KR101731078B1 - Bilayer tablets comprising bepotastine or its salt - Google Patents

Abstract

The present invention provides a bilaterasin-containing bilayer tablet for once-a-day dosage. It is possible to avoid the use of polyethylene oxide which is a stimulable polymer and to manufacture medicine by using a suitable additive without the use of a separate optical stabilizer. The bilayer tablet includes a non-swellable matrix layer and a swellable matrix layer.

Description

[0001] Bilayer tablets comprising bepotastine or its salts [

The present invention relates to a double layered tablet comprising bevotastine or a salt thereof, and more particularly to avoiding the use of polyethylene oxide, which is a stimulant polymer, and also to formulate it using a suitable additive without the use of a separate optical stabilizer Layered tablets for once-a-day dosing which can be simply applied at the production site.

Bepotastine is an antihistamine agent whose chemical name is (S) -4- [4- [(4-chlorophenyl) -pyridin-2- ylmethoxy] piperidin- 1 -yl] butanoic acid [ S) -4- [4 - [(4-chlorophenyl) -pyridin-2-ylmethoxy] piperidin-1-yl] butanoic acid] (US Patent No. 4,929,618). Bepotastine is a non-sedative selective antagonist of the H1-histamine receptor and represents a modulation of eosinophil migration to inflamed tissues. Thus, beportatin is useful for the treatment of allergic rhinitis, urticaria / pruritus, and the like.

Bepotastine is used, for example, in the form of bepotastine besilate or calcium salt dihydrate (for example bepotastine calcium dihydrate), and has a short half-life in vivo, . However, twice daily dosing of the immediate release formulation of bevitalastine results in a peak penetration profile due to the short half-life and rapid removal of the drug. In addition, high systemic exposure (Cmax) of the drug may cause systemic side effects.

Release-regulating pharmaceutical compositions provide many advantages over immediate release pharmaceutical compositions. The controlled-release pharmaceutical composition can reduce the frequency of administration to improve patient compliance, maintain effective blood levels for longer periods of time, and reduce side effects associated with systemic drug exposure. International Patent Publication No. WO 2012/104818 (Korean Patent Laid-Open No. 10-2014-0016260) discloses an oral controlled-release pharmaceutical composition of beportastine. International Patent Publication No. WO 2012/104818 discloses a pharmaceutical composition comprising a bilayer tablet comprising a release-controlling layer containing, for example, bevitalystine besylate and a mucoadhesive layer, and a drug layer containing bevitalystine besylate, Layer tablet comprising a push pull layer. However, in order to include the biocompatible layer or the push layer as a separate layer, it is necessary to use a stimulable polymer such as polyethylene oxide, and also to formulate the release-controlling layer and the drug layer using polyethylene oxide .

In addition, International Patent Publication No. WO 2012/104818 discloses a pharmaceutical composition comprising a release modulating matrix layer, an inactive layer, a release modulating coating layer, a betapastin drug layer and a remaining betapastin betylate, Multi-layered tablets containing; Layer tablet comprising a drug layer containing bevitalystine besylate, a mucoadhesive layer, a CR coating layer, and an active IR coating layer. However, due to the complicated manufacturing process due to the multi-layer structure, There is a problem that is difficult to apply.

On the other hand, it has been known that the (S) -array beapotastine exhibits a remarkably high pharmacological activity as compared with the (R) -configuration bevetastatin (Japanese Patent Application Laid-Open Nos. 2-25465 and 10-237070) . In addition, besides being not stable due to its hygroscopicity, the (S) -configuration of beapotastine is not stable, and when formulated using additives such as conventional excipients and binders, beportastine is racemized by water in the additive, - < / RTI > For example, when (Talon) tablets, a commercially available product of the (S) -configured bevapastastin besylate, are stored for one month under severe conditions (60 ° C, 75% relative humidity) Of beportantine is produced in an amount of 10% or more. In order to solve such a problem, Korean Patent Laid-Open Publication No. 10-2015-0138104 discloses a formulation using an optical stabilizer such as glyceryl behenate.

