KR20190069954A - Sustained-release preparations comprising bepotastine or pharmaceutically acceptable salt thereof - Google Patents

Abstract

The present invention provides a sustained-release formulation comprising: bepotastine or a pharmaceutically acceptable salt thereof; a water-soluble diluent; a sustained-release carrier; and magnesium metasilicate aluminate. The sustained-release formulation of the presenet invention, by applying gastric retention drug delivery and sustained-release techniques without increasing a size thereof, can secure bioavailability equivalent to that of a tarion tablet, which is a control drug, even though a dosage is reduced from twice a day to once a day. Therefore, the sustained-release formulation can improve drug taking convenience of a patient and can be usefully used for treating allergic rhinitis or pruritus.

Description

[0001] Sustained-release preparations comprising bepotastine or a pharmaceutically acceptable salt thereof,

≪ / RTI > or a pharmaceutically acceptable salt thereof.

Bepotastine is a salt of (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].

[Chemical Formula 1]

The above-mentioned bepotastine has antiallergic activity, and is an excellent medicine as a therapeutic drug for anaphylactic airway stenosis, asthma or allergic rhinitis. It is known that the (S) -isomeric bepotastine exhibits significantly higher pharmacological activity than the (R) -isomer.

Currently, beportastine (bezylate) has been developed as an immediate release formulation and is marketed by Mitsubishi Tanabe of Japan under the trade name of " Talion ". Tarion shows a tendency to disappear rapidly after the mean blood concentration of bepotastine reaches the maximum level 1 hour after administration, and therefore the dosage and dosage are set to twice a day to maintain a certain therapeutic level have. Therefore, it is necessary to develop a sustained-release formulation to reduce the side effects associated with systemic drug exposure by maintaining a constant blood concentration through sustained release of drug through the application of controlled release technology and to improve the antihistamine effect, tolerability, and compliance with the drug .

However, in the case of be- phatastine, it is known that the absorption site is confined to the upper part of the small intestine (Effect of P-glycoprotein on intestinal absorption and brain penetration of antiallergic agent bepotastine besilate, Ohashi et al., Drug Metabolism and Disposition, 34 ), 793-799] It is not possible to achieve the desired level of bioavailability with a typical sustained release.

Korean Patent Laid-Open Publication No. 2008-0083276 discloses a pharmaceutical composition comprising a sustained-release composition comprising a sustained-release composition comprising a pharmaceutically active ingredient, a release-controlling agent and a pharmaceutically acceptable carrier, Lt; RTI ID = 0.0 > a < / RTI > carrier. However, it is difficult to obtain clinical significance in that the pharmaceutical composition produced by this method has almost no absorption at or below the upper part of the small intestine.

Korean Patent Laid-Open Publication No. 2014-0016260 discloses an oral controlled-release pharmaceutical composition comprising bepotastine. However, since the pharmaceutical preparation can be completed after complicated processes such as the first drug layer production, the bioadhesive layer production, the slow coating, the second drug layer production, and the immediate coating, Is difficult. In addition, it is difficult to obtain clinical significance in that beportastine is hardly absorbed after the upper part of the small intestine. Therefore, in order to obtain equivalent bioavailability, excess amount of beportastine bevacillate I can confirm the fact.

Korean Patent Laid-Open Publication No. 2014-0052540 discloses a pharmaceutical preparation comprising a pharmaceutically acceptable salt of bepotastine, a water-insoluble basic substance and a sustained-release carrier. However, it is difficult to obtain clinical significance in that the pharmaceutical composition prepared by this method has little absorption after the top of the small intestine.

Korean Patent Publication No. 1731078 discloses a bilayer tablet comprising a non-swellable matrix layer for rapid release of bevitalystine and a swellable matrix layer for controlled release of bevitalystine. However, since the pharmaceutical composition produced by this method is hardly absorbed after the upper part of the small intestine, it is difficult to obtain clinical significance and the process becomes complex due to the production of double layer, It is difficult to do. In addition, there is a problem that the size of the tablets becomes large and the adherence to medicines decreases.

Therefore, there is a need to develop a slow release formulation that improves compliance with medication compliance, tolerability, and antihistamine effects and reduces side effects associated with systemic drug exposure by improving dosing regimens twice daily, once daily, Do.

