to the target volume, (Table 5 and Figure 2).

As a result of carrying out an accelerated storage stability test using the inhalation capsules containing the inhalable dry powder composition according to the present invention, it was found that in the capsules containing the dry powder composition according to the present invention, It was confirmed that the amount of substance produced was significantly lower (FIGS. 3 and 4).

As a result of confirming the amount of effective particles delivered to the lungs by using the inhalation capsule containing the inhalable dry powder composition according to the present invention, it was found that in the capsule containing the dry powder composition according to the present invention, , And it was confirmed that the inhalation capsule containing the pulverized milk powder, the neutralized milk powder and the high-fat milk powder at a certain ratio delivered the active ingredient more uniformly (Table 6).

Accordingly, the dry powder composition according to the present invention increases the uniformity and stability of the content of thiotoluium, which is an active ingredient, per unit transfer amount, and when the capsule is made into a capsule, the content of the active ingredient in the capsule is uniform, Pulmonary diseases or asthma. ≪ Desc / Clms Page number 2 >

Hereinafter, the present invention will be described in detail with reference to examples. The following examples illustrate the present invention, but the scope of the present invention is not limited thereto.

Example  1 to 5: Thiotropium , And manufacture of inhalation capsules having different contents of lactose and lactose rather than fine lactose and fine lactose

First, according to the composition shown in the following Table 1, the active ingredient, thiotoluium bromide (Sicor SRL (TEVA)), the lactose with an average particle size of about 17 탆 (Respitose ML006, DFE pharma) (Respitose SV003, DEF pharma) having an average particle size of about 60 占 퐉 and Respitose SV010 (DEF pharma) having an average particle size of about 105 占 퐉 were respectively weighed. The weighed thiotropium bromide was mixed with micronized lactose and sieved in a 100 mesh sieve. The mixture was mixed with neutralized milk powder and milk powdered milk mixed in 40 mesh and mixed for about 30 minutes. The resulting mixture was filled into clear 3 capsules using a capsule filler (GKF702, Bosch).

(Unit: mg) Example 1 Example 2 Example 3 Example 4 Example 5 Thiotropium bromide
(Amount of thiotropium contained) 0.0217
(0.018) 0.0217
(0.018) 0.0217
(0.018) 0.0217
(0.018) 0.0217
(0.018) Differential milk sugar 0.55 1.10 1.65 1.65 1.65 Lactose not lactose Neutralized lactose
(SV003) 2.46 2.19 1.91 3.83 0 Tofu sugar
(SV010) 2.47 2.19 1.92 0 3.83 The ratio of the content of lactose, which is not pulverized milk powder and pulverized milk powder 1: 9 1: 4 1: 2.3 1: 2.3 1: 2.3 Gross weight 5.50 5.50 5.50 5.50 5.50

Comparative Example  1 and 2: Thiotropium , And a content ratio of lactose other than lactose and lactose, 1: 0.4 and 1: 1,

As shown in the following Table 2, the inhalation capsules were prepared in the same manner as in Example 1, except that the content of lactic acid was varied depending on the contents of lactic acid, lactose, and lactose.

(Unit: mg) Comparative Example 1 Comparative Example 2 Thiotropium bromide
(Amount of thiotropium contained) 0.0217
(0.018) 0.0217
(0.018) Differential milk sugar 2.75 3.85 Lactose not lactose Neutralized lactose
(SV003) 1.36 0.81 Tofu sugar
(SV010) 1.37 0.82 The ratio of the content of lactose, which is not pulverized milk powder and pulverized milk powder 1: 1 1: 0.4 Gross weight 5.50 5.50

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

The content uniformity test of the thiourethane, which is the active ingredient packed in the inhalation capsules of Examples 1 to 5 and Comparative Examples 1 and 2, was carried out as follows.

< Thiotropium  Analysis conditions>

Column: A column (LiChrospher ^占 60 RP-select B, Merck Millipore) packed with octylsilylated silica gel for liquid chromatography having a particle size of 5 占 퐉 in a stainless steel tube having an inner diameter of about 4.0 mm and a length of about 125 mm,

Mobile phase: 1.4 g of sodium octanoic sulfonate was dissolved in 700 ml of purified water, adjusted to pH 3.2 with 0.05 mol / l phosphoric acid, and then mixed with 250 ml of acetonitrile

Detector: Ultraviolet absorption spectrophotometer (measurement wavelength: 237 nm)

Temperature: 30 ℃

Flow rate: 2.0 ml / min

Injection volume: 100 μl

The inhalation capsules of Examples 1 to 5 and Comparative Examples 1 and 2 were each used in amounts of 10, and the results were as shown in Table 3 and FIG. 1 below.

(unit: %) Example 1 Example 2 Example 3 Example 4 Example 5 Comparative Example 1 Comparative Example 2 One 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

As a result, as shown in Table 3 and FIG. 1, the inhalation capsules of Examples 1 to 5 contained a high amount of thiotoluium of about 94 to 106%, and all the standard deviations were all less than 5.0, Uniformity. Also, the flow of dry powder for inhalation from the hopper to the dosing disk and from the dosing disk to the capsule during the filling process of the capsule was also good. However, Comparative Examples 1 and 2 contained about 40 to 99% of thiourethmium and had a standard deviation of 5.0 or more, so that the uniformity of content of thiotoluium in the capsules was not good. Particularly, in Comparative Example 2, There was a difference in the amount of dry powder for inhalation which was transferred to the dosing disk because the flow of the inhalable dry powder moving from the hopper to the dosing disk was not smooth.