The present inventors have conducted various studies in order to avoid the use of the polyethylene oxide, which is a stimulant polymer, and to develop a double-layered tablet of bevathastin-containing which can be easily applied on a production site without using a separate optical stabilizer. The present inventors evaluated the compatibility of the (S) -configuration with the bevitalystine salt and various additives to determine the generation of the flexible substance and the formation of the (R) -configuration of bevetastatin. It was also found from the results obtained in the formulation compatibility test that the non-swellable matrix layer containing some of the betapatastine and the compounding suitable additives, hydroxypropylmethylcellulose as the release-controlling polymer and the appropriate additive It has been found that when a bilayer tablet is designed with a swellable matrix layer, tablets having excellent chemical and optical stability as well as being able to be administered once a day by the release controlling mechanism of each layer can be produced.

Accordingly, it is an object of the present invention to provide a bevitalustine-containing bilayer tablet which is once-a-day administered formulated using suitable additives, without the use of polyethylene oxide and a separate optical stabilizer.

According to one aspect of the present invention there is provided a once-daily double-dose tablet comprising a therapeutically effective amount of bevotastine or a pharmaceutically acceptable salt thereof, wherein (a) 50% by weight of bepotastine or a pharmaceutically acceptable salt thereof; At least one diluent selected from isomalt, D-mannitol, silicified microcrystalline cellulose, polyethylene glycol 6000, and lactose; At least one disintegrant selected from carboxymethylcellulose or its calcium salt and croscarmellose or its sodium salt; And a non-swellable matrix layer essentially comprising at least one lubricant selected from stearic acid or its magnesium salt, stearyl fumaric acid or its sodium salt, and colloidal silicon dioxide, and (b) 70% by weight of bepotastine or a pharmaceutically acceptable salt thereof; Hydroxypropylmethylcellulose as a release-controlling polymer; Isomalt, D-mannitol, silicified microcrystalline cellulose, and polyethylene glycol 6000; And a swellable matrix layer essentially comprising at least one lubricant selected from stearic acid or its magnesium salt, stearyl fumaric acid or its sodium salt, and colloidal silicon dioxide.

In the bilayer tablet of the present invention, the swellable matrix layer may comprise bevetastatin salicylate, and preferably both the non-swellable matrix layer and the swellable matrix layer may comprise bevapastastin salicylate . The hydroxypropyl methylcellulose may be present in an amount of 20 to 40 wt% based on the total weight of the swellable matrix layer.

In one embodiment, per unit unit bilayer tablet, 7.5 mg to 9.64 mg of bepotastine salicylate, 25 mg to 30 mg of isomalt, 15 mg to 25 mg of D-mannitol, 40 mg to 50 mg of microcrystalline cellulose sulphate, polyethylene glycol 6000 Swellable matrix layer essentially comprising 5 mg to 15 mg, lactose or lactose 25 mg to 35 mg, carboxymethylcellulose calcium 3 mg to 5 mg, and glutamate 1 mg to 5 mg, and beportastine salicylate Mannitol 15 mg to 25 mg, microcrystalline cellulose microcrystalline cellulose 40 mg to 50 mg, polyethylene glycol 6000 5 mg to 15 mg, hydroxypropyl methylcellulose 45 mg to 65 mg, mg and a swellable matrix layer essentially comprising 1 mg to 5 mg of a lubricant.

The bilayer tablets of the present invention may further comprise a protective-coating layer, wherein the protective-coating layer may comprise one or more additives selected from the group consisting of hydroxypropylcellulose 2910, polyethylene glycol 6000, titanium oxide, and talc. have.

The bilayer tablets according to the present invention can be applied at the production site simply at low cost by avoiding the use of the stimulable polymer polyethylene oxide and also by formulating them using a suitable additive without the use of a separate optical stabilizer. In particular, the bilayer tablets according to the present invention have excellent chemical and optical stability by using in combination the additives found to be suitable according to the invention. In addition, the double layered tablet according to the present invention can be administered once a day by the release controlling mechanism of each layer, so that the patient's compliance with medicines can be improved. In particular, when beportastine salicylate is used, its solubility is lower than other salt forms (for example, beportastine besylate), so that the release of beopostatin can be effectively controlled while preventing sudden release of bepostatin.

1 to 3 show the dissolution test results of the double-layer tablets prepared according to the present invention.
Figure 4 shows the results of a pharmacodynamic test of a bilayer tablet (single oral administration) and a comparative preparation (two oral administrations) prepared according to the present invention.