Korean Patent Publication No. 2012-0083276 Korean Patent Laid-Open Publication No. 2014-0016260 Korean Patent Publication No. 2014-0052540 Korean Patent Registration No. 1731078

The present invention provides a sustained-release preparation which can be administered once a day while ensuring the bioavailability equivalent to that of beatifastine or a pharmaceutically acceptable salt thereof twice a day, and having optical and chemical stability will be.

In order to solve the above-mentioned problems, the present invention provides a pharmaceutical composition comprising bevetastine or a pharmaceutically acceptable salt thereof; Water-soluble diluent; Sustained release carrier; And magnesium metasilicate aluminate.

For purposes of the present invention, "pharmaceutically acceptable salts" refer to salts prepared according to methods conventional in the art, and such methods of preparation are known to those skilled in the art. Specifically, the pharmaceutically acceptable salts include, but are not limited to, salts derived from the following inorganic or base salts which are pharmacologically or physiologically acceptable. Examples of suitable acids include hydrochloric acid, hydrobromic acid, hydrobromic acid, sulfuric acid, nitric acid, perchloric acid, fumaric acid, maleic acid, phosphoric acid, glycolic acid, lactic acid, salicylic acid, succinic acid, toluene-p-sulfonic acid, tartaric acid, acetic acid, Benzoic acid, malonic acid, naphthalene-2-sulfonic acid, benzenesulfonic acid, and the like. Preferably, the salt of bepotastine according to the present invention may be bepotastine bevacillate.

In the present invention, the "water-soluble diluent" may be a sugar alcohol. For example, it may be selected from the group consisting of erythritol, arabitol, xylitol, ribitol, sorbitol, mannitol, galactitol, maltitol, lactitol, and mixtures thereof. Preferably, D-mannitol can be used.

In the present invention, the term "sustained-release carrier" includes, but is not limited to, hydroxypropylcellulose, hypromellose, ethylcellulose, hydroxypropylethylcellulose, hydroxyethylcellulose, hydroxyethylmethylcellulose, , Polyvinyl alcohol, alginic acid, chitosan, polyethylene glycol, polyethylene oxide, sodium alginate, sodium hyaluronate, xanthan gum, and mixtures thereof. Preferably, it may be selected from the group consisting of hydroxypropylcellulose, hypromellose, and mixtures thereof.

In the present invention, the above-mentioned magnesium metasilicate aluminate plays a role in allowing the sustained-release preparation of the present invention to float immediately in gastric juice. It is preferable that the magnesium metasilicate aluminate is contained in the sustained release preparation of the present invention in an amount of 10 to 30% by weight. If the amount of magnesium aluminometasilicate is less than 10% by weight in the sustained-release preparation of the present invention, the adverse effect in the gastric juice may be deteriorated, and if it exceeds 30% by weight, the binding force of the tablet may become insufficient.

According to an embodiment of the present invention, each ingredient in the sustained release preparation of the present invention can be comprised as follows:

5 to 15% by weight of bepotastine or a pharmaceutically acceptable salt thereof;

25 to 40% by weight of a water-soluble diluent;

30 to 45% by weight of a sustained-release carrier; And

10 to 30% by weight of magnesium metasilicate aluminate.

In the present invention, the sustained-release preparation may be a solid oral preparation such as a tablet or a capsule. Preferably, it may be a tablet.

When the sustained-release preparation is purified, the density of the tablet is 0.870 or more and less than 0.994 g / cm < ³ > at 37 DEG C, and excellent adduct performance and masks can be simultaneously achieved within the above range.

It is also preferable that the tablet has a hardness of 6 kP or more.

In the preparation of the sustained-release preparation of the present invention, the granule used for tabletting may be selected from a granulation method which can be generally used in a pharmaceutical process such as a direct method, a wet granulation method and a fluidized bed granulation method. At this time, it is preferable that the static pressure is 4.0 to 5.5 kN.

Sustained release formulations prepared according to the present invention exhibit the properties of gastric retention, that is, they float immediately in the stomach fluids and float until the disintegration of the formulation is terminated or the release of the bevitalustine or its pharmaceutically acceptable salts is terminated .

