KR101278572B1 - Pharmaceutical combinations of leukotriene antagonist and epinastine and their preparing methods - Google Patents

Abstract

The present invention comprises a leukotriene antagonist and efinastin as an active ingredient, at least one of these two active ingredients comprises a pharmaceutical unit (pharmaceutical unit) having an environment separate from the other active ingredient (leucotriene antagonist) The present invention relates to a composite formulation of efinnastin and a method for producing the same.
The combination preparation has excellent dissolution rate and bioavailability of the leukotriene antagonist, and furthermore, the two active ingredients can be used very effectively for the prevention or treatment of bronchial asthma by exerting synergistic eosinophil reduction or airway hypersensitivity inhibitory effect. .

Description

Pharmaceutical combinations of leukotriene antagonist and epinastine and their preparing methods}

The present invention relates to a combination preparation of leukotriene antagonist and efinastin, and a method for preparing the same. More specifically, the present invention includes leukotriene antagonist and efinastin as an active ingredient, and among these two active ingredients. At least one is composed of a pharmaceutical unit having an environment separate from the other active ingredient, so that the dissolution rate and bioavailability of the leukotriene antagonist are excellent, and the two active ingredients are mutually synergistic eosinophils. The present invention relates to a combination formulation and a method for producing the same, which are very useful for the prevention or treatment of bronchial asthma by exerting a reducing and airway hypersensitivity effect.

In general, asthma patients are prevented or treated by airway obstruction by administering steroid preparations or beta-2 agonists in the form of inhalants as the primary treatment. However, in the case of the steroid preparations, there is a possibility that side effects such as poor growth, decreased bone density, immune deficiency, as well as resistance during long-term use. In addition, the beta-2 agonist expresses a quick effect, but also has a problem in that the treatment effect in an emergency due to the occurrence of resistance falls. Furthermore, all of the above inhalants have limitations in that the drug is difficult to be delivered to the bronchioles in the human body, and thus the drug is not sufficiently exerted.

In order to improve this problem, a leukotriene antagonist, an oral agent for inhibiting bronchial inflammation, is used in combination as an adjuvant therapy for the inhalants. However, since these leukotriene antagonists alone do not have sufficient effect on improving bronchial inflammation, efforts have been made to improve and supplement them.

As part of this effort, International Publication No. WO1999 / 32125 (published on July 1, 1999) discloses pharmaceutical compositions comprising leukotriene antagonists and antihistamines as active ingredients and therapeutic uses for bronchial asthma. The patent discloses montelukast, franlukast, zafirlukast and the like as a leukotriene antagonist, and cetirizine, fexofenadine, evastin, astemisol, nolastemizole, epinastine, epleti as anti-histamines. Lysine and the like are shown.

However, in this patent, among the various leukotriene antagonists and antihistamines, which component and which combination shows the most synergistic pharmacological effect, and when the combination of specific components with each other, what side effects can be found in the pharmaceutical formulations? Furthermore, no specific data are available on the extent of therapeutic effects associated with bronchial asthma.

International Publication WO1999 / 32125 (published date 1999. 07. 01.)

The inventors of the present invention were studying the combination of leukotriene antagonist and antihistamine as an active ingredient for bronchial asthma prevention and treatment, and showed the positive synergistic pharmacological effect when using epinastine as antihistamine. In the formulation process, a simple mixing of leukotriene antagonist and epinastine and the contact of these two components in the same formulation led to the negative finding that the leukotriene antagonist aggregated with each other and the dissolution rate of the leukotriene antagonist rapidly decreased.

Accordingly, the technical problem to be solved by the present invention is to find a combination of the most pharmaceutically effective ingredients in a combination preparation using a leukotriene antagonist and an antihistamine as an active ingredient, and further prevents the two active ingredients from contacting each other By providing an environment separated from the above, it is a conclusion to provide a composite formulation and a method for producing the same, which is very excellent in dissolution rate and bioavailability of the active ingredient.

Another problem to be solved by the present invention is to provide a combination of leukotriene antagonist and efinastin and a method for producing the same that can be useful for the prevention or treatment of bronchial asthma, excellent in eosinophil reduction and airway hypersensitivity effect.

