KR101748796B1 - Inhalation capsule with enhanced delivery rate of active ingredients - Google Patents

Abstract

The present invention relates to a capsule for inhalation improved in the amount of active ingredient delivery, wherein the capsule for inhalation contains thiotropium as an active ingredient and titanium dioxide is contained in the base to control the stability of the active ingredient and the target- And even when punching by a suction device, a large amount of capsule fragments are not generated, so that it can be useful as a capsule for inhalation for the treatment of respiratory diseases.

Description

BACKGROUND OF THE INVENTION 1. Field of the Invention [0001] The present invention relates to an inhalation-

It enhanced the delivery amount of the active ingredient, including; (TiO ₂ titanium dioxide) The present invention is the delivery amount of the active ingredient to an improved inhalation capsules for, in particular free of tiotropium as an active ingredient, and the titanium dioxide in the capsule base To a capsule for inhalation.

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, its use in asthma treatment is also increasing.

For the treatment of respiratory diseases such as chronic obstructive pulmonary disease or asthma, many inhalation preparations are used. In the inhalation preparations, the particle size of the active ingredient is generally undifferentiated to 5 탆 or less due to the nature of the formulation. Therefore, the active ingredient contained in the inhalation preparation has a large surface area due to microfibrillation of the particles. Such an active ingredient having a large surface area is problematic in that it is difficult to ensure stability due to the influence of the diluent or the external environment contained together to be produced as an inhalation preparation. In addition, since the unit dose of the active ingredient contained in the inhalation preparation is very low, it is well known that the stability of the active ingredient and the importance of having a high level of unit dose in the quality control of medicines.

However, there has been no report on an inhalation capsule that increases the stability of an active ingredient. International Publication WO 2000/07572 discloses a capsule for inhalation using an insoluble hydrophobic synthetic material, Or the amount of drug delivery.

Accordingly, the present inventors have found that when a capsule for inhalation containing thiotoluium as an active ingredient and containing titanium dioxide in a capsule base increases the stability and delivery amount of the active ingredient, and even when punching by an inhalation device, And thus it can be used as a capsule for inhalation for the treatment of respiratory diseases, thus completing the present invention.

European Patent No. 0418716 International Publication WO 2000/07572

Accordingly, an object of the present invention is to provide a capsule for inhalation having an increased amount of the active ingredient tiotropium.

In order to achieve the above object, the present invention provides a capsule for inhalation containing tiotropium or a pharmaceutically acceptable salt thereof, wherein the capsule base contains titanium dioxide (TiO ₂ ) .

The capsule for inhalation according to the present invention increases stability and delivery amount of thiotropium, which is an active ingredient, and does not produce capsule fragments even when punching by an inhalation device. Therefore, it is possible to provide a capsule for inhalation, especially chronic obstructive pulmonary disease or asthma May be useful as an inhalation capsule for treatment.

FIGS. 1 to 3 are graphs showing the results of measurement of the amount of BIIH27SE, a thiotropium-derived flexible substance, in the accelerated experiment using the inhalation capsules of Examples 1 to 6 and Comparative Examples 1 to 7 over time.
FIG. 4 is a graph showing the target-unit transfer amount reaching amounts of thiotropium inhaled in the inhalation capsules of Examples 1 to 6 and Comparative Examples 1 to 7. FIG.
FIG. 5 is a graph showing the target-unit transfer rate of thiotropium in the inhalation capsules of Examples 1 to 6 and Comparative Examples 1 to 7. FIG.

Hereinafter, the present invention will be described in detail.

The present invention provides a capsule for inhalation containing tiotropium or a pharmaceutically acceptable salt thereof and containing a titanium dioxide (TiO ₂ ) as a capsule base.

The inhalation capsules according to the present invention may contain thiotropium or a pharmaceutically acceptable salt thereof as an active ingredient and may be used for the treatment of chronic obstructive pulmonary disease (COPD), which can be treated through the control of respiratory diseases, especially bronchoconstriction, inflammation and airway mucus secretion chronic obstructive pulmonary disease (COPD) or asthma. 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 is packed in the form of a dry powder. The thiotropium in the form of a dry powder or a pharmaceutically acceptable salt thereof may be contained in an amount of 0.001 to 0.05 mg based on the unit dosage form, and may be contained in an amount of 0.009 to 0.024 mg. In one embodiment of the present invention Thiotropium bromide is included in 0.0217 mg. 0.0217 mg of thiotoluium bromide corresponds to about 0.018 mg of thiotropium. However, the content of thiotropium bromide as an active ingredient may vary depending on various factors such as the subject to be prescribed and the disease state.

