KR20210012082A - A pharmaceutical composition comprising mirabegron and tamsulosin - Google Patents

Abstract

The present invention relates to a complex refining composition comprising mirabegron and tamsulosin and, more specifically, to a complex refining composition capable of dramatically improving convenience of taking by a patient.

Description

Pharmaceutical composition comprising mirabegron and tamsulosin {A pharmaceutical composition comprising mirabegron and tamsulosin}

The present invention relates to a combination composition for controlling release for the prevention or treatment of urinary diseases, including mirabegron and tamsulosin.

Overactive bladder sydrome (OAB) refers to symptoms of frequent (more than 8 times a day) unbearable urinary urination without any other special disease and frequent urination even during sleep. According to the definition of the International Society of Urinary Incontinence, an overactive bladder has no urinary tract infection and no other obvious disease, with or without urinary incontinence (a symptom of unbearable cramping when urinating is tired) while feeling urinary urgency (strong and sudden urinary intention). It is defined as a case where there is an unbearable symptom when urinating is difficult), and frequent urination and nocturia (urinating during the night sleep time) are accompanied.

Drugs commonly used as treatments for irritable bladder syndrome are anticholinergics (parasympathetic inhibitors) or beta-3 agonists, oxybutynin, trospium, tolterodine, solifenacin ), Mirabegron, etc. are used.

Recently, in order to treat irritable bladder syndrome, a co-administration method of mirabegron, an overactive bladder treatment, and tamsulosin, a treatment for benign prostatic hyperplasia (BPH), has been studied.

Mirabegron is used as a beta-3 agonist class of irritable bladder syndrome treatment, and has the structure of Formula 1:

[Formula 1]

Tamsrosine is used as a therapeutic agent for prostatic hyperplasia, and has the structure of Formula 2:

[Formula 2]

In general, when developing a combination formulation containing two or more active ingredients, in order not to deteriorate the stability of each active ingredient, the decomposition of each active ingredient is minimized, and the generation of related substances is suppressed, while storage stability. The excipients that enable them to be formulated should be selected and formulated.

However, in reality, excipients known to not impair the stability of any one active ingredient may adversely affect the stability of other active ingredients. Therefore, even if it is already being used as an excipient in any one active ingredient, each active ingredient does not impair the stability even in the formulation of a combination formulation, and each active ingredient has the same dissolution and pharmacokinetic (PK) profile as in a single formulation There is no guarantee that it will exert an equivalent medicinal effect by making it appear.

In particular, in the case of manufacturing a composite matrix formulation in the form of a single-layer tablet with the same composition as the composition of the conventional Mirabegron sustained-release tablet and the tamsulosin sustained-release tablet, the elution pattern in the single-layered tablet is a single drug containing only Mirabegron and a tamsulo. It was found that the dissolution pattern of the single drug containing only Shin appeared differently, and the stability of the combined drug was not secured.

Accordingly, the present inventors studied to develop a multi-layered tablet-type composite agent in which each main component was separated. Even in the case of a multi-layered tablet composite agent, the dissolution rate of the main component was delayed depending on the type of the sustained-release agent used in each layer and the layer separation phenomenon. Problems such as appearing were found. These phenomena did not occur in the case of manufacturing the composite agent into a three-layer tablet including an inert intermediate layer, but a new tableting device is required to manufacture a three-layer tablet.

Accordingly, the present inventors developed a composite formulation that can be manufactured with a double-layer tablet tablet press, but as a result of a study to develop a composite formulation that does not cause the above problems, as a multi-layered tablet composite formulation including both tamsulosin and mirabegron , It was confirmed that the dissolution and PK profile equivalent to that of the control single formulation was shown, and at the same time, it was physicochemically stable, and the delamination phenomenon did not appear, and it was confirmed that a combination formulation having excellent hardness and low friability can be prepared. Completed.

Korean Patent Registration No. 10-0506568

An object of the present invention is to provide a controlled-release pharmaceutical composition, which is a combination formulation comprising Mirabegron and tamsulosin, which is stable and exhibits a dissolution rate and PK profile equivalent to that of a single formulation. In addition, the present invention is to provide a controlled release pharmaceutical composition as a multi-layered tablet, excellent hardness, low friability, and does not exhibit an interlayer separation phenomenon.