The present invention relates to a once-daily double-dose tablet comprising a therapeutically effective amount of bevotastine or a pharmaceutically acceptable salt thereof, wherein (a) the therapeutically effective amount of 30-50% Phytastine or a pharmaceutically acceptable salt thereof; At least one diluent selected from isomalt, D-mannitol, silicified microcrystalline cellulose, polyethylene glycol 6000, and lactose; At least one disintegrant selected from carboxymethylcellulose or its calcium salt and croscarmellose or its sodium salt; And a non-swellable matrix layer essentially comprising at least one lubricant selected from stearic acid or its magnesium salt, stearyl fumaric acid or its sodium salt, and colloidal silicon dioxide, and (b) 70% by weight of bepotastine or a pharmaceutically acceptable salt thereof; Hydroxypropylmethylcellulose as a release-controlling polymer; Isomalt, D-mannitol, silicified microcrystalline cellulose, and polyethylene glycol 6000; And a swellable matrix layer essentially comprising at least one lubricant selected from stearic acid or its magnesium salt, stearyl fumaric acid or its sodium salt, and colloidal silicon dioxide.

As used herein, "essentially comprising" refers to the inclusion of the listed constituents, but may additionally include non-essential elements other than essential elements. The non-essential elements include, for example, coloring agents and the like. The essential elements include, for example, polyethylene oxide, which is a stimulable polymer, and an optical stabilizer. The 'polyethylene oxide' refers to a nonionic homopolymer of ethylene oxide represented by H (OCH ₂ CH ₂ ) _n OH, wherein n represents the average number of oxyethylene groups in the range of about 2000 to 200,000 . On the contrary, 'polyethylene glycol' refers to an additional polymer of ethylene oxide and water represented by HOCH ₂ (CH ₂ OCH ₂ ) _m CH ₂ OH, wherein m is less than about 200. For example, 'polyethylene glycol 6000' refers to a polymer having a molecular weight of about 170 and an average molecular weight of about 7,300 to 9,300, and a polymer which is distinguished from the polyethylene oxide by the polymerization degree (and thus the average molecular weight) of the oxyethylene group Which is known in the art.

In the bilayer tablet of the present invention, the therapeutically effective amount of the above-mentioned bevetastin or a pharmaceutically acceptable salt thereof refers to an amount which achieves the desired therapeutic effect and also enables administration once a day. For example, in the bilayer tablets of the present invention, the therapeutically effective amount of bevastastin may range from 12 to 16 mg per unit bilayer tablet, but is not limited thereto. In addition, pharmaceutically acceptable salts of bevapastastine (e.g., bevacillate, etc.) can be calculated based on a therapeutically effective amount of a free base of bevetastine.

In the bilayer tablet of the present invention, bepotastine salicylate may be particularly preferably used as the pharmaceutically acceptable salt of bepotastine. Bepotastine salicylate is significantly lower in water solubility than commercially available bepotastine besylate. That is, the amount of water required to dissolve 1 g of the bevapastastin beetillate is 80 ml, while the amount of water required to dissolve 1 g of the beetapastin salicylate is 6,000 ml, which indicates a very low water solubility. This low water solubility allows the sustained release of bepotastine from the swellable matrix layer, thereby effectively controlling the release of beopostatin, while preventing the sudden release of beopostatin.

Therefore, the double-layer tablet of the present invention can preferably use a salt of bepotastine in salicylic acid salt form as an active ingredient, and the therapeutically effective amount of bepotastine salicylate is 17 to 23 mg, preferably 17.14 to 23.0 mg, 21.42 mg, more preferably about 19.28 mg. In one embodiment, the swellable matrix layer may comprise beportastine salicylate. In other embodiments, both the non-swellable matrix layer and the swellable matrix layer may comprise bevetastatin salicylate.

The non-swellable matrix layer does not contain polyethylene oxide and optical stabilizers and is formulated with additives found suitable for formulation by the present invention to provide rapid release of bevitalustine. Wherein the non-swellable matrix layer comprises a therapeutically effective amount of 30-50 wt% beportatine or a pharmaceutically acceptable salt thereof, preferably beportatin salicylate, with isomalt, D-mannitol , Silicified microcrystalline cellulose, polyethylene glycol 6000, and lactose; At least one disintegrant selected from carboxymethylcellulose or its calcium salt and croscarmellose or its sodium salt; And at least one lubricant selected from stearic acid or its magnesium salt, stearyl fumaric acid or its sodium salt, and colloidal silicon dioxide. In addition, if desired, the non-swellable matrix layer may also contain a colorant such as yellow ferric oxide.

