KR20190049023A - Controlled-release monolithic matrix tablets comprising bepotastine or its pharmaceutically acceptable salt and process for preparing the same - Google Patents

Abstract

The present invention relates to a controlled-release monolithic matrix tablet for once-a-day administration, comprising bepotastine or a pharmaceutically acceptable salt thereof; a swellable polymer; and a certain release controller. Further, the present invention relates to a method of preparing the controlled-release monolithic matrix tablet. The controlled-release monolithic matrix tablet of the present invention initially shows a fast-releasing release pattern, and later shows a continuous-releasing release pattern, and thus can be administered once a day, and can minimize absorption variations by achieving the release independent of changes in the pH of the digestive tracts due to digestive tract environments and/or food, and the like. Further, the controlled-release monolithic matrix tablet according to the present invention exhibits a biological equivalence to conventional preparations administered twice a day. Furthermore, the controlled-release monolithic matrix tablet prepared according to the method of the present invention can effectively maintain the stability of bepotastine.

Description

Controlled release single matrix tablets comprising beportantine or a pharmaceutically acceptable salt thereof and a process for preparing the same,

The present invention relates to a controlled-release single matrix tablet for once-a-day administration and a method of making the same. More particularly, the present invention relates to a pharmaceutical composition comprising bevetastine or a pharmaceutically acceptable salt thereof; A swellable polymer; Controlled release single matrix tablets for once-a-day dosing, and a method of making the same.

Bepotastine is a compound of formula (I) wherein the chemical name is (S) -4- [4- [(4-chlorophenyl) -2-pyridylmethoxy] piperidin- . BePotastine is a new second-generation antihistamine drug that not only inhibits the onset of symptoms of allergic rhinitis but also does not pass through the blood-brain barrier and does not cause side effects such as sleepiness that the first-generation antihistamines have.

≪ Formula 1 >

Bephotastine has been developed as an immediate release formulation in the form of a vesicular salt and is marketed under the trade name Tarion. The formulation is administered 10 mg twice a day. According to PMDA and 'Drugs' 2010 (Volume 70, pages 1579-1591) 'Oral Bepotastine in allergic disorders' in Japan PMDA and beverages do not take meals, but when the drug is taken after meals, It is known that the absorption rate in the body is lowered. Also, it is known that the solubility of bepotastine in pH solution is decreased and the solubility decreases with increasing pH.

Various studies have been made on the preparation of controlled release beportastine-containing release form for once-a-day administration in order to improve compliance with the patient's medication compliance [for example, Korean Patent Publication No. 2012-0083276, Korean Patent No. 10 -1731078, Korean Patent Laid-open Publication No. 10-2014-0016260 (International Patent Publication No. WO 2012/104818), Korean Patent Laid-open Publication No. 10-2015-0138104, etc.]. These conventional preparations of controlled release of bevetastin-containing preparation are prepared by separating the immediate-release part and the extended part. For example, they may have a form in which the extended part is surface-coated with a water-insoluble polymer (Korean Patent Publication No. 2008-0083276 ) Or a bilayer tablet form in which the inner and the outer portions are separately contained in separate layers (Korea Patent No. 10-1731078, Korean Patent Publication No. 10-2014-0016260, Korean Patent Publication No. 10-2015-0138104 Etc). However, such conventional preparations have a problem in that they are required to be coated with a water-insoluble polymer or to perform a plurality of tableting processes for forming a multi-layered structure including a double-layered tablet, . For example, Korean Patent Laid-open Publication No. 10-2014-0016260 discloses a pharmaceutical composition comprising a release-controlling matrix layer containing some bevapastastin besylate, an inactive layer, a release-controlled coating layer, a betapastin drug layer and the remaining betapastin besylate A multi-layered tablet comprising a drug layer; 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, as described above, it has been known that when the drug is taken after meals, the absorption rate of bepotastine in the body is lower than that in fasting, and that the higher the pH is, the lower the solubility of bepotastine is. Therefore, the immediate release preparation shows a phenomenon that the dissolution rate is lowered due to the effect of the meal and the absorption is lowered. In addition, even in the case of the sustained-release formulation, the dissolution profile of the drug changes due to the effect on the diet, resulting in a decrease in absorption of the drug and a high variation in the individual.