Test Example  2: Content uniformity test per unit transfer amount

) 및 미국약전(USP)에 기재된 시험기구인 장치 B(Apparatus B)를 사용하여 측정하였다. 이때, 42 ℓ/min의 흡입 유속으로 약 6.2초간 흡입시키고, 장치 내부 및 필터를 정제수로 세척하여 세척된 정제수로부터 하기와 같은 조건으로 티오트로피움의 양을 분석하였다.
When the inhalation capsules of Examples 1 to 5 and Comparative Examples 1 and 2 were inhaled, in order to confirm the uniformity of the amount of the powder filled in the capsule through the inhalation device, The device Capsuhaler ^® (air resistance value 0.047

) And the apparatus B (Apparatus B) described in USP (USP). At this time, the tube was sucked at a suction flow rate of 42 l / min for about 6.2 seconds, and the inside of the apparatus and the filter were washed with purified water, and the amount of thiotropium was analyzed from the washed purified water under the following conditions.

< Thiotropium  Analysis conditions>

Column: A column (LiChrospher ^占 60 RP-select B, Merck Millipore) packed with octylsilylated silica gel for liquid chromatography having a particle size of 5 占 퐉 in a stainless steel tube having an inner diameter of about 4.0 mm and a length of about 125 mm,

Mobile phase: 1.25 g of sodium 1-heptanesulfonate was dissolved in 700 ml of purified water, adjusted to pH 3.2 with diluted phosphoric acid, and then dissolved in 330 ml of acetonitrile

Detector: Ultraviolet absorption spectrophotometer (measurement wavelength: 240 nm)

Temperature: 25 ℃

Flow rate: 1.7 ml / min

Injection volume: 100 μl

The contents of thiotropium analyzed using ten inhalation capsules of Examples 1 to 5 and Comparative Examples 1 and 2 are shown in Table 4 and FIG. 2 as percentage relative to the target delivery amount of 10.2 占 퐂.

(unit: %) Example 1 Example 2 Example 3 Example 4 Example 5 Comparative Example 1 Comparative Example 2 One 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 inhalation and nasal drug products (aerosols, sprays, and powder-performance quality tests) of inhalants and nasal drug products: aerosols, sprays and powders described in the US Pharmacopia <601> The content uniformity should be included in the ± 25% of the target delivery for each of the 10 results.

As shown in Table 4 and FIG. 2, the inhalation capsules of Examples 1 to 5 of the present invention had an average content of about 100% per unit transfer amount, similar to the target delivery amount, Respectively. However, in Comparative Examples 1 and 2, the average of the content per unit transport amount was about 67 to 89%, which was lower than the target delivery amount, and it was confirmed that there was a large deviation in the content between the capsules. Also, in the case of Comparative Examples 1 and 2, the resultant value was inadequate to the US Pharmacopoeia standard.

Test Example  3: Accelerated storage stability test of active ingredient

The inhalation capsules of Examples 1, 3 to 5, and Comparative Examples 1 and 2 were stored under accelerated conditions under the following conditions, and the degree of generation of the thiotropium was examined to compare the stability. The test results were shown in the average value after three repeated tests using 10 capsules.

<Accelerated Storage Test Conditions>

Storage conditions: A1-A1 Storage in blister packaging at 40 ° C

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

Analyzed with: Thiotropium derived flexible material BIIH27SE

&Lt; Conditions for analyzing the content of tiotropium &

Column: A column (Merck, USA) filled with propylsiyl silica gel for liquid chromatography having a particle diameter of about 3.5 占 퐉 was inserted into a stainless steel tube having an inner diameter of about 3.0 mm and a length of about 150 mm.

Mobile phase A: 1.0 g of sodium methanesulfonate and 5.0 g of potassium dihydrogenphosphate were dissolved in 980 ml of purified water, adjusted to pH 3.0 with dilute phosphoric acid, and adjusted to a total volume of 1,000 ml

Mobile phase B: methanol: acetonitrile: mobile phase A = 10: 40: 50 (v / v / v)

Mobile phase concentration gradient conditions Time (minutes) A (%) B (%) 0-3 90 10 3-17 90 → 80 10 → 20 17-28 80 → 25 20 → 75 28-30 25 75

Detector: Ultraviolet absorption spectrophotometer (measurement wavelength: 240 nm)

Flow rate: 1.2 ml / min

Injection volume: 15 μl

Column temperature: 50 ° C

As a result, changes in the content of BIIH27SE derived from thiotropium are shown in FIGS. 3 and 4. FIG.