When the sustained-release preparation prepared according to the present invention was tested in a paddle method at a rotation speed of 50 rpm in a state floating in a pH 1.2 solution, the effective ingredient was 10 to 40% in 1 hour, 40 to 70% in 2 hours, 6 hours , And can be administered once a day.

The sustained-release preparation prepared according to the present invention is substantially biologically equivalent to a conventional administration of Tarion tablets twice a day when administered once a day to human subjects and has a relative Cmax of 80 to 125 AUC.

The sustained-release preparation produced according to the present invention exhibits a Cmax in the range of about 50 to 150 ng / mL when administered in a once-a-day dosage form to human subjects and exhibits an AUC in the range of about 400 to 900 ng · h / mL.

Although the sustained-release preparation of the present invention was applied to the above-mentioned drug delivery and sustained-release technology without increasing the size, the usage was reduced from twice a day to one time per day, but the same bioavailability as that of the control drug, Thereby improving the convenience of taking a patient, and can be useful for the treatment of allergic rhinitis or pruritus.

In addition, the sustained-release preparation of the present invention has excellent optical and chemical stability as compared with the conventional preparation, Taro's preparation, so that the racemization to the (R) -configuration occurs and the pharmacological activity is lowered or the purity The problem can be prevented.

In addition, the present invention can be manufactured in a general and simple manner, thereby satisfying the work convenience of the manufacturer and expecting a high production yield and cost reduction in the industry.

Fig. 1 is a graph showing the results of the above-described sustained-release sustained-release preparations prepared in Example 1 and Tarion tablets of Comparative Example 1, This is the dissolution test result of the veicillate.
Fig. 2 shows the results of dissolution test of bevapastastin besylate in the sustained-release sustained-release preparations prepared in Examples 1 to 3. Fig.
FIG. 3 is a pharmacokinetic test result of bevapastine bevacillate in a beagle dog using the sustained-release preparation prepared in Comparative Example 2 as a test drug and the Tarion tablet as a comparative Example 1 as a control.
4 is a pharmacokinetic test result of bepotastine besylate in a beagle dog using the two-layered tablet prepared in Comparative Example 3 as a test drug and the Tarion tablet as a comparative example as a control .
FIG. 5 is a pharmacokinetic test result of bevapastin bevacillate in beagle dogs using the above-described sustained-release sustained-release preparation prepared in Example 1 as a test drug and the Tarion formulation as a comparative example 1 as a control.
FIG. 6 is a pharmacokinetic test result of beportaustic bevacillate in a healthy adult using the sustained-release sustained-release preparation prepared in Example 3 as a test drug and the Tarion tablet as a comparative example 1 as a control.
Fig. 7 is a test result in which the adverse effect of the above-mentioned sustained-release sustained-release prepared in Examples 2, 4 and 5 and Comparative Examples 4 and 5 was evaluated.
Fig. 8 shows the results of evaluation of the physical properties of the above-mentioned sustained-release sustained-release preparations prepared in Examples 6 to 9 and Comparative Examples 6 and 7. Fig.
9 is a dissolution test result of bevetastine bevacillate in the sustained-release sustained-release preparations prepared in Examples 2, 10 and 11.
Fig. 10 shows the dissolution test results of bevapastin bevacillate in the sustained-release sustained-release preparations prepared in Example 2, Comparative Examples 8 and 9. Fig.

Hereinafter, the present invention will be described in more detail with reference to Examples. However, the scope of the present invention is not limited by these embodiments. The embodiments of the present invention are intended to provide a more complete understanding of the present invention to those skilled in the art.

Example  1. According to the invention Stay  Manufacture of West Jungjeong

In the composition shown in the following Table 1, bevapastastin besylate, hydroxypropylcellulose, D-mannitol, hypromellose and magnesium metasilicate alumina were mixed well, and then magnesium stearate, which was sieved through a No. 40 sieve, was added and mixed . The mixture was tableted according to the following Table 1 to prepare a white round tablet having 200 mg per unit tablet.

[Table 1]

Example  2. According to the present invention Stay  Manufacture of West Jungjeong

Hydroxypropylcellulose was dissolved in purified water corresponding to 190 mg of the purified hydroxypropylcellulose to prepare a binding solution. Then, the binding solution was prepared, and the bevapastastin besylate, D-mannitol and hypromellose were mixed well. The mixture was placed in a fluidized bed granulator and sprayed with a binding solution to prepare granules. The resulting granules were sieved with a No. 30 sieve and mixed with magnesium metasilicate aluminate. The granules were agitated with magnesium stearate, which was then sieved through a No. 40 sieve, and then tableted according to the following Table 2 to prepare a white round tablet having 200 mg per unit tablet.