Thus, it is desirable to avoid complicated formulation processes (e.g., water-insoluble polymer coating processes, formation processes of multi-layer structures, etc.) while avoiding emission changes due to changes in gastrointestinal environment and / Lt; RTI ID = 0.0 > 1 < / RTI >

The present inventors have conducted various studies to develop a pharmaceutical composition in the form of a single matrix tablet once a day. As a result, the present inventors have found that when a swellable polymer and a specific release modifier are combined and formulated into a release-controlled monolithic matrix tablet, they exhibit an immediate release pattern at the beginning and a sustained release pattern at a later time Administration is possible; It has also been found that release changes (and thus absorption deviations) due to changes in gastrointestinal pH due to gastrointestinal environment and / or food or the like can be minimized. Further, it has been found that the stability of bevetastine can be effectively maintained when the single matrix tablet is prepared according to the direct tableting method or dry granule tableting method.

Accordingly, it is an object of the present invention to provide a once-daily controlled release single matrix tablet obtained by formulating bevetastine or a salt thereof using a combination of a swelling polymer and a specific release modifying agent.

It is another object of the present invention to provide a method for producing the above-mentioned release-controlled single matrix tablet.

According to one aspect of the present invention, beportastine or a pharmaceutically acceptable salt thereof; A swellable polymer; And one or more release regulators selected from the group consisting of citric acid, succinic acid, tartaric acid, oxalic acid, glutamic acid, ascorbic acid, malic acid, maleic acid, lactic acid, fumaric acid, formic acid, acetic acid, alginic acid, and polyacrylic acid. A controlled release single matrix tablet is provided.

According to another aspect of the present invention there is provided a pharmaceutical composition comprising: (a) bevitalastine or a pharmaceutically acceptable salt thereof; A swellable polymer; At least one release controlling agent selected from the group consisting of citric acid, succinic acid, tartaric acid, oxalic acid, glutamic acid, ascorbic acid, malic acid, maleic acid, lactic acid, fumaric acid, formic acid, acetic acid, alginic acid and polyacrylic acid; And a diluent; And (b) mixing the mixture obtained in step (a) with a lubricant, and then titrating the resulting mixture. The present invention also provides a process for preparing a release-controlled single matrix tablet for once-a-day administration.

According to a further aspect of the present invention there is provided a pharmaceutical composition comprising (a ') bepotastine or a pharmaceutically acceptable salt thereof; A swellable polymer; At least one release controlling agent selected from the group consisting of citric acid, succinic acid, tartaric acid, oxalic acid, glutamic acid, ascorbic acid, malic acid, maleic acid, lactic acid, fumaric acid, formic acid, acetic acid, alginic acid and polyacrylic acid; diluent; Preparing a dry granulate of a mixture of a lubricant and a lubricant; And (b ') mixing the dry granules obtained in step (a ') with a lubricant, and then titrating the resultant mixture, wherein the release-controlled single matrix tablet is prepared for once- .

The release-controlled, single-matrix tablets of the present invention exhibit an immediate release pattern at the beginning (up to about 6 hours) and a continuous release pattern at a later stage (up to about 6 hours) by formulation with a combination of a swellable polymer and a specific release modifier It is possible not only to administer once a day but also to dissolve irrespective of changes in gastrointestinal pH due to the gastrointestinal tract environment and / or food or the like, so that the absorption deviation can be minimized. In addition, since the release-controlled single matrix tablet of the present invention administered once a day is biologically equivalent to the conventional twice-a-day formulation, it is possible to improve the patient's compliance with the medicament once administered once a day. In addition, the release-controlled single matrix tablets prepared according to the preparation method of the present invention can effectively maintain the stability of bevetastine.

Figure 1 shows the dissolution test results of the release-controlled single matrix tablets of the present invention.
Figure 2 shows the dissolution test results of a single matrix tablet (Comparative Example 1) containing no release modifier.
FIG. 3 is a plasma concentration profile obtained after administering the release-controlled single matrix tablets (single dose) and the control preparation (double-dose, two doses) of the present invention to beagle dogs, respectively.

The present invention relates to a pharmaceutical composition comprising bevetastine or a pharmaceutically acceptable salt thereof; A swellable polymer; And one or more release regulators selected from the group consisting of citric acid, succinic acid, tartaric acid, oxalic acid, glutamic acid, ascorbic acid, malic acid, maleic acid, lactic acid, fumaric acid, formic acid, acetic acid, alginic acid, and polyacrylic acid. ≪ / RTI > a single matrix tablet.