The swellable matrix layer does not contain polyethylene oxide and optical stabilizers and is formulated with additives found suitable for formulation by the present invention to provide controlled release of bevitalastine. Wherein the swellable matrix layer comprises a therapeutically effective amount of 50-70% by weight of bepotastine or a pharmaceutically acceptable salt thereof (preferably beportastine salicylate) and a release controlling polymer together with hydroxypropylmethylcellulose , Isomalt, D-mannitol, silicified microcrystalline cellulose, and polyethylene glycol 6000; And at least one lubricant selected from stearic acid or its magnesium salt, stearyl fumaric acid or its sodium salt, and colloidal silicon dioxide. The hydroxypropylmethylcellulose functions as a release-controlling polymer which gradually swells in the gastrointestinal tract and gradually releases the bevitalystine. Preferably, the hydroxypropylmethylcellulose may be present in an amount of 20 to 40% by weight based on the total weight of the swellable matrix layer.

In one embodiment of the present invention, in the unit bilayer tablet, 7.5 mg to 9.64 mg of bepotastine salicylate, 25 mg to 30 mg of isomalt, 15 mg to 25 mg of D-mannitol, 40 mg to 50 mg of microcrystalline cellulose, A non-swellable matrix layer essentially comprising 5 mg to 15 mg of polyethylene glycol 6000, 25 mg to 35 mg of lactose or lactose hydrate, 3 mg to 5 mg of carboxymethylcellulose calcium, and 1 mg to 5 mg of glutamate; And isoprostol salicylate, 9.64 mg to 11.78 mg of bepotastine salicylate, 52.22 mg to 64.36 mg of isomalt, 15 mg to 25 mg of D-mannitol, 40 mg to 50 mg of microcrystalline cellulose, 5 mg to 15 mg of polyethylene glycol 6000, Layer tablet consisting of a swellable matrix layer essentially comprising 45 mg to 65 mg of methylcellulose, and 1 mg to 5 mg of a lubricant.

In another embodiment of the present invention, in the unit bilayer tablet, 7.5 mg to 9.64 mg of bepotastine salicylate, 27.36 mg to 29.5 mg of isomalt, 20 mg of D-mannitol, 46 mg of microcrystalline cellulose silicate, 10 mg of polyethylene glycol 6000, A non-swellable matrix layer essentially comprising 30 mg of lactose or lactose hydrate, 4 mg of carboxymethylcellulose calcium, and 3 mg of glutamate; And 50 mg to 60 mg of hydroxypropylmethylcellulose, and 10 mg to 10 mg of isoproterenol acetate, 9.64 mg to 11.78 mg of bepotastine salicylate, 52.22 mg to 64.36 mg of isomalt, 20 mg of D-mannitol, 43 mg of microcrystalline cellulose, 10 mg of polyethylene glycol 6000, Layer tablet comprising a swellable matrix layer essentially comprising a lubricant of 3 mg is provided.

In another embodiment of the present invention, 7.5 mg of bepotastine salicylate, 29.5 mg of isomalt, 20 mg of D-mannitol, 46 mg of microcrystalline cellulose silicate, 10 mg of polyethylene glycol 6000, 30 mg of lactose hydrate, 4 mg of carboxymethylcellulose calcium, and 3 mg of sodium stearyl fumarate; And 11.78 mg of bepotastine salicylate, 52.22 mg of isomalt, 20 mg of D-mannitol, 43 mg of microcrystalline cellulose silicate, 10 mg of polyethylene glycol 6000, 60 mg of hydroxypropylmethylcellulose and 3 mg of sodium stearyl fumarate as essential Layer tablet comprising a swellable matrix layer comprising a < / RTI >

The bilayer tablet according to the present invention can be administered once a day and can exhibit bioequivalence to a twice-a-day administration of a commercially-marketed immediate-release preparation (Tarrying).

In addition, the bilayer tablet according to the present invention may further comprise a conventional protective-coating layer for protecting the tablets. The protective coating layer may be formed using coating compositions commonly used in pharmaceutical industry. For example, the protective-coating layer may be coated with a mixture of hydroxypropylcellulose 2910, polyethylene glycol 6000, titanium oxide, talc, and the like.

Hereinafter, the present invention will be described in more detail through examples and test examples. However, the following examples and test examples are provided for illustrating the present invention, and the present invention is not limited to these examples and test examples.