In order to achieve the above object, the present invention is a first layer containing tamsulosin or a pharmaceutically acceptable salt thereof; And it provides a controlled-release tablet composition for preventing and treating urinary diseases comprising a second layer containing Mirabegron or a pharmaceutically acceptable salt thereof.

Here, it is preferable that the second layer containing Mirabegron or a pharmaceutically acceptable salt thereof contains a sustained-release base. As a sustained-release base that can be used in the second layer, polyethylene oxide, methyl cellulose, ethyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl ethyl cellulose, poly Vinyl acetate, polyvinyl alcohol, polymethacrylate, glyceryl stearate, hydrogenated vegetable oil, poloxamer, carbomer, alkyl hydroxypropylmethylcellulose, sodium carboxymethylcellulose, povidone and its derivatives, corn starch, potato starch, gelatinization Starch and its derivatives, hydroxyethyl starch, dextrin and its derivatives, dextran, maltodextrin, cyclotextin, polydextrose, alginate or its derivative, natural gum, synthetic gum, casein, gelatin, collagen, protamine, zein, poly Acrylamide, polyvinyl acetal diethylamino acetate, glucomannan, glucosamine, arabinogalactan, percelleran, fluran, chitosan, chitin, agar, pectin and carrageenan one or more selected from the group consisting of can be used.

In addition, it is preferable that the first layer containing tamsulosin or a pharmaceutically acceptable salt thereof in the present invention includes a sustained-release base. As the sustained-release base of the first layer, one or more selected from the group consisting of hydroxypropylmethylcellulose, ethylcellulose, hypromellose phthalate, hypromellose acetate succinate, and methacrylic acid copolymer may be used. have.

In the present invention, the first layer or the second layer may further include a lubricant, and may further include any one or more of a diluent, a binder, a disintegrant, or a colorant in a conventional amount.

As the lubricant that can be used in the present invention, at least one selected from the group consisting of magnesium stearate, stearic acid, sodium stearyl fumarate, talc, glyceryl behenate, colloidal silicon dioxide, light anhydrous silicic acid and hydrogenated vegetable oil can be used. have. Particularly, when glyceryl behenate or glyceryl behenate and magnesium stearate are used together as a lubricant, a two-layer tablet having excellent hardness and low abrasion can be manufactured to prevent a delamination phenomenon.

The diluent, binder, disintegrant or colorant that can be used in the present invention is not particularly limited as long as it is pharmaceutically acceptable.

For example, as the diluent, lactose, starch, microcrystalline cellulose, mannitol, anhydrous calcium hydrogen phosphate or carboxymethyl cellulose may be used.

As the binder, for example, povidone, hypromellose or hydroxypropyl cellulose may be used.

As the disintegrant, for example, crospovidone, croscarmellose sodium, sodium starch glycolate, low-substituted hydroxypropyl cellulose (L-HPC), corn starch, and the like may be used.

As the colorant, for example, titanium oxide or iron sulfate may be used.

In addition, in the present invention, one or more inert intermediate layers may be further included between the first layer and the second layer. Herein, the inert intermediate layer refers to a layer made of any inert excipient (additive) without including a pharmacologically active ingredient.

In the present invention, the content of the sustained-release base of the first layer may be 5 to 30% by weight of the total weight of the first layer, and the content of the sustained-release base of the second layer is of the total weight of the second layer. It may be 5 to 70% by weight.

While the tablet composition according to the present invention contains two active ingredients at the same time, the dissolution pattern and PK profile of each active ingredient are equivalent to the dissolution pattern and PK profile of the single formulation of each active ingredient, and thus, can exhibit equivalent pharmacological effects. Therefore, the present invention can dramatically improve the convenience of taking the patient.

In addition, the tablet composition according to the present invention is a multi-layered tablet, has high hardness and low friability, and does not exhibit an interlayer separation phenomenon.

The tablet composition according to the present invention can be used for preventing or treating irritable bladder syndrome, or for simultaneous prevention and treatment of dysuria and irritable bystander syndrome caused by benign prostatic hypertrophy.

1 is a graph showing the results of a tamsulosin dissolution test at pH 7.2 for the tablets of Examples 3 and 4 and a single-component reference drug.
2 is a graph showing the results of the Mirabegron dissolution test for the tablets of Examples 7 and 8 and the reference drug of a single component.