The release-controlled single matrix tablets of the present invention comprise bevotastine or a pharmaceutically acceptable salt thereof as an active ingredient. The pharmaceutically acceptable salts of bevapastastin include, without limitation, salts derived from pharmacologically or physiologically acceptable inorganic acids, organic acids, bases. Examples of the inorganic acid or organic acid 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, Methanesulfonic acid, formic acid, benzoic acid, malonic acid, naphthalene-2-sulfonic acid, benzenesulfonic acid and the like. Examples of such bases include alkali metals (e.g., sodium or potassium), alkaline earth metals (e.g., magnesium), and the like. In one embodiment, the pharmaceutically acceptable salt of bepotastine may be bepotastine bevacillate. Beptotastine or a pharmaceutically acceptable salt thereof may be used as a therapeutically effective amount, for example, from 10 mg to 40 mg, preferably from 15 mg to 30 mg, more preferably from 10 mg to 40 mg, Lt; RTI ID = 0.0 > mg / ml < / RTI >

In the release-controlled, single matrix tablet of the present invention, the swellable polymer enables sustained release / elution of the betapastin or a pharmaceutically acceptable salt thereof. The swelling polymer may be selected from the group consisting of polyvinyl alcohol, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, methylcellulose, carboxymethylcellulose, polyethylene oxide, polyvinylpyrrolidone, xanthan gum, guar gum, chitosan, Carrageenan, carboxymethylcellulose, and sodium alginate. When a specific combination of swellable polymers, that is, a combination of hydroxypropylmethylcellulose and polyvinyl alcohol is used, the initial elution of bevetastin (elution up to about 6 hours) shows a rapid elution pattern, and the additional elution pattern is a continuous elution pattern ≪ / RTI > is shown by the present invention. Therefore, it is preferable to use a combination of hydroxypropyl methylcellulose and polyvinyl alcohol as the swelling polymer. In the combination of hydroxypropyl methylcellulose and polyvinyl alcohol, the weight ratio of hydroxypropyl methylcellulose and polyvinyl alcohol may be 1: 1 to 2, preferably about 1: 1.5. As the hydroxypropylmethylcellulose, hydroxypropylmethylcellulose having a viscosity of 50 mPa.S to 100,000 mPa.S, more preferably 4,000 mPa.S to 100,000 mPa.S, may be used. The polyvinyl alcohol preferably has a weight average molecular weight of 20,000 to 250,000. The swellable polymer may be present in an amount of 20 to 80 wt.%, Preferably 30 to 70 wt.%, More preferably about 50 wt.%, Based on the total weight of the tablet.

In the release-controlled, single-matrix tablet of the present invention, the release modifier allows the formulation containing beportastine and a swellable polymer to exhibit a constant release pattern, even when the pH changes in the gastrointestinal tract according to the behavior of the body. In general, the gastrointestinal pH is about 1.2, the duodenum is about pH 5, the plant is about pH 6, the ileum is about pH 7, and the dissolution rate changes depending on the position where the preparation stays, Furthermore, the pH of the stomach may increase to between 3 and 5 due to the influence of food after the meal, and when the preparation is carried out using a conventional sustained-release polymer, the release is lowered, There is a high possibility of causing a decrease in absorption in the body. According to the present invention, when a specific release modifying agent is used, the absorption deviation can be minimized since the gastrointestinal environment and / or the dissolution regardless of the change of pH of the gastrointestinal tract caused by food or the like can be achieved. The release modifier is at least one selected from the group consisting of citric acid, succinic acid, tartaric acid, oxalic acid, glutamic acid, ascorbic acid, malic acid, maleic acid, lactic acid, fumaric acid, formic acid, acetic acid, alginic acid and polyacrylic acid. These release modifiers can enhance the release of bepotastine under neutral conditions without strong acidity. In addition, these release modifiers do not significantly affect the elution of the drug that controls the release under acidic conditions, but as the pH increases, the releasing formulation becomes acidic and increases the release of beportatin, To exhibit the same dissolution pattern. As the release regulator, it is preferable to use at least one release modifier selected from the group consisting of citric acid, fumaric acid, tartaric acid, succinic acid, malic acid, and alginic acid, more preferably citric acid. The release modifying agent is preferably present in an amount of 5 to 30% by weight, more preferably 5 to 25% by weight, and more preferably 7 to 20% by weight, based on the total weight of the tablets desirable. If the amount of the release modifier is less than 5% by weight, the effect of the release modifier may not be exhibited. If the amount of the release modifier exceeds 30% by weight, the stability including the light stability may be adversely affected.

In one embodiment, 900 ml of each of purified water, pH 1.2, pH 4.0, and pH 6.8 was used as an eluant, and the elution test was performed according to the Korean Pharmacopoeia dissolution test 1 method while stirring at 100 rpm for 12 hours (Ii) the dissolution rate in the pH 1.2 solution, the dissolution rate in the purified water, and the pH value in the pH 1 solution and the purified water, respectively, at any point between 4 hours and 12 hours. (Iii) a difference in dissolution rate in pH 1.2 solution, a purified water dissolution rate and a dissolution rate in pH 4.0 solution, and (iv) a dissolution rate in pH 1.2 solution and a dissolution rate in purified water and pH 6 A controlled release single matrix tablet is provided wherein the difference in dissolution rate in the .8 solution is 10% or less.