The combination formulation of the leukotriene antagonist and epinastine according to the present invention includes a leukotriene antagonist and epinastine as an active ingredient, wherein at least one of these two active ingredients has a separate environment from the other active ingredient. It is characterized by consisting of (pharmaceutical unit).

The combination preparations are characterized by having eosinophil reduction and airway hypersensitivity inhibitory effects.

The pharmaceutical unit is characterized in that it is in the form of coating powder, granules, granules, beads, microcapsules, pellets or core tablets.

The pharmaceutical unit is characterized in that it is separated into an inert layer or an inert membrane.

The inert layer or inert membrane may be an inert coating or an enteric coating.

In the above, the leukotriene antagonist is characterized in that any one or more selected from montelukast, (Pranlukast), Zafirlukast (zafirlukast).

More specifically, the pharmaceutical unit is characterized in that the granules comprising at least one of montelukast sodium and microcrystalline cellulose, lactose hydrate, crospovidone and hydroxypropyl cellulose.

The pharmaceutical unit is characterized in that the granules comprising at least one of epinastine hydrochloride and microcrystalline cellulose, lactose hydrate, crospovidone, hydroxypropyl cellulose, colloidal silicon dioxide and magnesium stearate.

The pharmaceutical unit is characterized in that the core tablet comprising any one or more of epinastine hydrochloride and microcrystalline cellulose, lactose hydrate, crospovidone, colloidal silicon dioxide and magnesium stearate.

In addition, a method for preparing a leukotriene antagonist and an epinastine co-formulation according to a first embodiment of the present invention comprises the steps of preparing a first granule comprising a leukotriene antagonist; Preparing a second granule comprising efinastin; Tableting multi-layer tablets each comprising the first and second granules; Characterized in that consists of.

According to a second embodiment of the present invention, a method for preparing a leukotriene antagonist and an epinastine complex preparation includes the steps of preparing a granule comprising a leukotriene antagonist; Preparing a mixed powder comprising efinastin; Compressing the granules first and then compressing the mixed powder on the second to compress them into bilayer tablets; .

Since the co-formulation according to the present invention has a pharmaceutical environment in which the active ingredient leukotriene antagonist and epinastine are separated from each other, it is possible to prevent agglomeration of the leukotriene antagonist caused by the contact between these two components. Can be.

Therefore, the dissolution rate and bioavailability of the leukotriene antagonist are excellent, and furthermore, the two active ingredients exert synergistic eosinophilic reduction and airway hypersensitivity effect, which can be very useful for the prevention or treatment of bronchial asthma.

1 is a graph showing the montelukast dissolution rate in a composite formulation according to an embodiment of the present invention in comparison with a comparative example,
Figure 2 is a graph showing the blood concentration of montelukast in the combination preparation according to Example 2 of the present invention in comparison with a commercially available product.

The combination preparation of a leukotriene antagonist and epinastine according to the present invention is characterized in that at least one of the two active ingredients is composed of a pharmaceutical unit having an environment separated from the other active ingredient. That is, only the active ingredient of any one of the leukotriene antagonist and efinastin may be composed of the pharmaceutical unit, and the leukotriene antagonist and efinastin may be each composed of the pharmaceutical unit.

As described above, when the leukotriene antagonist and epinastine contact each other in one unit formulation, the leukotriene antagonist aggregates with each other, and the dissolution rate rapidly decreases. The pharmaceutical unit thus functions to prevent contact with two active ingredients in one formulation unit.

Preferred forms of the pharmaceutical unit, which is a feature of the present invention, may illustrate coated powders, granules, fines, microcapsules, pellets, beads, core tablets, etc., but are not limited thereto. Alternatively, any form of pharmaceutical unit may be used as long as it can achieve the object of the present invention.

In addition, in the present invention, a boundary consisting of an inert ingredient such as an inert layer or an inert membrane may be disposed between the two active ingredients to prevent contact between the two active ingredients. For example, one of the leukotriene antagonist and epinastine may be coated with a general coating or an enteric substrate to form a time-release sustained-release formulation for differently controlling the dissolution sites of the two active ingredients.