As shown in FIG. 3 and FIG. 4, it was found that the encapsulant of Comparative Examples 1 and 2 significantly increased the amount of the flexible substance over time. However, the capsules of Examples 1 and 3 to 5 showed a slight increase in the amount of the suppositories at a level lower than that of Comparative Examples 1 and 2, so that the content ratio of lactose rather than lactose and lactose added as excipients was 1: 2.3 to 1: , It was confirmed that the stability of the active ingredient in the capsule was excellent.

Test Example  4: Effective Particle Size Test

When the inhalation capsules of Examples 1 to 5 and Comparative Examples 1 and 2 were inhaled, the amount of effective particles of 5 mu m or less absorbed into the lungs was measured in the amount of thiotropium sprayed through the inhaler.

) 및 미국약전(USP)에 기재된 시험기구인 장치 3(Apparatus 3)을 사용하여 측정하였다. 이때, 42 ℓ/min의 흡입 유속으로 약 6.2초간 흡입시키고, Stage 2~7을 세척하여 상기 시험예 2에 기재된 조건으로 티오트로피움의 양을 분석하였다. 이때, 분석된 티오트로피움의 함량 유효입자량은 실시예 1 내지 5, 및 비교예 1 및 2의 캡슐제를 각각 6개 사용하여 그 평균값으로 나타내었다. 실험은 3회 수행하였고, 그 값을 하기 표 6에 나타내었다.Specifically, the fine particle dose to the lungs that is absorbed is a suction device which Capsuhaler ^® (air flow resistance value 0.047

) And USP (Apparatus 3) described in USP. At this time, the sample was aspirated for about 6.2 seconds at an inhalation flow rate of 42 l / min, and Stage 2 to 7 were washed to analyze the amount of thiotropium under the conditions described in Test Example 2 above. At this time, the effective amount of the content of thiotropium analyzed was represented by the average value of 6 capsules of Examples 1 to 5 and Comparative Examples 1 and 2, respectively. The experiment was carried out three times and the values are shown in Table 6 below.

(Unit: ㎍) Example 1 Example 2 Example 3 Example 4 Example 5 Comparative Example 1 Comparative Example 2 One 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

As shown in Table 6 above, the inhalation capsules of Examples 1 to 5 of the present invention delivered about 2.5 to 3.1 의 of thiotoluium, which means that a larger amount of thiotropium was obtained compared to Comparative Examples 1 and 2 To the lungs.

On the other hand, the relative standard deviation of the effective particle size means a deviation of the amount of thiotropium delivered deep into the lung, and the larger the relative standard deviation, the greater the deviation of the drug efficacy. In Examples 1 to 5, the relative standard deviation of the effective particle amount was about 3 to 7%, while Comparative Examples 1 and 2 showed 12 to 16.5%, so that the capsules of Examples 1 to 5 each had a uniform amount Can be transferred to the lungs and exhibit uniform drug efficacy. When comparing Examples 1 to 5 of the present invention, the relative standard deviation of the inhalation capsules of Examples 1 to 3 was confirmed to be a lower level, and the amount of the lactose, the lactose and the lactose as the excipients , It can be seen that the active ingredient is delivered more uniformly.

Claims (13)

Tiotropium or a pharmaceutically acceptable salt thereof, and
Lactose rather than lactose and lactose,
Wherein the weight ratio of lactose to lactose is from 1: 1.5 to 1:19,
The mean particle size of the fine powdered sugar is 10 to 30 mu m,
Wherein the lactose rather than the fine lactose is composed of neutralized lactose and high-fat milk sugar, and the neutralized milk powder and the high-fat milk sugar are contained in a weight ratio of 9: 1 to 1: 9,
The mean particle size of the neutralized milk sugar is 45 to 70 mu m,
Wherein the mean particle size of the high molecular weight lactose is 90 to 130 탆.
The dry powder composition of claim 1, wherein the pharmaceutically acceptable salt of thiotoluium is tiotropium bromide.
2. The dry powder composition of claim 1, wherein the thiotropium or a pharmaceutically acceptable salt thereof is included in an amount of 0.018 to 0.90% by weight based on the total weight of the composition.
delete The dry powder composition according to claim 1, wherein the mean particle size of the fine powdered sugar is 15 to 20 mu m.
delete delete delete delete 1) blending and sieving and mixing fine powdered lactose, and thiotropium or a pharmaceutically acceptable salt thereof; And
2) adding lactose, which is not a fine lactose, to the mixture obtained in the step 1) so that the weight ratio of lactose to lactose is not more than 1: 1.5 to 1:19
Lt; / RTI &gt;
The mean particle size of the fine powdered sugar is 10 to 30 mu m,
Wherein the lactose rather than the fine lactose is composed of neutralized lactose and high-fat milk sugar, and the neutralized milk powder and the high-fat milk sugar are contained in a weight ratio of 9: 1 to 1: 9,
The mean particle size of the neutralized milk sugar is 45 to 70 mu m,
Wherein the average particle size of the high-fat milk sugar is 90 to 130 탆.
The method of claim 10, wherein the sieve body size in step 1) is 50 to 250 탆.
The method for producing a dry powder composition according to claim 10, wherein the sieve body size in the step 2) is 280 to 700 탆.
A capsule for inhalation, which is filled with the dry powder composition according to any one of claims 1 to 5.

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