Test Example  1: Compatibility test with additives

The beptastatin salicylate (API) was mixed with various additives to obtain a mixture of the initial conditions (i.e., mixing), acceleration conditions (40 캜 / 75% relative humidity, 10 days), and harsh conditions (60 캜 / 10 days), and then the content of the flexible material and the R-configuration was measured. The results are shown in Tables 1 to 3 below.

MEBE: MEBE: (1R, 2R, 5R) -2-Isopropyl-5-methylcyclohexyl 4- (4- ((S) - (4- chlorophenyl) pyridin- 2- yl) methoxy) piperidine- Pyridin-2-yl) methoxy) piperidin-1-yl) butanoate [(1R, 2R, 5R) -2-isopropyl- 5- methylcyclohexyl 4- yl) butonate]

* N / D: Not detected

MEBE: MEBE: (1R, 2R, 5R) -2-Isopropyl-5-methylcyclohexyl 4- (4- ((S) - (4- chlorophenyl) pyridin- 2- yl) methoxy) piperidine- Pyridin-2-yl) methoxy) piperidin-1-yl) butanoate [(1R, 2R, 5R) -2-isopropyl- 5- methylcyclohexyl 4- yl) butonate]

* N / D: Not detected

MEBE: MEBE: (1R, 2R, 5R) -2-Isopropyl-5-methylcyclohexyl 4- (4- ((S) - (4- chlorophenyl) pyridin- 2- yl) methoxy) piperidine- Pyridin-2-yl) methoxy) piperidin-1-yl) butanoate [(1R, 2R, 5R) -2-isopropyl- 5- methylcyclohexyl 4- yl) butonate]

* N / D: Not detected

As can be seen from the results of Tables 1 to 3, the bevetastatin salicylate was stable in terms of the formation of a flexible substance and an optical isomer at initial and accelerated conditions for various additives. However, in the severe condition, a mixture of bepotastine salicylate and polyethylene oxide was identified as a contraceptive ingredient by increasing the amount of the flexible substance at the elapsed time of 5 days and 10 days, and a mixture of bepotastine salicylate and neissylin (magnesium aluminum silicate) (R-arginate bepotastine salicylate) was found to be a contraindicated raw material, although the amount of the eluent was not increased.

Example  1-7: Double layer  Manufacture of tablets

A double layer tablet was prepared according to the ingredients and contents in Table 4 below. The contents of the ingredients in Table 4 represent mg per unit bilayer tablet.

Mixture A was prepared by mixing beptastatin salicylate, D-mannitol, isomalt, microcrystalline silicic acid cellulose, polyethylene glycol 6000, and Hypromellose 2910 (10,000 cp) and further mixing sodium stearyl fumarate . And the mixture of yellow ferric oxide ferrate and sodium stearyl fumarate is mixed to obtain a mixture of beefutastatin salicylate, D-mannitol, isomalt, Flowlac 100, silicified microcrystalline cellulose, polyethylene glycol 6000 and carboxymethylcellulose calcium, B was prepared. The mixture A and the mixture B were subjected to double layer purification (untreated) using a double tablet machine (JCMCO, JC-DH-23). Hypromellose 2910, polyethylene glycol 6000, titanium oxide, and talc were mixed with purified water to prepare a coating solution. The tablets obtained above were coated with the coating solution (manufactured by KANSEI CHEMICAL CO., LTD., Model No. KC50FS) to prepare double-layer tablets containing bepotastine.

Example One 2 3 4 5 6 7 ratio- Swelling  Matrix layer Bepotastine salicylate 9.64 9.64 9.64 9.64 8.7 8.2 7.5 Isomalt 27.36 27.36 27.36 27.36 28.3 28.8 29.5 D-mannitol 20.0 20.0 20.0 20.0 20.0 20.0 20.0 Silicified microcrystalline cellulose 46.0 46.0 46.0 46.0 46.0 46.0 46.0 Polyethylene glycol 6000 10 10 10 10 10 10 10 Lactose Liquid (Flowlac100) 30 30 30 30 30 30 30 Carboxymethylcellulose calcium 4 4 4 4 4 4 4 Yellow ferric oxide 0.05 0.01 0.01 0.05 0.01 0.01 0.01 Sodium stearyl fumarate 3 3 3 3 3 3 3 Swelling  Matrix layer Bepotastine salicylate 9.64 9.64 9.64 9.64 10.58 11.08 11.78 Isomalt 64.36 54.36 44.36 54.36 53.42 52.92 52.22 D-mannitol 20.0 20.0 20.0 20.0 20.0 20.0 20.0 Silicified microcrystalline cellulose 43 43 43 43 43 43 43 Polyethylene glycol 6000 10 10 10 10 10 10 10 Hypromellose 2910 (10,000 cp) 50 60 70 60.0 60.0 60.0 60.0 Sodium stearyl fumarate 3 3 3 3 3 3 3 Protection - Coating HPMC2910 6.0 6.0 6.0 6.0 6.0 6.0 6.0 Polyethylene glycol 6000 0.8 0.8 0.8 0.8 0.8 0.8 0.8 Titanium oxide 1.0 1.0 1.0 1.0 1.0 1.0 1.0 Talc 1.2 1.2 1.2 1.2 1.2 1.2 1.2