The controlled release single matrix tablets of the present invention may further comprise one or more pharmaceutically acceptable additives selected from the group consisting of diluents, surfactants, lubricants, flavors, and coatings.

Examples of the diluent include lactose, glucose, microcrystalline cellulose, crystalline cellulose, calcium dihydrogen phosphate or its hydrate (for example, dihydrate), mannitol, isomalt, sorbitol, pregelatinized starch, sucrose, starch, lactitol, xylitol, Dextrose, dextran, betacyclodextrin, cellulotose ^TM (a mixture of lactose and cellulose), prosolve ^TM (a mixture of silica and microcrystalline cellulose), maltitol, corn starch, low substituted hydroxypropyl cellulose, potato starch, and the like.

Examples of such surfactants include, but are not limited to, sodium lauryl sulfate, polysorbate 80, polysorbate 60, polysorbate 40, sucrose fatty acid ester, cremophor RH 40 ^TM , and the like.

Examples of the lubricant include stearic acid or a salt thereof (e.g., magnesium stearate, calcium stearate, etc.), stearyl fumaric acid or its salts (such as sodium stearyl fumarate), light silicic anhydride, palmitic acid, talc, Waxes, hydrogenated vegetable oils, mineral oils, polyethylene glycols, and the like.

The present invention also provides a method of making the release-controlled single matrix tablet. That is, the present invention provides a method for producing the release-controlled single matrix tablet through a direct tableting method or a dry granule tabletting method, wherein the release-controlled single matrix tablet prepared according to the preparation method of the present invention effectively inhibits the stability of bevetastine .

In one aspect, the present invention provides a pharmaceutical composition comprising (a) bepotastine or a pharmaceutically acceptable salt thereof; A swellable polymer; At least one release controlling agent selected from the group consisting of citric acid, succinic acid, tartaric acid, oxalic acid, glutamic acid, ascorbic acid, malic acid, maleic acid, lactic acid, fumaric acid, formic acid, acetic acid, alginic acid and polyacrylic acid; And a diluent; And (b) mixing the mixture obtained in step (a) with a lubricant and then titrating the resulting mixture. The present invention also provides a process for preparing a controlled release single matrix tablet for once-a-day administration.

In another aspect, the invention provides a pharmaceutical composition comprising (a ') bepotastine or a pharmaceutically acceptable salt thereof; A swellable polymer; At least one release controlling agent selected from the group consisting of citric acid, succinic acid, tartaric acid, oxalic acid, glutamic acid, ascorbic acid, malic acid, maleic acid, lactic acid, fumaric acid, formic acid, acetic acid, alginic acid and polyacrylic acid; diluent; Preparing a dry granulate of a mixture of a lubricant and a lubricant; And (b ') mixing the dry granules obtained in step (a') with a lubricant, and then titrating the resultant mixture, to prepare a release-controlled single matrix tablet for once-a-day administration .

In the preparation method of the present invention, beportastine or a pharmaceutically acceptable salt thereof; A swellable polymer; Release modifiers; Pharmaceutically acceptable additives (for example, diluents, lubricants, etc.) are as described above. These components are preferably sieved using a suitable mesh screen, for example a 400-700 μm mesh sieve.

In the production process of the present invention, the mixing can be carried out according to a conventional method used in the pharmaceutical industry. The production of the dry granules may also be carried out according to the conventional methods used in the pharmaceutical industry, for example, by compressing the resulting mixture using a roller compactor or the like. The tableting may also be carried out according to conventional methods used in the field of medicine. The static pressure can be adjusted appropriately to obtain a hardness of about 7-10 kp.

The release-controlled single matrix tablets of the present invention can be used in an amorphous form and, if necessary, can additionally include conventional coating layers such as film coating layers. The film coating layer may be formed using a conventional film such as polyvinyl alcohol, hydroxypropylcellulose, xanthan gum, lactose, hydroxypropyl methylcellulose, triacetin, polyvinylpyrinolidone, polyethylene glycol, propylene glycol, talc, titanium dioxide, And may include components for forming a coating. Film coating formation can be carried out by a method such as spray coating according to a conventional method.

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 thereto.