Hereinafter, examples and experimental examples will be described in detail to aid understanding of the present invention. However, the following Examples and Experimental Examples are for illustrative purposes only, and the scope of the present invention is not limited to the following Examples and Experimental Examples. Examples and experimental examples of the present invention are provided to more completely describe the present invention to those of ordinary skill in the art.

Example 1: Test on the basis of setting the amount of raw material

(1) Confirmation of the interaction and suitability of tamsulosin and mirabegrones with excipients

<Test method>

After mixing tamsulosin (hereinafter, main ingredient 1), Mirabegron (hereinafter, main ingredient 2) and the excipients of Table 1 below to a weight ratio of 1:1:1, the initial content was checked, and an accelerated test (temperature 45°C) , RH 75%, period 1 month), and the interaction and compatibility between the active ingredient and the excipient were confirmed by a content test.

For example, when testing microcrystalline cellulose, tamsulosin, mirabegron, and microcrystalline cellulose were weighed 1 g each and mixed in a powder state, and then an accelerated test was performed on the mixture.

The test results are shown in Table 1 below:

additive Initial content test (%) Content test after accelerated test (%) standard result
Main ingredient 1 result
Main ingredient 2 Judgment standard result
Main ingredient 1 result
Main ingredient 2 Judgment Microcrystalline cellulose 95~105 100.1 99.9 fitness 95~105 99.9 99.8 fitness Prosolve Easy Top 95~105 99.1 99.5 fitness 95~105 99.6 99.3 fitness Prosolve 95~105 100.5 99.7 fitness 95~105 99.9 99.5 fitness Rudy Press 95~105 99.1 99.7 fitness 95~105 99.4 100.2 fitness Low-substituted hydroxypropyl cellulose 95~105 100.4 100.1 fitness 95~105 99.8 99.7 fitness Lactose hydrate 95~105 99.5 99.4 fitness 95~105 99.9 99.7 fitness Crospovidone 95~105 99.1 99.7 fitness 95~105 99.7 99.3 fitness Croscarmellose Sodium 95~105 99.5 99.6 fitness 95~105 97.5 99.3 fitness Aerosil 95~105 100.2 100.0 fitness 95~105 100.1 99.5 fitness Sodium starch glycolate 95~105 100.3 100.1 fitness 95~105 100.1 99.4 fitness Star Cap 1500 95~105 100.8 100.1 fitness 95~105 99.9 99.8 fitness Starch 1500 95~105 99.9 100.0 fitness 95~105 99.8 100.0 fitness Hydroxypropylcellulose 95~105 100.7 99.7 fitness 95~105 99.8 99.8 fitness Mannitol 95~105 100.2 99.6 fitness 95~105 99.7 99.7 fitness Magnesium stearate 95~105 99.8 99.7 fitness 95~105 98.9 98.9 fitness Glyceryl behenate 95~105 99.7 100.1 fitness 95~105 99.6 99.3 fitness Stearic acid 95~105 100.2 100.0 fitness 95~105 98.9 99.1 fitness Stearate fumarate 95~105 99.1 99.0 fitness 95~105 99.6 99.2 fitness Polyethylene oxide 95~105 98.8 98.7 fitness 95~105 97.8 98.7 fitness Hypromellose 95~105 99.9 99.8 fitness 95~105 99.8 100.1 fitness Butylhydroxytoluene 95~105 99.8 99.7 fitness 95~105 98.7 99.8 fitness Collidone SR 95~105 99.7 99.6 fitness 95~105 100.1 99.9 fitness Polyvinylpidolidone 95~105 100.1 100.0 fitness 95~105 99.9 100.1 fitness Hypromellose acetate succinate 95~105 99.8 99.7 fitness 95~105 98.8 98.4 fitness Povidone 95~105 99.7 99.5 fitness 95~105 100.0 99.9 fitness Corn starch 95~105 99.8 99.7 fitness 95~105 98.8 99.7 fitness Ethyl cellulose 95~105 99.6 99.6 fitness 95~105 98.9 98.6 fitness Methacrylic acid copolymer 95~105 100.2 100.0 fitness 95~105 100.1 100.0 fitness Crystalline cellulose 95~105 100.0 99.9 fitness 95~105 99.9 99.8 fitness Talc 95~105 100.2 100.1 fitness 95~105 99.9 98.6 fitness

As a result of the experiment, it was confirmed that the additives listed in Table 1 can be suitably used for both tamsulosin and mirabegron.