Example  8: Double layer  Manufacture of tablets

Double-layer tablets were prepared according to the ingredients and contents in Table 5 below. The content of the ingredients in Table 5 represents mg per unit bilayer tablet.

(10,000 cp), followed by mixing the purified conjugate with distilled water and Hypromellose 2910 (10,000 cp) to prepare a binding liquid. , Granulation was performed using a high speed mixer (Yenchen, model number YC-SMG-10), and then dried at 60 ° C. The dried granules were poured in 20 mesh, and polyethylene glycol 6000 and sodium stearyl fumarate were mixed to prepare a mixture A. The mixture B was prepared by further mixing yellow oxidant diiron and sodium stearyl fumarate, and mixing the mixture to obtain a mixture B, Respectively. The mixture A and the mixture B were subjected to double layer purification (untreated) using a double tablet machine (JCMCO, JC-DH-23). Hypromellose 2910, polyethylene glycol 6000, titanium oxide, and talc were mixed with purified water to prepare a coating solution. The tablets obtained above were coated with the coating solution (manufactured by KANSEI CHEMICAL CO., LTD., Model No. KC50FS) to prepare double-layer tablets containing bepotastine.

Example 8 ratio- Swelling  Matrix layer Bepotastine salicylate 7.5 Isomalt 29.5 D-mannitol 20.0 Silicified microcrystalline cellulose 46.0 Polyethylene glycol 6000 10 Lactose Liquid (Flowlac100) 30 Carboxymethylcellulose calcium 4 Yellow ferric oxide 0.01 Sodium stearyl fumarate 3 Swelling  Matrix layer Bepotastine salicylate 11.78 Isomalt 52.22 D-mannitol 20.0 Silicified microcrystalline cellulose 43 Polyethylene glycol 6000 10 Hypromellose 2910 (10,000 cp) 59.8 Hypromellose 2910 (10,000 cp) (binding solution) 0.2 Sodium stearyl fumarate 3 Protection - Coating HPMC2910 6.0 Polyethylene glycol 6000 0.8 Titanium oxide 1.0 Talc 1.2

Test Example  2. Dissolution test

Six tablets of the tablets obtained in Examples 1 to 8 were taken and the dissolution test was carried out according to the following conditions.

- Dissolution test method: Korean Pharmacopoeia 2nd Act (Paddle Method)

- Elute: Water (900 mL)

- Leaching temperature: 37 ± 0.5 ℃

- Rotation speed: 50 rpm

- Examination time: 12 hours

- Detector: Absorber spectrophotometer (measuring wavelength: 225 nm)

- Column: Capcellpak C ₁₈ (150 mm x 4.6 mm, 5 m) column

- Injection volume: 20 μL

- Flow rate: 1.2 mL / min

- Column temperature: 35 ° C

- Sample temperature: 20 ° C

- mobile phase: A pH 5.8 buffer / B acetonitrile (72/28, v / v)

  (pH 5.8 buffer: 2.84 g of disodium hydrogenphosphate was dissolved in 1 L of purified water and adjusted to pH 5.8 with phosphoric acid)

The results of the dissolution test performed as described above are shown in FIGS. 1 to 3. As can be seen from the results of Figs. 1 to 3, the double-layer tablets obtained according to the present invention exhibited a zero-order emission pattern.

Test Example  3. Chemical stability test

The tablets obtained in Examples 1 to 8 were stored in a long-term condition (25 ° C / 60% relative humidity, 3 months) and under accelerated conditions (40 ° C. / 75% relative humidity, 3 months) Are shown in Tables 6 to 8 below.