[Table 2]

Example  3. According to the present invention Stay  Manufacture of West Jungjeong

Opa-dry white was dispersed in purified water corresponding to 72 mg of the tablet in the composition shown in Table 3 below to prepare a coating solution. The tablets prepared in the same manner as in Example 2 were filled in a pan coater and sprayed with a coating solution to prepare film-coated tablets. After completion of the spraying of the coating solution, the residual heat of the coater was used to visualize with Carbowaban wax.

[Table 3]

Comparative Example  One. Tarion  tablet

10 mg of tarontin, a commercially available beportantine bevicillin preparation, was used as Comparative Example 1

Comparative Example  2. Bepotastine Veylate  Manufacture of sustained-release preparations containing

Hydroxypropylcellulose, D-mannitol, microcrystalline cellulose, and hypromellose were well mixed with the composition described in Table 4 below, and the mixture was reacted with magnesium stearate, which was sieved through a No. 40 sieve. This mixture was triturated to produce a white round tablet of 200 mg per unit tablet.

[Table 4]

Comparative Example  3. Bepotastine Veylate  Containing Internal preservation  And West  Manufacture of two-layer definition

D-mannitol, red iron oxide and crospovidone were mixed well with the composition described in Table 5 below, and the mixture was sieved through a No. 40 sieve with magnesium stearate, Hydroxypropylcellulose, D-mannitol, and hypromellose were mixed well, and then the mixture was sieved with a magnesium stearate sieved through a No. 40 sieve, and the mixture was allowed to stand for one hour. The two mixtures were tableted with a two-layer tablet machine to produce a circular two-layer tablet consisting of two white and red layers of 260 mg per unit tablet.

[Table 5]

Example  4 and 5, Comparative Example  4 and 5. Stay  Manufacture of West Jungjeong

A white round tablet of 200 mg per unit tablet was prepared according to the procedure of Example 2 with the composition shown in Table 6 below.

 [Table 6]

Example  6 to 9, Comparative Example  6 and 7. Stay  Manufacture of West Jungjeong

A white round tablet of 200 mg per unit tablet was prepared in the same manner as in Example 2 with the composition shown in Table 7 below.

[Table 7]

Example  10 and 11. < RTI ID = 0.0 > Stay  Manufacture of West Jungjeong

20 mg of the hypromellose purified by the composition shown in Table 8 below was dissolved in purified water to prepare a binding solution, and the remaining amount of bevetastatin bead salt, D-mannitol, and hypromellose was mixed well. The mixture was placed in a fluidized bed granulator and sprayed with a binding solution to prepare granules. The resulting granules were sieved with a No. 30 sieve and mixed with magnesium metasilicate aluminate. The granules were agitated with magnesium stearate, which had been sieved through a No. 40 sieve, and then tableted according to the following Table 8 to prepare a white round tablet having 200 mg per unit tablet.

[Table 8]

Comparative Example  8 and 9. Stay  Manufacture of West Jungjeong

Hydroxypropylcellulose was dissolved in purified water corresponding to 190 mg of the purified hydroxypropylcellulose to prepare a binding solution. Then, the bevapastastin besylate, D-mannitol, microcrystalline cellulose and hypromellose were mixed well . The mixture was placed in a fluidized bed granulator and sprayed with a binding solution to prepare granules. The resulting granules were sieved with a No. 30 sieve and mixed with magnesium metasilicate aluminate. 40 was sieved with magnesium stearate and the tablets were tabletted according to the following Table 9 to prepare a white round tablet having 200 mg per unit tablet.

[Table 9]

Experimental Example 1 in vitro  Dissolution test

The above-mentioned sustained-release sustained-release preparations prepared in Examples 1 to 3, Tarion tablets prepared in Comparative Example 1, sustained-release preparations prepared in Comparative Example 2, and double-layered dissolution tests including the fast- The release pattern of the active ingredient bepotastine besylate from the formulation was measured.