Example 2: Preparation of composition (1) for tamsulosin-containing layer

5 g of malto syrup (maltose syrup) powder and 1 g of tamsulosin hydrochloride are dissolved in purified water. Granules are prepared by spraying the prepared solution onto 200 g of mannitol in a fluid bed dry granulator. The prepared granules are secondarily granulated by spraying an appropriate amount of methacrylic acid copolymer LD, an appropriate amount of ethyl cellulose spray, and an appropriate amount of ethyl acrylate/methyl methacrylate copolymer dispersion, and then sizing.

The prepared sized product was mixed with 250 g of lactose hydrate, 120 g of HPMC, 50 g of ethyl cellulose, 20 g of calcium stearate, and 5 g of glyceryl behenate, to prepare a mixture to be used in the tamsulosin-containing layer.

Using this mixture, tablets are prepared by tableting so that the weight per tablet is 200.2 mg.

Example 3: Preparation of composition (2) for tamsulosin-containing layer

After dry granulation of 0.85 g of tamsulosin hydrochloride, 394 g of microcrystalline cellulose, 90 g of hypromellose, and 2 g of starch glycolic acid, 50 g of Acryl-EZE and 0.15 g of tamsulosin were dissolved in purified water in a fluid bed granulator. The dry granules are coated by spraying.

The coated granules were mixed with 2.5 g of magnesium stearate and 2.5 g of glyceryl behenate to prepare a mixture to be used in the tamsulosin-containing layer.

Using this mixture, tablets are prepared by tableting so that the weight per tablet is 108.4 mg.

Example 4: Preparation of composition (3) for tamsulosin-containing layer

5 g of malto syrup powder and 1 g of tamsulosin hydrochloride are dissolved in purified water. Granules are prepared by spraying the prepared solution on 200 g of Ludipress in a fluid bed dry granulator. An appropriate amount of an ethyl cellulose spray solution, an appropriate amount of an ethyl acrylate/methyl methacrylate copolymer dispersion, Eudragit L30D-55, and an ethyl cellulose solution are sprayed to secondary granulate the prepared granules, and the resulting granules are sieved.

The prepared sized product was mixed with 50 g of ethyl cellulose, 250 g of microcrystalline cellulose, 2 g of crospovidone, 120 g of hypromellose, and 20 g of magnesium stearate to prepare a mixture to be used in the tamsulosin-containing layer.

Using this mixture, tablets are prepared by tableting so that the weight per tablet is 200.2 mg.

Example 5: Preparation of composition (1) for Mirabegron-containing layer

250 g of Mirabegron, 27 g of colloidal silicon dioxide, 45 g of hydroxypropyl cellulose, and 800 g of polyethylene oxide are added to a speed mixer and granulated using ethanol as a binding solution. After the granulation, it is dried using a fluid bed dryer and sized.

The prepared sized product was mixed with 2 g of butylhydroxytoluene, 2.7 g of colloidal silicon dioxide, and 11.5 g of magnesium stearate to prepare a mixture to be used for the Mirabegron-containing layer.

Using this mixture, tablets are prepared by tableting so that the weight per tablet is 229.8 mg.

Example 6: Preparation of composition (2) for Mirabegron-containing layer

250 g of Mirabegron, 250 g of polyethylene oxide, 598 g of polyethylene glycol, and 37.5 g of hydroxypropyl cellulose were added to a speed mixer and granulated using ethanol as a binding solution. After the granulation, it is dried using a fluid bed dryer and sized.

The prepared sized product was mixed with 1 g of butylhydroxytoluene and 12.5 g of glyceryl behenate to prepare a mixture to be used in the Mirabegron-containing layer.

Using this mixture, tablets are prepared by tableting so that the weight per tablet is 229.8 mg.

Example 7: Preparation of two-layer tablet (1)

Using a two-layer tablet press, a two-layer tablet containing the composition of Example 4 as a first layer and the composition of Example 5 as a second layer is tableted.