Examples of pharmaceutically acceptable salts of thiotropium include the addition salts with pharmaceutically acceptable non-toxic organic and inorganic acids 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.

The thiotropium according to the invention is administered using an inhaler suitable for optimal delivery, in which a dry powder inhaler (DPI) is filled into a cyst or capsule and the cyst is removed using a dry powder inhaler Or by punching in peel capsules and then inhaled by the patient's breathing.

The dry powder for inhalation is very undifferentiated to a particle size of the active ingredient of less than about 5 占 퐉 in order to effectively transfer the active ingredient to the lungs. The undifferentiated particles are thermodynamically unstable due to their large surface area relative to the volume ratio, 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. It has been known in the art to prepare dry powder for inhalation by mixing the active ingredient with an excipient for effective delivery of the active ingredient.

Such excipients include, for example, monosaccharides such as glucose or arabinose; Disaccharides such as lactose, maltose or sucrose; Polysaccharides such as starch, dextrin or dextran; Polyalcohols such as solbitol, manitol or xylitol; And hydrates thereof, but are not limited thereto. According to one embodiment of the present invention, as the excipient, a monosaccharide or a disaccharide may be used, and preferably lactose may be used.

The excipient may be included in an amount of about 2 to 50 mg, specifically about 4 to 20 mg, more specifically 4 to 6 mg, based on the unit dose. 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 an advantage that it is possible to manufacture in a pharmaceutical production factory which can produce general capsules without the need of installing special equipment for inhaler production.

In the capsule for inhalation according to the present invention, the capsule has titanium dioxide (TiO ₂ ) in its base to enhance the delivery amount of the active ingredient in the capsule.

The titanium dioxide may be contained in an amount of 0.1 to 10% by weight based on the total weight of the capsule base, specifically 1 to 9% by weight, more specifically 2 to 7% by weight, 5% by weight. When titanium dioxide is contained in an amount of less than 0.1% by weight, the target-unit transfer amount reaching ratio is low and the amount of active ingredient is low due to the high residual amount of active ingredient in the capsule after inhalation. There are many problems. On the other hand, when titanium dioxide is contained in an amount of 10 wt% or more, the amount of the substance produced from thiotoluium increases and the stability of the active ingredient may deteriorate.

The capsule can be used without limitation as long as it is a general hard capsule used for medicines. For example, a hard capsule containing one selected from the group consisting of gelatin, hydroxypropylmethylcellulose (HPMC) or pluran or a mixture thereof may be used as the main component of the capsule base, preferably gelatin or hydroxypropyl Methylcellulose can be used. According to one embodiment of the present invention, it is more preferable to use HPMC capsules.

The capsule may contain additives used in capsules such as a gelling aid, a pigment, and a pigment in the base. The gelling aid may be selected depending on the type of the gelling agent and may include water-soluble gums. The water-soluble gum may be carrageenan, gellan gum, xanthan gum, pectin, or a mixture thereof. Particularly when kappa carrageenan is used, potassium ion, ammonium ion, calcium ion A water-soluble compound capable of imparting ions such as potassium chloride, ammonium chloride, ammonium acetate, and calcium chloride can be used. When iota carrageenan is used, a water-soluble compound that gives calcium ions such as calcium chloride can be used.

In addition, the capsules used in the present invention may contain plasticizers, emulsifiers or mixtures thereof as other additives in the base. The plasticizer serves to improve the film strength of the capsule, and may be glycerol, sorbitol, propylene glycol, polyethylene glycol, and the like. The emulsifier serves to improve the capsule formability of the composition for making a capsule, and the emulsifier may be sodium lauryl sulfate (SLS), sucrose esters of fatty acids, or a mixture thereof.

The size of the hard capsule that can be used in the present invention can be any size as long as it is a general capsule size used in medicine. The size of the capsule has various internal capacities depending on the lake. For example, the No. 0 capsule is about 0.68 ml, the No. 1 capsule is about 0.47 ml, the No. 2 capsule is about 0.37 ml, the No. 3 capsule is about 0.27 ml, The call capsule is known to have 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 inhalation capsules according to the present invention can 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. Examples of such devices include GSK's ROTAHALER ?, Boehringer Ingelheim's HANDIHALER? And AEROLIZER? Of Plastiape. The HANDIHALER? And AEROLIZER? Have a groove in which a capsule is inserted into a cap of a suction device. When a button is pressed, a pin is pulled out and the capsule is pierced and lifted.