Example  One. In direct tattooing  ≪ / RTI >

Tablets containing beportastine bevacillate were prepared according to the contents and compositions of Table 1 below. The content of each component in Table 1 represents the refined sugar content (mg). Hydroxypropylmethylcellulose 2208 (15,000 mPa.S, shinetsu), polyvinyl alcohol (EMPROVE 40-88 ^TM , manufactured by Merck), microcrystalline cellulose, and citric acid were each ap- plied in a 20 mesh sieve and mixed for about 10 minutes. To the resulting mixture was added 40 ml of apple stearyl fumarate in a 40 mesh sieve, followed by mixing for about 5 minutes. The resulting mixture was compressed on a compression tablet machine to prepare a circular tablet having a weight of 200 mg per tablet. The tableting pressure was adjusted so that the hardness of the tablet was about 10 kp.

ingredient Example 1 (mg / tablet) Bepotastine acetate 20.0 Hydroxypropylmethylcellulose 2208 (15,000 mPa.s) 80.0 Polyvinyl alcohol 20.0 Microcrystalline cellulose 55.0 Citric acid 20.0 Sodium stearyl fumarate 5.0 1 Total content per unit (mg) 200.0

Example  2. In dry granule tabletting method  ≪ / RTI >

Tablets containing beportastine bevacillate were prepared according to the contents and compositions in Table 2 below. The content of each component in Table 2 represents the refined sugar content (mg). Hydroxypropylmethylcellulose 2208 (15,000 mPa.S, shinetsu), polyvinyl alcohol (EMPROVE 40-88 ^TM , manufactured by Merck), microcrystalline cellulose, and citric acid were each ap- plied in a 20 mesh sieve and mixed for about 10 minutes. The obtained mixture was further mixed with magnesium stearate and colloidal hard anhydrous silicic acid in a 40-mesh sieve for about 5 minutes. The resulting mixture was compressed on a roller compactor to produce dry granules, which were then applicated in an oscillator with a 16 mesh sawmill. To the resulting granules was added 40 ml of apple stearyl fumarate in a 40 mesh sieve, followed by mixing for about 5 minutes. The resulting mixture was compressed on a compression tablet machine to prepare a circular tablet having a weight of 200 mg per tablet. The tableting pressure was adjusted so that the hardness of the tablet was about 10 kp.

ingredient Example 2 (mg / tablet) Bepotastine acetate 20.0 Hydroxypropylmethylcellulose 2208 (15,000 mPa.s) 80.0 Polyvinyl alcohol 20.0 Microcrystalline cellulose 50.0 Citric acid 20.0 Magnesium stearate 2.0 Colloidal hard anhydrous silicic acid 3.0 Sodium stearyl fumarate 5.0 Total content per 1 200.0

Example  3 to 6. Preparation of Single Matrix Tablets

Tablets containing beportastine bevacillate were prepared according to the contents and compositions in Table 3 below. The content of each component in Table 3 represents the refined sugar content (mg). Hydroxypropylmethylcellulose 2208 (100,000 mPa.S, shinetsu) / hydroxypropylmethylcellulose 2208 (15,000 mPa.S, shinetsu) / hydroxypropylmethylcellulose 2910 (4,000 mPa.S., Shinetsu), polyvinyl alcohol (EMPROVE 40-88 ^TM , manufactured by Merck), microcrystalline cellulose / D-mannitol / calcium dihydrogenphosphate, and citric acid were each ap- plied to a 20-mesh sieve and mixed for about 10 minutes. To the obtained mixture, magnesium stearate / sodium stearyl fumarate in an amount of 40 mesh sieve was added and mixed for about 5 minutes. The resulting mixture was compressed on a compression tablet machine to prepare a circular tablet having a weight of 200 mg per tablet. The tableting pressure was adjusted so that the hardness of the tablet was about 10 kp.

ingredient EXAMPLES (mg / tablet) 3 4 5 6 Bepotastine besylate 20.0 20.0 20.0 20.0 Hydroxypropyl methylcellulose 2208 (100,000 mPa.s) 40.0 40.00 - - Hydroxypropylmethylcellulose 2208 (15,000 mPa.s) - - 20.0 - Hydroxypropylmethylcellulose 2910 (4,000 mPa.s) - - - 50.0 Polyvinyl alcohol 60.0 60.0 80.0 50.0 D-mannitol - - 30.0 - Microcrystalline cellulose 55.0 56.00 37.0 50.0 Dihydrogen phosphate dihydrate - - - 17.0 Citric acid 20.0 20.0 10.0 20.0 Magnesium stearate - 2.0 3.0 3.0 Sodium stearyl fumarate 5.0 2.0 - - 1 Total content per unit (mg) 200.0 200.0 200.0 200.0