In the preparation method of the composite preparation according to the present invention, first, an independent pharmaceutical unit is prepared by using a conventional direct method, a dry method, a wet method, an extrusion method, a fluidized bed method, and the like, and then a conventional method using the pharmaceutical unit. To form capsules, single tablets, bilayers or triple layers, or multi-layer tablets in the form of a core, coated tablets, enteric coated tablets, film formulations and the like.

In the present invention, the leukotriene antagonist is selected from montelukast, franlukast or zafirlukast. And the preferred dosage is 1 to 2 times a day, it is preferable to take 4 to 10 mg of montelukast sodium once. Other doses of franlukast or zafirlukast are taken at conventional dosages. In addition, it is preferable to use the hydrochloride as efinastin, and the content is preferably taken 1 to 2 times a day, but preferably 5 to 20 mg at a time.

Hereinafter, preferred examples and experimental examples of the present invention are presented. However, these Examples and Experimental Examples are provided only to assist in understanding the present invention, and the scope of the present invention is not limited by these Examples and Experimental Examples.

Example 1 Preparation of capsules Using the wet granulate

In a speed mixer, 208 g of montelukast sodium, 770 g of microcrystalline cellulose, 1,838 g of lactose hydrate, and 80 g of crospovidone were mixed, and 84 g of hydroxypropyl cellulose was dissolved in purified water, followed by mixing again. The mixture thus obtained was dried and granulated to prepare wet granules, to which 20 g of magnesium stearate was added as a lubricant (hereinafter, referred to as 'first granules').

Separately, 400 g of efinastin hydrochloride, 600 g of microcrystalline cellulose, 1,888 g of lactose hydrate, and 32 g of crospovidone were mixed in a speed mixer, and a binder solution prepared by dissolving 60 g of hydroxypropyl cellulose in purified water was added and mixed again. The mixture thus obtained was dried and granulated to prepare wet granules, to which 20 g of magnesium stearate was added as a lubricant (hereinafter referred to as 'second a granule').

The 1a granules and the 2a granules were mixed in a weight ratio of 1: 1, and then filled with 300 mg per capsule to prepare a hard capsule. The capsules contained 10 mg of montelukast sodium and 20 mg of efinastin hydrochloride per capsule.

[Example 2] Manufacture of the bilayer tablets using a wet granulation water

In the same manner as in Example 1, the first a granule containing montelukast and the second a granule containing efinastin were prepared.

150 mg of the first granules were first compressed using a bilayer tablet press, and then 150 mg of the second granules were placed in the upper portion thereof to prepare a bilayer tablet. The tablet contained 10 mg of montelukast sodium and 20 mg of efinastin hydrochloride per tablet.

Example 3 The mixed powder Preparation of Bilayer Tablets Used

In a speed mixer, 36.4 g of montelukast sodium, 309.8 g of microcrystalline cellulose, 309.8 g of lactose hydrate, and 21 g of croscarmellose sodium were mixed, and 19.6 g of hydroxypropyl cellulose was dissolved in purified water. . The mixture thus obtained was dried and granulated to prepare wet granules, and then 3.5 g of magnesium stearate was added thereto as a lubricant (hereinafter, referred to as 'firstb granules').

Separately, 700 g of epinastin hydrochloride, 271.3 g of microcrystalline cellulose, 235.6 g of lactose hydrate, and 5.6 g of crospovidone were mixed in a plastic bag, and 9.1 g of colloidal silicon dioxide and 3.5 g of magnesium stearate were added and mixed again. (Hereinafter referred to as 'the second b mixture').

First, 200 mg of the first b granules were first compressed using a bilayer tablet press, and then 170 mg of the second b mixture was put on the top thereof to prepare a double layer tablet.

Example 4 Preparation of bilayer tablets using a dry granulate

In a plastic bag, 100 g of efinastin hydrochloride, 387.5 g of microcrystalline cellulose, 336.5 g of lactose hydrate, and 8 g of crospovidone were mixed, and 13 g of colloidal silicon dioxide and 5 g of magnesium stearate were added and mixed again. The mixture thus obtained was compressed to a pressure of 4 MPa in a roller compactor to prepare a plate compact, which was then ground and granulated in an oscillator to produce dry granules (hereinafter referred to as 'second c granules'). ).