In an embodiment of the present invention, we prepared HPMC capsules for inhalation containing 3 or 5 wt.% Titanium dioxide (Tables 1 and 2) and in an accelerated storage stability test, the activity of the HPMC capsules for inhalation It was confirmed that the amount of the flexible substance derived from the thiotropium as a component is smaller than that of a commercial product containing thiotoluium as an active ingredient (see FIGS. 1 to 3).

Further, in the examples of the present invention, it was confirmed that the inhalation capsule material of the present invention had an excellent delivery ratio of the active ingredient contained in the capsules, that is, an excellent target-unit delivery rate, and a small amount of active ingredient remaining in the capsule after inhalation (See Tables 6 to 9 and Figs. 4 to 5).

In addition, in the embodiment of the present invention, the degree of occurrence of debris was measured when the suction capsule of the present invention was pierced by the suction device, and it was confirmed that the degree of fragmentation per capsule was small (see Table 10).

Hereinafter, the present invention will be described in more detail with reference to the following examples and experimental examples. However, the following examples and experimental examples are provided only for illustrating the present invention, and the scope of the present invention is not limited thereto.

Example  1 to 3: 5% by weight titanium dioxide; TiO ₂ ) ≪ / RTI > (< RTI ID = 0.0 > hydroxypropylmethylcellulose , HPMC ) Preparation of capsules for inhalation using capsules

According to the composition shown in the following Table 1, the active ingredient, tiotropium bromide, and lactose containing 20% by weight of total lactose as fine powdered milk having a size (X50) of about 17 탆 occupying 50% (Respitose? ML006, DFE pharma) were weighed, mixed and mixed in a mixer for about 30 minutes. The obtained mixture was stabilized for about 12 hours or longer, and then filled into HPMC No. 3 capsules containing 5 wt% TiO ₂ using a capsule filling machine. The HPMC capsules containing TiO ₂ were custom-made from Seoheung (Korea).

(Unit: mg) Example 1 Example 2 Example 3 Thiotropium bromide
(Amount of thiotropium contained) 0.0217
(0.018) 0.0217
(0.018) 0.0217
(0.018) Lactose 19.9783 12.4783 5.4783 Gross weight 20.0000 12.5000 5.5000

Example  4 to 6: 3 wt% TiO ₂ Containing HPMC  Preparation of capsule for inhalation using capsule

The inhaled capsules were prepared in the same manner as in Example 1, except that HPMC capsules containing 3% by weight of TiO ₂ were used.

(Unit: mg) Example 4 Example 5 Example 6 Thiotropium bromide
(Amount of thiotropium contained) 0.0217
(0.018) 0.0217
(0.018) 0.0217
(0.018) Lactose 19.9783 12.4783 5.4783 Gross weight 20.0000 12.5000 5.5000

Comparative Example  1 to 3: TiO ₂ Not including HPMC  Preparation of capsule for inhalation using capsule

The inhaled capsules were prepared in the same manner as in Example 1, except that the composition and the HPMC capsules without TiO _{2 shown} in Table 3 were used.

(Unit: mg) Comparative Example 1 Comparative Example 2 Comparative Example 3 Thiotropium bromide
(Amount of thiotropium contained) 0.0217
(0.018) 0.0217
(0.018) 0.0217
(0.018) Lactose 19.9783 12.4783 5.4783 Gross weight 20.0000 12.5000 5.5000

Comparative Example  4 to 6: 10 wt% TiO ₂ Containing HPMC  Preparation of capsule for inhalation using capsule

An inhalation capsule was prepared in the same manner as in Example 1, using the composition and HPMC capsules containing 10% by weight of TiO _{2 shown} in Table 4 below.

(Unit: mg) Comparative Example 4 Comparative Example 5 Comparative Example 6 Thiotropium bromide
(Amount of thiotropium contained) 0.0217
(0.018) 0.0217
(0.018) 0.0217
(0.018) Lactose 19.9783 12.4783 5.4783 Gross weight 20.0000 12.5000 5.5000

Comparative Example  7: Marketed Capsule

A commercially available product, Spiriva Handyhaler (Boehringer Ingelheim), comprising gelatin capsules, containing thiotropium bromide as the active ingredient, was used as Comparative Example 7.