Example  7 to 9. Preparation of Single Matrix Tablets

Tablets containing beportastine besylate were prepared according to the contents and compositions in Table 4 below. The content of each component in Table 4 represents the content of refined sugar (mg). Hydroxypropylmethylcellulose 2208 (100,000 mPa.S, shinetsu) / Eudragit L100 55 (Eudragit) ^TM L100 55, manufactured by Evinik), polyethylene oxide (Polyox303 ^TM , manufactured by Dow), microcrystalline cellulose / D-mannitol, and citric acid were each ap- plied in a 20-mesh sieve and mixed for about 10 minutes. To the obtained mixture, magnesium stearate was added to a 40 mesh sieve, and the mixture was further mixed for about 5 minutes. The resultant mixture was compressed in a compression tablet machine to prepare a circular tablet having a weight of 240 mg. The tableting pressure was adjusted so that the hardness of the tablet was about 10 kp.

ingredient EXAMPLES (mg / tablet) 7 8 9 Bepotastine besylate 20.0 20.0 20.0 Hydroxypropyl methylcellulose 2208 (100,000 mPa.s) 100.0 - 100.0 Polyethylene oxide - 100.0 - D-mannitol 50.0 30.0 30.0 Microcrystalline cellulose 57.0 47.0 37.0 Citric acid 10.0 40.0 50.0 Magnesium stearate 3.0 3.0 3.0 1 Total content per unit (mg) 240 240 240

Example  10 to 14. Preparation of Single Matrix Tablets

Tablets containing beportastine bevacillate were prepared according to the contents and compositions in Table 5 below. The content of each component in Table 5 represents the refined sugar content (mg). Hydroxypropylmethylcellulose 2208 (15,000 mPa.S, shinetsu), polyvinyl alcohol (EMPROVE 40-88 ^TM , manufactured by Merck), microcrystalline cellulose, and tartaric acid / fumaric acid / succinic acid / malic acid / alginic acid were each ap- plied in a 20 mesh sieve and mixed for about 10 minutes. To the resulting mixture was added 40 ml of apple stearyl fumarate in a 40 mesh sieve, followed by mixing for about 5 minutes. The resulting mixture was compressed on a compression tablet machine to prepare a circular tablet having a weight of 200 mg per tablet. The tableting pressure was adjusted so that the hardness of the tablet was about 10 kp.

EXAMPLES (mg / tablet) 10 11 12 13 14 Bepotastine besylate 20.0 20,000 20.0 20.0 20.0 Hydroxypropylmethylcellulose 2208
(15,000 mPa.s) 40.0 40.0 40.0 40.0 40.0 Polyvinyl alcohol 60.0 60.0 60.0 60.0 60.0 Microcrystalline cellulose 55.0 55.0 55.0 55.0 55.0 Tartaric acid 20.0 - - - - Fumaric acid - 20.0 - - - Suche mountain - - 20.0 - - Malian - - - 20.0 - Alginic acid - - - - 20.0 Sodium stearyl fumarate 5.0 5.0 5.0 5.0 5.0 1 Total content per unit (mg) 200.0 200.0 200.0 200.0 200.0

Example  15. Preparation of single matrix tablets

The film-coated substrate (OPADRY 03B28796 WHITE, colorcon) was dispersed in a 70% ethanol solution to prepare a coating solution. Using the obtained coating solution, a film of about 3% was formed on the Se-Jong SFC-30FN coating apparatus using the tablets prepared in Example 3 to prepare film-coated tablets.

Comparative Example  1. Preparation of single matrix tablets

A single matrix tablet was prepared in the same manner as in Example 3, except that citric acid was not used, according to the content and composition of Table 6 below.

ingredient Comparative Example 1 (mg / tablet) Bepotastine besylate 20.0 Hydroxypropyl methylcellulose 2208 (100,000 mPa.s) 40.0 Polyvinyl alcohol 60.0 Microcrystalline cellulose 76.0 Magnesium stearate 2.0 Sodium stearyl fumarate 2.0 1 Total content per unit (mg) 200.0

Comparative Example  2. In the wet granulation method  ≪ / RTI >

Tablets containing bevapastastin beetle were prepared according to the content and composition of Table 7 according to the wet granulation method. The content of each component in Table 7 represents the content of refined sugar (mg). Hydroxypropylmethylcellulose 2208 (100,000 mPa.S, shinetsu), polyvinyl alcohol (EMPROVE 40-88 ^TM , manufactured by Merck), microcrystalline cellulose, and citric acid were each ap- plied in a 20-mesh sieve, followed by mixing in a high-shear mixer for about 4 minutes. And 40 mL of 90% ethanol (v / v) as a binding liquid was slowly added to the high-speed mixer and granulated. The obtained granules were dried for about 4 hours in a hot-air dryer so that the drying loss was measured at 90 ° C for 10 minutes to be not more than 2%. The dried granules were applicated in an oscillator with a 16 mesh saw blade. To the resulting granules, magnesium stearate was added to a 40 mesh sieve, and the mixture was further mixed for about 5 minutes. The resulting mixture was compressed on a compression tablet machine to prepare a circular tablet having a weight of 200 mg per tablet. The tableting pressure was adjusted so that the hardness of the tablet was about 10 kp.