150 mg of the first granules 1a prepared in Example 1 were first compressed using a double-layer tablet press, and then 170 mg of the second c granules were put into the upper end thereof to prepare a bilayer tablet.

Example 5 Preparation of a triple layer tablets

In the same manner as in Example 1, the first a granule containing montelukast and the second a granule containing efinastin were prepared.

Separately, 395 g of lactose and 100 g of microcrystalline cellulose were mixed, and 5 g of magnesium stearate was mixed thereto to prepare an inert mixture.

A triple layer tablet was prepared by inserting 100 mg of the inert mixture between 150 mg of the first granules and 150 mg of the second granules using a triple layer tablet press.

Example 6 Preparation of tablets using a fluidized bed coater

First, an active coating solution containing 52 g of montelukast sodium, 175 g of hydroxypropyl methylcellulose, 25 g of polyethylene glycol 6000, and 15 g of talc in a methylene chloride-ethanol mixed solution; An inert coating solution was prepared in which 25 g of 6000 and 15 g of talc were dissolved.

Separately, 437 g of microcellac was added to a fluidized bed coater, and the active coating solution was sprayed therein to prepare granules, and then the inactive coating solution was sprayed again on the inert granules.

100 g of epinastine hydrochloride, 187.5 g of microcrystalline cellulose, 163.5 g of lactose hydrate, 32.5 g of crospovidone, and 12.5 g of magnesium stearate were added to the inert granules, and the mixture was sufficiently mixed. It was.

Example 7 Preparation of press-coated tablet

In a speed mixer, 20.8 g of montelukast sodium, 245.2 g of microcrystalline cellulose, 495.6 g of lactose hydrate, and 20 g of croscarmellose sodium were mixed, and 14.4 g of hydroxypropyl cellulose was dissolved in purified water. . The mixture thus obtained was dried and granulated to prepare wet granules, to which 4 g of magnesium stearate was added as a lubricant (hereinafter, referred to as 'first c granules').

Separately, 200 g of efinastin hydrochloride, 250 g of microcrystalline cellulose, 527 g of lactose hydrate, and 5 g of crospovidone were mixed in a plastic bag, 13 g of colloidal silicon dioxide and 5 g of magnesium stearate were added and mixed again. The resulting mixture was compressed into tablets at 100 mg per tablet to prepare a nuclear tablet. One tablet of the core tablet contained 20 mg of efinastin hydrochloride.

150 mg of the 1c granules were placed in a die cavity of a tableting machine, 1 tablet of the core tablet was placed at the center thereof, and then 250 mg of the 1c granules were placed thereon, and 1 ton of carbpress was used. Pressurized to produce a nucleated tablet.

[ Comparative example  One]

In a plastic bag, 20.8 g of montelukast sodium, 177 g of microcrystalline cellulose, 342.2 g of lactose hydrate, 12 g of crospovidone, and 40 g of epinastine hydrochloride were mixed, and 2 g of colloidal silicon dioxide and 6 g of magnesium stearate were added and mixed again. . The mixture thus obtained was filled with 300 mg per capsule to prepare a hard capsule. The capsules contained 10 mg of montelukast sodium and 20 mg of efinastin hydrochloride per capsule.

[ Comparative example  2]

After the mixture was prepared in the same manner as in Comparative Example 1, the mixture was tableted to 300 mg per tablet to prepare a tablet. The tablet contained 10 mg of montelukast sodium and 20 mg of efinastin hydrochloride per tablet.

[ Comparative example  3]

In a plastic bag, 31.2 g of montelukast sodium, 264 g of microcrystalline cellulose, 286.8 g of lactose hydrate, and 9 g of crospovidone were mixed, followed by addition of 3 g of colloidal silicon dioxide and 6 g of magnesium stearate, followed by mixing again. ').

Separately, 60 g of efinastin hydrochloride, 75 g of microcrystalline cellulose, 447 g of lactose hydrate, and 9 g of crospovidone were mixed in a plastic bag, followed by addition of 3 g of colloidal silicon dioxide and 6 g of magnesium stearate, followed by mixing again. 2d mixture).