The elution and analysis conditions are as follows.

≪ Dissolution condition >

- Test method: Republic of Korea Pharmacopoeia second law (paddle method)

- Test Solution: First Solution of Korean Pharmacopoeia (pH 1.2)

- Test liquid volume: 900 mL

- Test temperature: 37 ± 0.5 ℃

- Rotation speed: 50 rpm

<Analysis condition>

- Detector: Ultraviolet absorptiometer (measuring wavelength 260 nm)

- Column: CapcellPAK C18 MG 5 μm, 4.6 mm id x 150 mm L

- Column temperature: 40 ° C

- Mobile phase: Dissolve sodium pentane sulfonic acid to 0.1% in a phosphate buffer solution of pH 3.0 (dissolve in purified water to make 0.05 M potassium dihydrogenphosphate and adjust pH 3.0 with phosphoric acid): acetonitrile = 7: 3 mixture.

- Flow rate: 1.0 mL / min

- Injection volume: 20 μL

The results are shown in FIGS. 1 and 2.

As shown in Fig. 1, it was confirmed that the release of Taranje Tab of Comparative Example 1 was completed within one hour, whereas the release of the Taranje Tab of Example 1 and Comparative Example 2 occurred over 6 hours. Also, in Comparative Example 3, which includes the immediate and extended portions, it was confirmed that the release of the immediate release was completed at the beginning and then the release was made over 6 hours thereafter.

Further, as shown in Fig. 2, it was confirmed that the sustained-release sustained-release sustained-release sustained-release sustained-release sustained-release sustained-release sustained-release sustained-release sustained-release sustained-release sustained-release sustained-release sustained-release sustained-release sustained-

Experimental Example  2. Beagles in vivo Pharmacokinetics  exam

Comparative Example 1 The sustained-release preparation prepared in Comparative Example 2, the bilayer prepared in Comparative Example 3, and the sustained-release sustained-release preparation prepared in Example 1 were subjected to the test drug And cross-over pharmacokinetic tests were conducted on 12 male beagle dogs (about 10 kg).

In the case of the control drug, one tablet was administered orally twice at intervals of 12 hours, and 0.33, 0.67, 1, 1.5, 2, 4, 6, 9 and 12 hours after the first administration, Blood was collected at 1, 1.5, 2, 4, 8, and 12 hours. In the case of the test drug, one tablet was orally administered and blood was collected at 0, 0.5, 1, 1.5, 2, 3, 4, 6, 9, 12, 15 and 24 hours before and after administration.

Plasma was separated by centrifugation of 3 mL of blood collected from the umbilical vein and stored in the freezer until analysis. LC-MS / MS was used for the analysis of plasma buttetastine, and Olmesartan RNH-6270 was used as the internal standard.

Analysis and MS conditions are as follows.

<Analysis condition>

- Device: Agilent 1200/6430 Triple Quad

Column: Unison UK C18 (3 [mu] m, 2 mm ID X 50 mm L)

- Column temperature: 35 ° C

- Mobile phase: Ammonium formate 5 Mm in distilled water (adjust to pH 3.5 using formic acid): Acetonitrile = 64: 36

- Flow rate: 0.4 mL / min

- Injection volume: 2 μL

- Sample temperature: 4 ℃

<MS condition>

- Ionization: Positive ion electrospray (ESI +)

- Quantitation: Multiple Reaction Monitoring, Bepotastine 389.2

202.1, Olmesartan 447.2 → 207.2

The results are shown in Tables 10 to 12 and Figs. 3 to 5 below.

[Table 10]

[Table 11]

[Table 12]

As shown in Table 10 and FIG. 3, the sustained-release preparation prepared in Comparative Example 2 showed poor bioavailability because neither release nor absorption of the bevapastastin besylate was accomplished.

In addition, as shown in Table 11 and FIG. 4, even in the case of the double layer definition including the fast and the western portions manufactured in Comparative Example 3, the blood concentration of the bevitalystine besylate rises rapidly at an early stage As a result, it was confirmed that the bioavailability was lowered because the release and absorption of the drug were not completely performed. This suggests that it is difficult to administer bevetastatin bevacillate once a day by using a general slow-release tablet because it is hardly absorbed after the upper part of the small intestine.