Example 8: Preparation of two-layer tablet (2)

Using a two-layer tablet tablet press, a two-layer tablet containing the tableting mixture prepared in Example 4 as a first layer and the tableting mixture prepared in Example 6 as a second layer is tableted.

Example 9: Preparation of single-layer tablet

Using a general tablet press, the tabletting mixture prepared in Example 4 and the tableting mixture prepared in Example 6 were mixed with each other and then compressed into a single layer to prepare a composite single-layer tablet.

Experimental Example 1: Test according to the type of lubricant

The composition and content of the two-layer tablet of Example 8 (that is, the composition of Example 4 and of the composition of Example 6) are the same, but differ only in the composition and/or content of the lubricant used in each layer. Was prepared, and the two-layer tablet prepared as described above and the two-layer tablet of Example 8 were subjected to a friability test and observation of whether or not a layer separation phenomenon occurred.

The types and contents of the lubricants used in this test are shown in Table 2 below.

The friability test is one of the methods of indicating the physical strength of a tablet, and is obtained by measuring the amount of powder produced or the degree of damage when a tablet is placed in a cylinder and dropped from a certain height while rotating at a constant speed. It is judged as an evaluation of the tablet's ability to withstand breakage during handling, packaging and transport of tablets.

20 double-layer tablets of each composition are placed in the cylinder of the Masondo Tester and operated at a speed of 25 rmp for 4 minutes, and then the state of the tablets is checked.

The test results were evaluated as follows, and the test results are shown in Table 2 below.

★: There are no tablets that are separated between layers or rims are removed during the test tablets.

●: Among the test tablets, there are no tablets that are separated between layers, but there are no more than 2 tablets with the edges falling off.

▲: Among the test tablets, there are at least one tablet that is separated between layers, and two or more tablets with a rim

X: Among the test tablets, two or more tablets separated between layers and three or more tablets with a rim

Example Lubricant ingredient and content The border of the tablet
Part that fell off Delamination final result First floor Second floor Example 10: 1st layer ^(*) : stearic acid 20g none One 2 X 2nd layer ^(**) : Stearic acid 12.5g Example 11: 1st layer ^(*) : 20 g of calcium stearate none One none ● 2nd layer ^(**) : Calcium stearate 12.5g Example 12: First layer: 20 g of magnesium stearate none One none ● 2nd layer ^(**) : Magnesium stearate 12.5g Example 13: 1st layer ^(*) : 5g of glyceryl behenate none none none ★ 2nd layer ^(**) : glyceryl behenate 4g Example 14: 1st layer ^(*) : sodium stearyl fumarate 20g none none One ▲ 2nd layer ^(**) : sodium stearyl fumarate 12.5g Example 15: 1st layer ^(*) : 5g of hydrogenated vegetable oil none 2 One ▲ 2nd layer ^(**) : 4g of hydrogenated vegetable oil Example 8: 1st layer: Stearate Magnesum 20g none none none ★ 2nd layer: glyceryl behenate 12.5 Example 17: 1st layer ^(*) : glyceryl behenate 20g none none none ★ 2nd layer ^(**) : Magnesium stearate 12.5g

(*) It means the lubricant used in place of 20 g of magnesium stearate, which is the lubricant used in Example 4, and its content.

(**) It means the lubricant used in place of 12.5 g of glyceryl behenate, which is the lubricant used in Example 6, and its content.

As can be seen in Table 2, in the two-layer tablets using glyceryl behenate or magnesium stearate in the first and second layers (Examples 8, 13 and 17), the rim of the tablet did not come off, No delamination occurred in the first and second layers.

Accordingly, it can be seen that when magnesium stearate or glyceryl behenate is used as the lubricant used in the composition of the present invention, the friability is low and interlayer separation does not occur.

More preferably, glyceryl behenate is used as a lubricant in at least one of the first layer and the second layer.

Experimental Example 2: Hardness test

As in Experimental Example 1, a hardness test was performed on the two-layer tablets of Examples 8, 10 to 15, and 17.

The hardness test is a test for measuring the breaking strength of a tablet, and the tablet is placed in a hardness tester and the hardness is measured.