A first compression of 200 mg of the 1d mixture was first performed using a double-layer tablet press, and then 200 mg of the 2d mixture was added to the upper portion thereof to prepare a double layer.

[Example 1] asthma-related inflammation, and improving effect on airway sensitivity

20 mg of aluminum hydroxide and 100 μm of ovalbumin (OVA) were mixed in a 0.2 ml saline solution and administered intraperitoneally to Balb / c mice on the day (D0) and day 14 (D14), respectively. (IP) and OVA sensitization was performed.

Subsequently, D15, D16, and D17 were classified into seven test groups of 10 mice each, and no test drug was administered to one test group one hour before the OVA challenge (challenge). After administering an experimental drug such as 1, 150 μm / 50 μl of OVA was intranasally administered to challenge asthma.

Types and dosages of test drugs administered to each test group division Administered Test Drug Dosage (mg / kg / day) Normal group  none -

asthma
Trigger group

 none - Dexamethasone 3 Montelukast 0.5 Efinastin 0.5 Levocetrizine 0.5 Montelukast + Epineast 0.5 + 0.5 Montelukast + Levocetirizine 0.5 + 0.5

In each group, airway hypersensitive response (AHR) was measured by measuring whole body plethysmography and the enhanced pause (method) for methacholine using an airway resistance meter in each experimental group. Eosinophil count in the wash solution (BALF: Broncho Alveolar Lavage Fluid) was measured to confirm the degree of inflammation improvement.

The test results are listed in Table 2 below in comparison with the test group which did not receive the test drug among the normal group and the asthma-induced group that did not cause asthma.

Reduction of eosinophil count and inhibitory airway hypersensitivity in BALF division Administered Test Drug Eosinophil count (x10 ⁵ / ml) Pehn * Normal group  none 0.01 2.47

asthma
Trigger group

 none 14.10 3.86 Dexamethasone 0.20 3.07 Montelukast 10.48 3.95 Efinastin 11.12 3.80 Levocetrizine 13.96 4.01 Montelukast + Epineast 7.02 2.92

In Table 2, whole body plethysmography and the enhanced pause (Pehn) means one of the airway hypersensitivity indexes of mouse asthma.

As shown in Table 2, as a result of confirming airway inflammation and airway hypersensitivity through eosinophil count in bronchoalveolar lavage fluid (BALF) in the short-term asthma model using Balb / c mice, first administered dexamethasone (dexamethasone) as a positive control In one experimental group, the number of eosinophils was significantly reduced compared to the asthma-induced group that did not receive the experimental drug.

In addition, when comparing the experimental group administered alone with montelukast, efinastin and levocetrizine as experimental drugs, and the experimental group administered with montelukast and efinastin in accordance with the present invention, the combined dose group was compared to the eosinophil count compared to the single dose group. The results showed a markedly increased inhibitory effect on reduction and airway hyperresponsiveness.

In particular, when montelukast and efinastin were used alone in airway hypersensitivity evaluation, they did not show any significant effect, but when they were administered in combination, the Pehn value was 2.92, indicating an excellent synergistic effect.

[Example 2] Comparative dissolution profile test

For each of the formulations prepared in Examples and Comparative Examples, the dissolution test was performed at a rotational speed of 50 rpm using a paddle method using 900 mL of purified water as the eluent. About 5 mL each was taken at 5, 10, 15, and 30 minutes after the start of the dissolution test, filtered through a membrane filter, discarded 3 mL, the remaining 1 mL was taken, and then subjected to high performance liquid chromatography (HPLC). Dissolution rate was analyzed.

First, the area values of the peaks corresponding to efinastin hydrochloride and montelukast sodium were integrated to calculate the concentration of each component. The dissolution rate (%) of each component is 100% of the concentration when all of the efinastin hydrochloride and montelukast sodium contained in the tablet are dissolved in the eluate. Represented by.

Separately, dissolution test for commercially available `` Singulair Tab. '' (Product of Singulair tab. Proceed to the results are shown in Table 3 and Table 4.