ingredient Comparative Example 2 (mg / tablet) Bepotastine besylate 20.0 Hydroxypropyl methylcellulose 2208 (100,000 mPa.s) 40.0 Polyvinyl alcohol 60.0 Microcrystalline cellulose 58.0 Citric acid 20.0 Magnesium stearate 2.0 1 Total content per unit (mg) 200.0

Test Example  1. Dissolution test

The elution test for the tablets of Example 3 and the tablets of Comparative Example 1 was performed using the purified water, pH 1.2, pH 4.0, and pH 6.8 as the eluant, 100 rpm). The elution test was performed at 37 ± 0.5 ° C in an eluent (900 mL) using 6 tablets each, and 10 mL of a sample was taken at a predetermined time and filtered through a 0.45 μm syringe filter. The content of bevetastatin in each sample was measured by high performance liquid chromatography (HPLC) under the following conditions.

<HPLC Conditions>

- Detector: Ultraviolet absorptiometer (measuring wavelength: 260 nm)

- Column: Kromasil C8 column, 150 x 4.6 mm, 5 탆

- Column temperature: about 40 ℃

- Flow rate: 1.0 mL / min

- mobile phase: 1 g / L pentane sulfonic acid mixture (A: B (70: 30)

Mobile phase A: 50 mM potassium dihydrogen phosphate solution (pH 3.0 adjusted with phosphoric acid)

Mobile phase B: acetonitrile

The results of the dissolution test of the tablet of Example 3 and the tablet of Comparative Example 1 are shown in Figs. 1 and 2, respectively. The tablets of Example 3 and the tablets of Comparative Example 1 both achieved an elution of about 70% for about 6 hours after initiation of drug elution, and thereafter release controlled elution profiles with sustained drug release at nearly zero order rate (controlled-release dissolution profile). However, the tablets of Comparative Example 1 showed a large difference in the elution rate according to the pH of the eluant, whereas the tablets of Example 3 exhibited an elution profile independent of the pH of the eluate. The difference between the dissolution rate in the pH 1.2 solution and the dissolution rate in the other pH solution for the tablets of Example 3 and the tablets of Comparative Example 1 are shown in Tables 8 and 9, respectively.

The dissolution rate difference of the tablets of Example 3 Elution time (hours) Difference in dissolution rate pH 1.2 solution & pH 4.0 solution pH 1.2 solution & water pH 1.2 solution & pH 6.8 solution 0 0.0 0.0 0.0 One 4.0 1.9 5.3 2 5.1 3.8 6.2 3 5.2 4.7 6.2 4 5.9 4.9 7.4 6 4.6 4.6 5.6 8 2.1 3.2 6.6 10 0.3 2.7 4.6 12 -0.1 2.9 3.6

The dissolution rate difference of the tablets of Comparative Example 1 Elution time (hours) Difference in dissolution rate pH 1.2 solution & pH 4.0 solution pH 1.2 solution & water pH 1.2 solution & pH 6.8 solution 0 0.0 0.0 0.0 One 5.0 7.1 9.5 2 7.2 9.0 12.5 3 7.6 10.2 14.7 4 7.8 10.7 16.0 6 6.2 10.1 16.5 8 5.5 9.4 16.6 10 3.8 7.5 15.2 12 2.3 5.9 12.4

1, 2, 8 and 9, it can be seen that the tablets according to the present invention exhibit a controlled release profile regardless of changes in the gastrointestinal tract environment and / or the gastrointestinal tract pH due to food or the like.

Test Example  2. Stability test

The tablets of Example 3 and the tablets of Comparative Example 2 were each placed in an HDPE bottle and subjected to a stability test for one month at an acceleration condition of 40 DEG C and a relative humidity of 75%. After 1 month, samples were collected and analyzed for the contents of the following substances. 20 mg of the sample was taken as a powder, and 20 mg of bepotastine besylate was placed in a 50 mL flask, and 10 mL of acetonitrile was added thereto. The mixture was ultrasonically extracted for 10 minutes, and subjected to liquid chromatography HPLC). &Lt; / RTI &gt;

<HPLC Conditions>

- Detector: Ultraviolet absorptiometer (measuring wavelength: 220 nm)

- Column: Kromasil C8 column, 150 x 4.6 mm, 5 탆

- Column temperature: about 40 ℃

- Flow rate: 1.0 mL / min

- mobile phase: 1 g / L pentane sulfonic acid mixture (A: B (70: 30)

Mobile phase A: 50 mM potassium dihydrogen phosphate solution (pH 3.0 adjusted with phosphoric acid)

Mobile phase B: acetonitrile

As a result of the stability test as described above, the tablets of Example 3 were found to be below the limit of the amount of the suppository. The tablets of Comparative Example 2 contained 4.01% of the total amount of the flexible material, exceeding the quality standard. Therefore, it is understood that preparation of the tablet by the direct tableting method or the dry granule tabletting method can secure excellent stability, while it is difficult to secure the stability of the tablet by the wet granule tableting method.