Example 1 Example 2 Example 3 Elapsed time Early long time Acceleration Early long time Acceleration Early long time Acceleration MEBE (%) N / D N / D N / D N / D N / D N / D N / D N / D N / D Individual unknowns (%) N / D 0.023 0.037 0.009 0.02 0.06 0.02 0.03 0.04 Total Flexible Substance (%) N / D 0.045 0.061 0.02 0.04 0.07 0.03 0.05 0.07 content(%) 98.6 97.9 98.3 98.9 98.5 97.8 98.2 98.9 98.1

MEBE: MEBE: (1R, 2R, 5R) -2-Isopropyl-5-methylcyclohexyl 4- (4- ((S) - (4- chlorophenyl) pyridin- 2- yl) methoxy) piperidine- Pyridin-2-yl) methoxy) piperidin-1-yl) butanoate [(1R, 2R, 5R) -2-isopropyl- 5- methylcyclohexyl 4- yl) butonate]

* N / D: Not detected

Example 4 Example 5 Example 6 Example 7 Elapsed time Early long time Acceleration Early long time Acceleration Early long time Acceleration Early long time Acceleration MEBE (%) N / D N / D N / D N / D N / D N / D N / D N / D N / D N / D N / D N / D Individual unknown
Flexible Substance (%) N / D 0.023 0.037 0.01 0.03 0.051 N / D 0.01 0.04 0.01 0.01 0.02 Total Flexible Substance (%) N / D 0.045 0.061 0.03 0.06 0.07 N / D 0.02 0.07 0.043 0.05 0.05 content(%) 99.2 98.7 99.1 99.9 99.7 99.3 99.5 99.0 100.1 100.3 100.7 100.0

MEBE: MEBE: (1R, 2R, 5R) -2-Isopropyl-5-methylcyclohexyl 4- (4- ((S) - (4- chlorophenyl) pyridin- 2- yl) methoxy) piperidine- 1-yl) butanoate

* N / D: Not detected

Example 8 Elapsed time Early long time Acceleration MEBE (%) N / D N / D N / D Individual unknowns (%) 0.01 0.02 0.03 Total Flexible Substance (%) 0.03 0.06 0.08 content(%) 100.2 100.1 99.5

MEBE: MEBE: (1R, 2R, 5R) -2-Isopropyl-5-methylcyclohexyl 4- (4- ((S) - (4- chlorophenyl) pyridin- 2- yl) methoxy) piperidine- 1-yl) butanoate

* N / D: Not detected

From the results shown in Tables 6 to 8, the double-layered tablets obtained according to the present invention have a stability criterion (hereinafter, referred to as MEBE 0.2% or less, 0.1% of individual unknown substances, 1.0% Or less).

Test Example  4. Optical stability test

The tablets obtained in Example 7 were stored for 1 month under accelerated conditions (40 占 폚 / 75% relative humidity) and harsh conditions (60 占 폚 / relative humidity 75% And the results are shown in Table 9 below.

R-array beapotastine (wt.%) Acceleration condition (40 ℃ / relative humidity 75%) 0.38 Severe conditions (60 ℃ / 75% relative humidity) 0.40

From the results shown in Table 9, it can be seen that the double-layered tablets obtained according to the present invention exhibit very excellent optical stability because almost no R-arranged bepotastine salicylate is formed even after storage for one month under accelerated conditions and severe conditions have.

Test Example  5. Pharmacokinetics  exam

The double layered tablets prepared in Example 7 were subjected to a single oral administration to 12 healthy male adults (body weight: 70 ± 10 kg) and then subjected to a pharmacodynamic test. For comparison, pharmacokinetic tests were conducted by oral administration of two commercially available immediate-release preparations, Tarion Jung (Dong-A Pharmaceutical), as a comparative example, to 12 healthy male adult (body weight: 70 ± 10 kg) Respectively. The blood concentration profile obtained by blood sampling at constant time intervals for 14 hours is shown in FIG. 4, and the pharmacodynamic parameters obtained from the blood concentration profiles are shown in Table 10 below.