Dissolution Rate of Montelukast (%) Division (min) 0 5 10 15 30 Singulare Tablets 0.0 42.1 77.4 75.3 75.4 Example 1 0.0 31.5 43.3 53.3 55.9 Example 2 0.0 22.2 41.4 58.1 78.1 Example 3 0.0 24.8 41.9 57.7 68.3 Example 4 0.0 32.5 50.2 49.7 49.4 Example 5 0.0 31.8 51.7 64.7 72.3 Example 6 0.0 8.3 22.5 47.3 57.7 Example 7 0.0 27.4 42.6 55.2 59.8 Comparative Example 1 0.0 7.2 4.3 2.3 2.1 Comparative Example 2 0.0 1.8 1.2 2.1 1.7 Comparative Example 3 0.0 6.0 3.2 2.5 1.9

Elution Rate of Epineast (%) Division (min) 0 5 10 15 30 Allegion tablets 0.0 18.8 72.9 96.7 96.9 Example 1 0.0 35.0 69.4 77.5 82.0 Example 2 0.0 64.5 75.8 78.1 89.1 Example 3 0.0 21.5 63.3 76.3 84.3 Example 4 0.0 37.2 61.3 65.9 73.8 Example 5 0.0 49.7 72.8 76.8 82.0 Example 6 0.0 48.9 78.3 84.4 84.5 Example 7 0.0 10.8 61.4 80.6 91.1 Comparative Example 1 0.0 51.1 69.5 73.0 72.7 Comparative Example 2 0.0 41.8 68.1 75.9 73.6 Comparative Example 3 0.0 56.7 79.2 76.2 73.7

As shown in Table 3 and Table 4, in the case of montelukast, the composite formulation of the present invention does not reach the dissolution rate of the singular tablet, which is a single formulation, but shows an excellent dissolution rate compared to the comparative example. In addition, it can be seen that the dissolution rate decreases over time due to recrystallization, which is a characteristic of poorly soluble drugs. On the other hand, efinastin did not show much difference between the examples and the comparative examples.

[Example 3] The comparative bioavailability

First, five healthy volunteers were sampled on an empty stomach to confirm that there was no montelukast blood residual. After the volunteers were separated into two experimental groups, one tablet of the bilayer tablet (test drug) and the commercially available 'Singulare tablet' (control drug) prepared according to Example 2 were taken, respectively, and after 2 hours and 6 hours, respectively. Blood was collected and the concentration of montelukast in the blood was measured.

Then, after two weeks, the concentration of montelukast was measured in the same manner after cross-administration of the test drug and the control drug for each experimental group, and the results are shown in FIG. 2.

As confirmed in FIG. 2, the combination formulation of montelukast and efinastin according to the present invention was confirmed to maintain a blood concentration almost similar to a single formulation of singular tablets.

Claims (11)

Montelukast and epinastine as active ingredients, at least one of these two active ingredients being coated powders, granules, granules, beads, micros having an environment separate from the other active ingredient A combination formulation of a leukotriene antagonist and efinastin, comprising a pharmaceutical unit in the form of a capsule, pellet, or core tablet.
The combination formulation of leukotriene antagonist and efinastin according to claim 1, wherein the combination formulation has an effect of reducing eosinophils and inhibiting airway hypersensitivity.
delete The combination formulation of leukotriene antagonist and efinastin according to claim 1, wherein the pharmaceutical unit is separated into an inert layer or an inert membrane of an inert coating or an enteric coating.
delete delete 2. The complex of leukotriene antagonist and efinastin according to claim 1, wherein the pharmaceutical unit is a granule comprising montelukast sodium and at least one of microcrystalline cellulose, lactose hydrate, crospovidone and hydroxypropyl cellulose. Formulation.
The method according to claim 1, wherein the pharmaceutical unit is a granule comprising an epiastine hydrochloride and any one or more of microcrystalline cellulose, lactose hydrate, crospovidone, hydroxypropyl cellulose, colloidal silicon dioxide and magnesium stearate A combination preparation of a leukotriene antagonist and epinastine.
The method of claim 1, wherein the pharmaceutical unit is a core tablet comprising any one or more of epinastine hydrochloride, microcrystalline cellulose, lactose hydrate, crospovidone, colloidal silicon dioxide and magnesium stearate. A combination preparation of a leukotriene antagonist and efinastin. delete delete

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