On the other hand, as shown in Table 12 and FIG. 5, the sustained-release sustained-release sustained-release sustained-release sustained-release sustained-release sustained-release sustained-release sustained-release sustained-release sustained-release sustained-release sustained-release sustained-release sustained-release sustained- As a result, it can be seen that the sustained-release sustained release of bepotastine besylate normally stays within the stomach.

Experimental Example 3: Pharmacokinetic test in humans

COMPARATIVE EXAMPLE 1 Pharmacokinetic tests were performed on 28 healthy adult male subjects using the intralion tablets as the reference drug and the uptake sustained-release tablets prepared in Example 3 as the test drug.

In the case of the control drug, one tablet was orally administered twice at intervals of 12 hours, and 0.33, 0.67, 1.5, 2, 3, 4, 5, 8 and 12 hours after the first administration, 0.33, 0.67, 1, 1.5, 2, 3, 6, and 12 hours. In the case of the test drug, one tablet was orally administered and blood was collected at 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12 and 24 hours before and after administration.

The collected blood was centrifuged and the plasma was separated and stored in the freezer until analysis. LC-MS / MS was used for the analysis of plasma isotacticin, and Bepotastine-d6 Besilate was used as the internal standard.

Analysis and MS conditions are as follows.

<Analysis condition>

- Appliance: Acquity UPLC system

Column: Acquity UPLC BEH C18 (1.7 μm, 2.1 mm ID X 50 mm L)

- Column temperature: 30 ° C

- mobile phase: 0.1% formic acid in distilled water: 0.1% formic acid in acetonitrile = 75: 25

- Flow rate: 0.3 mL / min

- Injection volume: 5 μL

- Sample temperature: 15 ° C

<MS condition>

- Ionization: Positive ion electrospray (ESI +)

- Quantitation: Multiple Reaction Monitoring, Bepotastine 389.39 → 202.15, Bepotastine-d6 395.39 → 202.15

The results are shown in Table 12 and Fig. 6 below.

[Table 12]

As shown in Table 12 and FIG. 6, it was confirmed that the sustained-release sustained-release preparation prepared in Example 3 exhibited bioavailability equivalent to that of Comparative Example 1 administered twice a day. As a result, it can be seen that the sustained-release sustained release of bepotastine besylate normally persists in the stomach for a long time.

Experimental Example  4. Stability test

The stability evaluation of the above-mentioned sustained-release sustained-release preparation prepared in Example 3 was carried out. The stability test was carried out under severe conditions (unpackaged, 40 ° C, 75% RH) for 6 months under long-term conditions (HDPE bottle packaging, 25 ° C and 60% RH) and accelerated conditions (HDPE bottle packaging, 40 ° C and 75% RH) The contents of the main storage, the amounts of the flexible substances (ethyl ester and unknown) and the optical isomer R-arrangement were evaluated. Each test and analysis conditions are as follows.

<Content test conditions>

Take more than 20 tablets of the slow-release tablets and make up the powder. One tablet is precisely weighed and dissolved in 200 mL of diluted solution (purified water: methanol = 1: 1) and filtered to prepare the sample solution.

<Content analysis condition>

- Detector: Ultraviolet absorptiometer (measuring wavelength 260 nm)

- Column: CapcellPAK C18 MG 5 μm, 4.6 mm id x 150 mm L

- Column temperature: 40 ° C

- Mobile phase: 0.1% Sodium pentanesulfonate in pH 3.0 Phosphate buffer (Potassium dihydrogen phosphate 0.05 M in distilled water, adjust to pH 3.0 using Phosphoric acid): Acetonitrile = 7: 3

- Flow rate: 1.0 mL / min

- Injection volume: 10 μL

&Lt; Conditions for testing a flexible substance &

Take more than 20 tablets of the sustained-release tablets and make a powder, and dissolve 1 tablet of the tablet in precisely weighed amount, and dissolve in 50 mL of mobile phase.