Experimental Example  1: Accelerated Storage Stability Test

The inhalation capsules of Examples 1 to 6 and Comparative Examples 1 to 7 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 repetitive tests using each of the ten formulations.

<Accelerated Storage Test Conditions>

Storage conditions: A1-A1 Storage in blister pack at 60 ℃

Testing time: Early, 5 days, 10 days and 30 days

Analyzed with: Flexible substance from thiotropium BIIH27SE

< Thiotropium Flexible material  Analysis conditions>

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: A solution of 1.0 g of sodium methanesulfonate and 5.0 g of dihydrogenphosphate in 980 ml of purified water, adjusted to pH 3.0 with diluted 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, the change in the content of BIIH27SE derived from thiotropium was shown in Figs.

As shown in Figs. 1 to 3, in the case of Comparative Examples 4 to 6 in which the HPMC capsules containing 10 wt% TiO ₂ were used, the amount of the suppositories was increased with the lapse of time, and Comparative Example 7, It was found that the amount of the flexible substance was remarkably increased. On the other hand, similar enough time in HPMC capsules of Examples 1-6 is lower than the Comparative Examples 4 to 7 containing the that do not contain TiO ₂ HPMC capsules of Comparative Examples 1 to 3, and TiO ₂ to 3 or 5% by weight The amount of the substance increased with the passage of time.

Therefore, from the above results, HPMC capsules containing 5% by weight or less of TiO ₂ do not affect the stability of thiotropium, which is an active ingredient, and exhibit higher stability than commercially available capsules, Respectively.

Experimental Example  2: Test of unit dose of active ingredient

Dosage Unit Sampling Apparatus (DUSA) tests were conducted using 10 inhalation preparations of Examples 1 to 6 and Comparative Examples 1 to 7, respectively. The test method was performed with apparatus B according to the DUSA test item of the inhalation powder in the USP (USP) general test items.

As a result, the thiotropic content inhaled in each of the ten capsules of Examples 1 to 6 and Comparative Examples 1 to 7 and the target-unit-amount-of-arrival ratio of thiotoluium were shown in FIGS. 4 and 5, The average was calculated and shown in Tables 6 and 7 below.

Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Thiotropium
(㎍) 14.4 ± 0.2 14.0 ± 0.2 13.9 ± 0.3 11.2 ± 0.3 11.1 ± 0.3 10.9 ± 0.5 Goal - Unit
Delivery
(10.2 [mu] g)
Reach% 141.2 ± 2.1 137.3 ± 2.0 136.3 ± 2.5 109.8 ± 2.5 108.8 ± 2.9 106.9 ± 4.8

Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Comparative Example 5 Comparative Example 6 Comparative Example 7 Thio
Tropium
(㎍) 10.1 ± 0.4 9.6 ± 0.3 9.5 ± 0.3 10.3 ± 0.7 9.5 ± 0.3 10.3 ± 0.7 10.3 ± 0.7 Goal - Unit
Delivery
(10.2 [mu] g)
Reach ratio
(%) 99.0 + 4.3 95.1 ± 2.6 93.1 ± 2.8 101.0 + - 6.7 93.1 ± 2.8 101.0 + - 6.7 101.0 + - 6.7

As shown in Figures 4 and 5 and Tables 6 and 7, the target-unit delivery rate of thiotropium, the active ingredient of the capsules prepared in Examples 1 to 6 and Comparative Examples 1 to 7, was found to be generally excellent . However, HPMC capsules containing 3 or 5 wt.% Of TiO ₂ have a target-unit transfer rate of about 106 to 141%, no TiO ₂ (Comparative Examples 1 to 3), 10 wt% TiO ₂ Unit delivery rate of the HPMC capsules (Comparative Examples 4 to 6) and the commercial capsule (Comparative Example 7), which is more than about 93 to 101%, which is the target-unit delivery rate.

Thus, HPMC capsules containing from 3 to 5% by weight of TiO ₂ according to the present invention exhibit a high target-unit-delivery-ratio and thus can be used for pharmaceutical applications.

Experimental Example  3: Confirm left over of active ingredient in capsule after inhalation

The capsules used in the DUSA test in Experimental Example 2 were recovered, and the residual amount of the active ingredient in the capsule was measured to calculate the average residual amount of the remaining thiotoluium. The results are shown in Tables 8 and 9 below. Generally, residual amount of active ingredient in capsule after inhalation is known to be less than 3 ㎍.

Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Thiotropium
(㎍) 2.2 ± 0.2 2.1 ± 0.2 2.1 ± 0.2 2.7 ± 0.2 2.7 ± 0.3 2.5 ± 0.2

Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Comparative Example 5 Comparative Example 6 Comparative Example 7 Thiotropium
(㎍) 3.6 ± 0.2 3.5 ± 0.2 3.5 ± 0.2 2.4 ± 0.2 2.3 ± 0.3 2.1 ± 0.3 2.5 ± 0.2

As shown in Tables 8 and 9, in the inhalation preparations prepared in Examples 1 to 6 or Comparative Examples 1 to 7, in the HPMC capsules without the TiO ₂ (Comparative Examples 1 to 3) The remaining amount of the thiothreopiomes was found to be the highest at 3.5 to 3.6 쨉 g, and HPMC capsules (Examples 1 to 6, Comparative Examples 4 to 6) containing TiO ₂ at 3, 5 or 10 wt% And the product (Comparative Example 7) was in the range of about 2.1 to 2.7 占 퐂.

Therefore, it was confirmed that HPMC capsules containing 3 to 10% by weight of TiO ₂ show a low residual amount in capsules after inhalation, and thus can be usefully used in pharmaceutical applications.

Experimental Example  4: Capsule break test (brittleness test)

In order to confirm the degree of breakage of the capsules containing 5 or 3 wt% of TiO ₂ , break tests were carried out using 20 capsules prepared in Examples 3 and 6 and Comparative Examples 3, 6 and 7 The extent of fragmentation was measured.

The device for the break test was carried out in Examples 1 to 6 and Comparative Examples 1 to 6 with its inhaler device and Comparative Example 7 with HANDIHALER ?, and in the case of inhalation, the device was performed three times with the strength to punch the capsules. In addition, the humidity was maintained at 40 to 60% during the test.

The results are shown in Table 10 below by calculating the average of three runs.

Example 3 Example 6 Comparative Example 3 Comparative Example 6 Comparative Example 7 Degree of fragmentation 0.7 pieces / capsule 0.8 capsules / capsule 1.9 capsules / capsule 0.5 capsules / capsule 4.3 pieces / capsule

As shown in Table 10, HPMC capsules (Examples 3 and 6) containing 3 or 5 wt% TiO _{2 produced} about 0.7 to 0.8 fragments per capsule, whereas capsules without TiO ₂ (Comparative Example 3 ) Was 1.9 pieces per capsule, and that of commercial capsule (Comparative Example 7) was 4.3 pieces per capsule. On the other hand, HPMC capsules containing 5 wt% TiO ₂ had 0.5 fragments per capsule, resulting in the lowest occurrence of debris.

Therefore, it was confirmed that the HPMC capsule containing TiO ₂ of the present invention had a significantly smaller fragmentation per capsule than a capsule commercially available in the cracking test, and thus it could be used for pharmaceutical applications.

Claims (9)

A cosmetic composition comprising tiotropium or a pharmaceutically acceptable salt thereof as an active ingredient and titanium dioxide (TiO ₂ ) in an amount of 0.1 to 10% by weight, based on the total weight of the capsule base, Wherein the capsules are in the form of tablets.
The inhalation capsule according to claim 1, wherein the pharmaceutically acceptable salt of thiotoluium is tiotropium bromide.
The inhalation capsule according to claim 1, wherein the thiotoluium is packed at 0.001 to 0.05 mg per unit dosage form.
The inhalation capsule according to claim 1, wherein the thiotoluium is filled in the form of a dry powder.
delete The inhalation capsule according to claim 1, wherein the titanium dioxide is contained in an amount of 3 to 5% by weight based on the total weight of the capsule base.
[Claim 7] The capsule according to claim 1, wherein the capsules are hydroxypropylmethylcellulose (HPMC) or gelatin as a main component of the capsule base.
The inhalation capsule of claim 1, wherein the capsule agent further comprises a pharmaceutically acceptable additive selected from the group consisting of a diluent, a disintegrant, a binder, a stabilizer, a lubricant, a colorant, and mixtures thereof.
The inhalation capsule according to claim 1, wherein the capsule further contains lactose as an excipient.

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