Ten double-layer tablets of each composition were tested. The test results were evaluated as follows, and the test results are shown in Table 3 below.

★: Among the test tablets, 10 tablets with a hardness of 10 kp or more

●: Among the test tablets, 7 or more tablets with a hardness of 10 kp or more

▲: Among the test tablets, 5 tablets or more with tablet hardness of 10 kp or more

X: Among the test tablets, less than 5 tablets with a hardness of 10 kp or less

Example Hardness test result Example 10 ▲ Example 11 ● Example 12 ★ Example 13 ★ Example 14 ● Example 15 ● Example 8 ★ Example 17 ★

As can be seen from Table 3, it was confirmed that the hardness of the two-layer tablets (Examples 8, 12, 13, 17) using glyceryl behenate or magnesium stearate in the first and second layers was the highest.

Therefore, it can be seen that the hardness is suitable when magnesium stearate or glyceryl behenate is used as the lubricant used in the composition of the present invention.

Experimental Example 3: Dissolution test

1) Tamsrosine dissolution test

The tablets prepared in Examples 3, 4, 8 and 9 were subjected to a dissolution test under the following conditions. As a control, a commercially available Harunaldi tablet was used.

<Test conditions>

Sample: Each tablet prepared in Examples 3, 4, 8, and 9 and Harunaldi tablet

Dissolution test solution: pH 1.2, 7.2 (1 ml of polysorbate 80 solution was added to 500 ml of the disintegration test method 1 (pH 1.2) of the general test methods of the Korean Pharmacopoeia, and carried out until 2 hours of dissolution test start. The test was continued by changing to 500 ml of the phosphate buffer of 7.2).

Dissolution method: Korean Pharmacopoeia dissolution test method 2 (paddle method), 100 rotations per minute

The results of the tamsulosin dissolution test are shown in Table 4 and FIG. 1 below.

As shown in Table 2, the tablets of Examples 3, 4, and 8 showed similar patterns within ±10% in the 30, 60, and 80% sections, which are the comparative dissolution comparison points, and in particular, Examples 4 and 8 It was confirmed that the dissolution rate of was more similar to the control drug.

Comparing the dissolution test results of Examples 8 and 9, the dissolution rate of the case where the two components were mixed and prepared as a single layer (Example 9) and the case that the two-layer tablet composed of a layer of each component (Example 8) was prepared was You can see that it is different.

2) Mirabegron dissolution test

The two-layer tablets prepared in Example 7 and Example 8 were subjected to a dissolution test under the following conditions, and as a control group, a currently commercially available Mirabegron sustained-release tablet, Betamiga Sustained-release tablet was used.

<Test conditions>

Specimen: Examples 7, 8 and Beta Miga sustained-release tablets

Dissolution test solution: pH 1.2

Dissolution method: Korean Pharmacopoeia dissolution test method 2 (paddle method), 50 rotations per minute

The results of the Mirabegron dissolution test are shown in Table 5 and FIG. 2 below.

Degree of elution in pH 1.2 buffer solution (%) Example 7 Example 8 Beta-miga slow release 15 minutes 6.7±0.1 6.1±0.2 6.2±0.3 30 minutes 11.8±0.7 11.2±0.8 10.5±0.7 60 minutes 20.4±1.2 17.8±0.4 18.8±1.3 90 minutes 29.0±1.9 28.4±1.5 27.4±1.8 120 minutes 37.3±2.1 36.8±1.8 35.1±3 180 minutes 55.9±5.7 52.4±3.6 50.1±3.7 300 minutes 81.7±5.8 79.2±5.9 77.4±5 360 minutes 91.2±7.9 89.7±4.3 88.4±5.1 480 minutes 98.6±6.2 96.5±3.7 97.5±2.8 600 minutes 98.6±3.8 99.7±2.9 100.6±7

As shown in Tables 5 and 2, both of Examples 7 and 8 exhibited a dissolution pattern similar to that of the sustained-release tablet, and the tablet of Example 8 was more similar to the dissolution pattern of the control drug.

Experimental Example 4: In vivo dynamics experiment

(i) the composite bilayer tablet of Example 8, (ii) Harunaldi tablet commercially available as tamsulosin tablets (tamsrosine hydrochloride 0.2mg), and (iii) Betamiga sustained-release tablets commercially available as Mirabegron tablets. In order to confirm each in vivo kinetics for each group, 6 dogs per group were divided into 3 groups, and 18 beagle dogs were administered under the same conditions under the following test conditions, and the results are shown in Tables 6 and 7 below.