&Lt; Conditions for analyzing &

- Detector: Ultraviolet absorptiometer (measuring wavelength 220 nm)

- Column: CapcellPAK C18 MG 5 μm, 4.6 mm id x 150 mm L

- Column temperature: 40 ° C

- Mobile phase: 0.1% Sodium pentanesulfonate in pH 3.0 Phosphate buffer (Potassium dihydrogen phosphate 0.05 M in distilled water, adjust to pH 3.0 using Phosphoric acid): Acetonitrile = 7: 3

- Flow rate: 1.0 mL / min

- Injection volume: 20 μL

&Lt; Optical isomer test conditions >

Take more than 20 tablets of sustained-release tablets to make a powder. One tablet is precisely weighed, dissolved in 100 mL of mobile phase, and then filtered to give the sample solution.

&Lt; Optical isomer analysis conditions >

- Detector: Ultraviolet absorptiometer (measuring wavelength 225 nm)

- Column: Ultron ES-OVM 5 μm, 4.6 mm id x 150 mm L

- Column temperature: 40 ° C

- mobile phase: 2.7 g of potassium dihydrogenphosphate is dissolved in 1 L of water and adjusted to pH 5.5 with 0.2 M sodium hydroxide solution. To 500 mL of this solution, add 75 mL of acetonitrile.

- Flow rate: 0.5 mL / min

- Injection volume: 10 μL

The results are shown in Tables 13 to 15 below.

[Table 13]

[Table 14]

[Table 15]

As shown in Tables 13 to 15, it was confirmed that the uptake sustained-release prepared in Example 3 exhibited excellent optical and chemical stability.

Experimental Example  5. Refining Secondary ability  evaluation

The adverse effects of the sustained-release sustained release prepared in Examples 2, 4 and 5 and Comparative Examples 4 and 5 were evaluated at room temperature. The vials were filled with 15 mL of purified water and the tablets were placed. After 2, 4, 8, 12, and 24 hours after the initiation, the shape of the tablets and whether they were suspended or not were visually observed. Before and after observation, the vial was shaken to prevent the tablets from sticking to the glass surface.

As shown in Table 16 and FIG. 7, in the case of Examples 2, 4 and 5, the form and suspension of the tablet were maintained normally until the end of the test, whereas in Comparative Example 4, It does not maintain the buoyancy such that it sinks after 8 hours and floats again after 24 hours. In Comparative Example 5, it does not lose the buoyancy, but after 8 hours, it can not maintain the shape of the tablet, Respectively.

If the fluidity is not maintained properly as in the case of Comparative Example 4, the migrating myoelectric complex (MMC) cycle, which is generally performed at 2-hour intervals, causes the tablet to be discharged from the stomach and transferred to the small intestine. There is a possibility that the bioavailability can be adversely affected.

On the other hand, when disintegration occurs due to the inability to maintain the tablet form as in Comparative Example 5, the release of the drug is accelerated and the duration of the blood concentration is shortened, thereby increasing the possibility of side effects.

[Table 16]

Experimental Example  6. Evaluation of Properties of Tablets

In order to confirm the physical properties of the sustained-release sustained-release preparations prepared in Examples 6 to 9 and Comparative Examples 6 and 7, the hardness, degree of abrasion, density and immediate suspension of the tablets were measured.

The hardness of the tablet was measured using a hardness tester. The density of the tablet was measured using a Micromeritics (Accupyc). The degree of fatigue of the tablet was evaluated using a fatigue tester, Was visually observed to see if the tablet was immediately floated.

[Table 17]

As shown in Table 17 and FIG. 8, it was confirmed that the hardness and density were increased in proportion to the static pressure. In the case of Comparative Example 6, wrinkles of the tablets were observed, but in Examples 6 to 9 and Comparative Example 7, no refinement of the tablets occurred. In the case of Examples 6 and 9, the tablets immediately floated when the tablets were added to the purified water, but the tablets were found to settle down in the case of Comparative Example 7.

Therefore, when the density of the tablet is lower than the density of water (about 0.994 g / cm ³ ) at 37 ° C, it can be known that the tablets are immediately added to the purified water. When the tablet is tableted, It should be understood that the management should be performed.

Experimental Example 7. in vitro  Dissolution test

The elution tests of the sustained-release sustained-release preparations prepared in Examples 2, 10 and 11 were carried out, and the release pattern of the active ingredient bebutastin beester was measured from these preparations. The elution and analysis conditions are the same as in Experimental Example 1.

As shown in Fig. 9, it was confirmed that Example 10 exhibited a higher elution rate than Example 2, whereas Example 11 showed a 0th order emission pattern at a dissolution rate similar to Example 2.