Comparative Example Example 7 T1 / 2 (hr) 2.97 ± 1.37 3.20 ± 0.22 Tmax (hr) 2.90 + - 4.31 2.01 + 1.38 Cmax (mg / mL) 88.90 +/- 14.70 92.35 + - 13.85 AUCt 485.78 + - 71.11 507.46 ± 119.14

From the results shown in the above Table 10, since the composition of Example 7 shows the AUC and Cmax values equivalent to those of the Trial-on-Chow administered twice a day upon administration once a day (bioequivalence criteria: AUC and Cmax values are 80% to 125% range), it can be seen that the single administration of the bilayer tablet of the present invention shows biological equivalence to the two administrations of the tarry warming.

Claims (8)

A bi-layer tablet for once-a-day administration comprising a therapeutically effective amount of a bevitalastin salicylate salt,
(a) 30% to 50% by weight of said therapeutically effective amount of bepotastine salicylate; At least one diluent selected from isomalt, D-mannitol, silicified microcrystalline cellulose, polyethylene glycol 6000, and lactose; At least one disintegrant selected from carboxymethylcellulose or its calcium salt and croscarmellose or its sodium salt; And a non-swellable matrix layer essentially comprising at least one lubricant selected from stearic acid or its magnesium salt, stearyl fumaric acid or its sodium salt, and colloidal silicon dioxide, and
(b) 50-70% by weight of said therapeutically effective amount of beportastine salicylate; Hydroxypropylmethylcellulose as a release-controlling polymer; Isomalt, D-mannitol, silicified microcrystalline cellulose, and polyethylene glycol 6000; And a swellable matrix layer essentially comprising at least one lubricant selected from stearic acid or its magnesium salt, stearyl fumaric acid or its sodium salt, and colloidal silicon dioxide,
≪ / RTI > delete delete The bi-layer tablet according to claim 1, wherein the hydroxypropylmethylcellulose is present in an amount of 20 to 40% by weight based on the total weight of the swellable matrix layer. The process according to claim 1, wherein the unit double-
Mannitol 15 mg to 25 mg, microcrystalline cellulose microcrystalline cellulose 40 mg to 50 mg, polyethylene glycol 6000 5 mg to 15 mg, lactose or lactose hydrate A non-swellable matrix layer essentially comprising from 25 mg to 35 mg, from 3 mg to 5 mg of carboxymethylcellulose calcium, and from 1 mg to 5 mg of a lubricant and
From about 9.64 mg to about 11.78 mg of bepotastine salicylate, from 52.22 mg to 64.36 mg of isomalt, from 15 mg to 25 mg of D-mannitol, from 40 mg to 50 mg of microcrystalline cellulose, from 5 mg to 15 mg of polyethylene glycol 6000, 45 mg to 65 mg of cellulose, and 1 mg to 5 mg of a lubricant,
≪ / RTI > The process according to claim 1, wherein the unit double-
D-mannitol 20 mg, microcrystalline cellulose microcrystalline 46 mg, polyethylene glycol 6000 10 mg, lactose or lactose hydrate 30 mg, carboxymethylcellulose calcium 4 mg , And a non-swellable matrix layer essentially comprising a lubricant of 3 mg and
, Isomalt 52 mg to 64.36 mg, D-mannitol 20 mg, microcrystalline cellulose silicic acid 43 mg, polyethylene glycol 6000 10 mg, hydroxypropylmethylcellulose 50 mg to 60 mg, and glutamic acid A swellable matrix layer essentially comprising a third < RTI ID = 0.0 > mg &
≪ / RTI > The process according to claim 1, wherein the unit double-
7.5 mg of beportastine salicylate, 29.5 mg of isomalt, 20 mg of D-mannitol, 46 mg of microcrystalline cellulose silicate, 10 mg of polyethylene glycol 6000, 30 mg of lactose hydrate, 4 mg of carboxymethylcellulose calcium and 3 mg of sodium stearyl fumarate A non-swellable matrix layer essentially comprising; And
11.78 mg of bepotastine salicylate, 52.22 mg of isomalt, 20 mg of D-mannitol, 43 mg of microcrystalline cellulose silicate, 10 mg of polyethylene glycol 6000, 60 mg of hydroxypropylmethylcellulose and 3 mg of sodium stearyl fumarate A swellable matrix layer
≪ / RTI > 8. A composition according to any one of claims 1 to 7, further comprising a protective-coating layer, wherein the protective-coating layer is selected from the group consisting of hydroxypropylcellulose 2910, polyethylene glycol 6000, titanium oxide, ≪ / RTI > wherein the additive comprises at least one additive selected from the group consisting of:

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