<Test conditions>

Specimen: Combined two-layer tablet of Example 8, Harunaldi tablet, Betamiga sustained-release tablet

Individuals by group: 3 groups of 6 animals per group, total of 18 animals

Dosing: Group 1 was administered with the combined bilayer tablet of Example 8 once, and the second group was administered with a single dose of Harunaldi tablet and the third group with a sustained-release tablet of Betami. Each group consisted of randomly distributed beagle dogs.

AUC(ug.hr/ml) Cmax(ug/ml) One day 69.59±24.35 6.07±1.84 Example 8 72.35±21.98 5.98±1.76

AUC(ug.hr/ml) Cmax(ug/ml) Beta-miga slow release 95.22±40.955 7.26±4.03 Example 8 92.17±36.95 7.05±2.07

As shown in Tables 6 and 7 above, as a result of the pharmacokinetic equivalence test, there was no statistically significant difference in the highest blood concentration (Cmax). There was also no statistically significant difference between the AUC value and the area under the curve (AUC) of the combination drug of Example 8. As described above, it was confirmed that the combination formulation of Example 8 expresses the same in vivo kinetics as each of the control groups.

Claims (12)

A first layer containing tamsulosin or a pharmaceutically acceptable salt thereof; And
The second layer containing Mirabegron or a pharmaceutically acceptable salt thereof
Controlled-release tablet composition for preventing and treating urinary diseases comprising a. The tablet composition of claim 1, wherein the second layer includes a sustained-release base. The method of claim 2, wherein the sustained-release base of the second layer is polyethylene oxide, methyl cellulose, ethyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl ethyl cellulose , Polyvinyl acetate, polyvinyl alcohol, polymethacrylate, glyceryl stearate, hydrogenated vegetable oil, poloxamer, carbomer, alkyl hydroxypropylmethylcellulose, sodium carboxymethylcellulose, povidone and derivatives thereof, corn starch, potato starch , Gelatinized starch and derivatives thereof, hydroxyethyl starch, dextrin and derivatives thereof, dextran, maltodextrin, cyclotexrin, polydextrose, alginate or derivative thereof, natural gum, synthetic gum, casein, gelatin, collagen, protamine, zein , Polyacrylamide, polyvinyl acetal diethylamino acetate, glucomannan, glucosamine, arabinogalactan, purseleran, fluran, chitosan, chitin, agar, pectin and carrageenan, characterized in that one or more selected from the group consisting of Tablet composition. The tablet composition according to claim 2 or 3, wherein the first layer contains a sustained-release base. The method of claim 4, wherein the sustained-release base of the first layer is one from the group consisting of hydroxypropylmethyl cellulose, ethyl cellulose, hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulose acetate succinate, and methacrylic acid copolymer. Tablet composition, characterized in that selected above. The tablet composition of claim 1 or 2, wherein the first layer or the second layer further comprises a lubricant. The method of claim 6, wherein the lubricant is one or more selected from the group consisting of magnesium stearate, stearic acid, sodium stearyl fumarate, talc, glyceryl behenate, colloidal silicon dioxide, light anhydrous silicic acid, and hydrogenated vegetable oil. Tablet composition characterized in that. The method according to claim 1 or 2,
The first layer and the second layer further include a lubricant,
Here, the lubricant is a tablet composition, characterized in that glyceryl behenate or magnesium stearate. The method according to claim 1 or 2,
The first layer and the second layer further include a lubricant,
Herein, at least one of the first layer and the second layer includes glyceryl behenate as a lubricant. The tablet composition according to claim 1 or 2, wherein at least one inert intermediate layer is further included between the first layer and the second layer. The tablet composition according to claim 1 or 2, further comprising any one or more of an excipient, a binder, a disintegrant or a colorant. The method of claim 5,
The content of the sustained-release base in the first layer is 5 to 30% by weight of the total weight of the first layer,
Tablet composition, characterized in that the content of the sustained-release base in the second layer is 5 to 70% by weight of the total weight of the second layer.

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