Experimental Example 8. in vitro  Dissolution test

Dissolution tests of the sustained-release sustained-release preparations prepared in Example 2 and Comparative Examples 8 and 9 were carried out, and the release pattern of the active ingredient bebutastin be- enylate was measured from these preparations. The elution and analysis conditions are the same as in Experimental Example 1.

As shown in FIG. 10, it was confirmed that the elution rates of Comparative Examples 8 to 9 were similar to those of Example 2 in the early stage, but the elution rate was decreased in the latter stage.

Both D-mannitol and microcrystalline cellulose are similar to those used frequently as a diluent, but unlike water-soluble D-mannitol, microcrystalline cellulose does not dissolve in water and therefore slows the disintegration of the preparation and affects the release pattern of the drug. If the dissolution rate is slowed and the dissolution end timing is delayed, there is a possibility that the bioavailability can be adversely affected due to the nature of the drug whose absorption site is limited to the small intestine.

Claims (19)

Bepotastine or a pharmaceutically acceptable salt thereof;
Water-soluble diluent;
Sustained release carrier; And
Magnesium metasilicate aluminate;
&Lt; / RTI &gt; 2. The sustained-release preparation according to claim 1, wherein said beatifastine or a pharmaceutically acceptable salt thereof is bepotastine bead salt. The sustained-release preparation according to claim 1, wherein the water-soluble diluent is a sugar alcohol. The sustained-release preparation according to claim 3, wherein the sugar alcohol is selected from the group consisting of erythritol, arabitol, xylitol, ribitol, sorbitol, mannitol, galactitol, maltitol, lactitol and mixtures thereof. The sustained-release preparation according to claim 3, wherein the sugar alcohol is D-mannitol. The sustained-release carrier according to claim 1, wherein the sustained-release carrier is at least one selected from the group consisting of hydroxypropylcellulose, hypromellose, ethylcellulose, hydroxypropylethylcellulose, hydroxyethylcellulose, hydroxyethylmethylcellulose, Wherein the sustained release preparation is selected from the group consisting of polyvinyl alcohol, alginic acid, chitosan, polyethylene glycol, polyethylene oxide, sodium alginate, sodium hyaluronate, xanthan gum, and mixtures thereof. The sustained-release preparation according to claim 6, wherein the sustained-release carrier is selected from the group consisting of hydroxypropylcellulose, hypromellose, and mixtures thereof. The sustained-release preparation according to claim 1, which comprises 10 to 30% by weight of magnesium metasilicate aluminate. 9. The method of claim 8,
5 to 15% by weight of bepotastine or a pharmaceutically acceptable salt thereof;
25 to 40% by weight of a water-soluble diluent;
30 to 45% by weight of a sustained-release carrier; And
10 to 30% by weight of magnesium metasilicate aluminate;
&Lt; / RTI &gt; The sustained-release preparation according to claim 1, which is a solid oral preparation. 11. The sustained-release preparation according to claim 10, which is a tablet. 11. A sustained release formulation according to claim 10, wherein the tablet has a density of less than 0.870 and less than 0.994 g / cm &lt; ³ &gt; 11. The sustained release preparation according to claim 10, wherein the tablet has a hardness of 6 kP or more. The sustained-release preparation according to claim 1, wherein the sustained-release preparation is a sustained-release formulation. 15. The sustained release formulation of claim 14, wherein the suspension is suspended immediately in the gastric juice and is suspended until the disintegration of the formulation is complete or the release of the bevitalystine or a pharmaceutically acceptable salt thereof is terminated. The pharmaceutical composition according to claim 1, wherein the pH 1.2 eluate is released at a rate of 10 to 40% for 1 hour, 40 to 70% for 2 hours, and 80% or more for 6 hours, Formulation. The sustained-release preparation according to claim 1, which is administered once a day. 18. The slow release formulation of claim 17, wherein the sustained release formulation exhibits a relative Cmax and AUC of 80 to 125 as compared to the immediate release formulation administered twice daily. 18. The sustained release formulation of claim 17, administered in a once-a-day dosage form, exhibiting a Cmax of 50 to 150 ng / mL and an AUC of 400 to 900 ng · h / mL.

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