Test Example  3. Pharmacokinetics test ( pharmacokinetic  study)

A pharmacokinetic test with the once-a-day administration of the tablet of Example 3 was carried out using Tarionje (Dong-A Pharmaceutical, beportastine bevacillate 10 mg / tablet, twice a day) as a control preparation. The beagle dog (Canis familiaris, male of 1.5 years of age) was administered twice a day for 10 days after the first administration of the control preparation and twice a day, and the tablet of Example 3 was administered once a day. 12 hrs, 13 hrs, 14 hrs, 16 hrs, 10 hrs, 10 hrs, 11 hrs (collecting only the control preparation), 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, And 2 mL of blood after 24 hours, respectively, and the concentration of bepotastine in plasma was analyzed. The plasma concentration profiles of the control and the tablet of Example 3 are shown in FIG. 3, and the calculated pharmacokinetic parameters (Cmax and AUC) are shown in Table 10.

Ratio
(Tablet / control preparation of Example 3) Control formulation The tablets of Example 3 Cmax 111.4 969.1 ± 275.8
(ng / mL) 1091.2 + - 349.9
(ng / mL) AUC 99.8 9720.4 ± 1590.9
(ng.hr / mL) 10048.6 + 708.8
(ng.hr / mL)

From the results of FIG. 3 and Table 10, it can be seen that the once-daily administration of the tablet of the present invention is biologically equivalent to administration of the control preparation twice a day.

Claims (19)

Bepotastine or a pharmaceutically acceptable salt thereof; A swellable polymer; And one or more release regulators selected from the group consisting of citric acid, succinic acid, tartaric acid, oxalic acid, glutamic acid, ascorbic acid, malic acid, maleic acid, lactic acid, fumaric acid, formic acid, acetic acid, alginic acid, and polyacrylic acid. A single matrix tablet with controlled release. The composition according to claim 1, wherein the swelling polymer is selected from the group consisting of polyvinyl alcohol, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, methylcellulose, carboxymethylcellulose, polyethylene oxide, polyvinylpyrrolidone, Wherein the matrix is selected from the group consisting of guar gum, chitosan, carbohydrate, carrageenan, carboxymethyl cellulose, and sodium alginate. The controlled release single matrix tablet of claim 1, wherein the swellable polymer is a mixture of hydroxypropyl methylcellulose and polyvinyl alcohol. 4. The release-controlled single matrix tablet according to claim 3, wherein the weight ratio of hydroxypropyl methylcellulose to polyvinyl alcohol in the mixture of hydroxypropyl methylcellulose and polyvinyl alcohol is 1: 1-2. The controlled release single matrix tablet of claim 1, wherein the swellable polymer is present in an amount of from 20 to 80% by weight based on the total weight of the tablet. The controlled release single matrix tablet of claim 1, wherein said release modifier is selected from the group consisting of citric acid, fumaric acid, tartaric acid, succinic acid, malic acid, and alginic acid. The controlled release single matrix tablet of claim 1 wherein said release modifier is present in an amount of 5 to 30% by weight, based on the total weight of the tablet. 8. The release-controlled single matrix tablet of claim 7, wherein the release-controlling agent is present in an amount of 7 to 20% by weight based on the total weight of the tablet. The method according to claim 1, wherein 900 ml of each of purified water, pH 1.2, pH 4.0 and pH 6.8 is used as an eluant, and the solution is eluted according to Korean Pharmacopoeia dissolution test method 1 while stirring at 100 rpm for 12 hours (I) the dissolution rate in the pH 1.2 solution and the dissolution rate in the purified water, (ii) the dissolution rate in the pH 1.2 solution and the dissolution rate in the purified water and pH 1 (Iii) the dissolution rate in pH 1.2 solution, the dissolution rate in purified water and the dissolution rate in pH 4.0 solution, and (iv) the dissolution rate in pH 1.2 solution and the dissolution rate in purified water wherein the difference in dissolution rate at pH 6.8 is 10% or less. 10. The release-controlled single matrix tablet of any one of claims 1 to 9, further comprising a pharmaceutically acceptable additive selected from the group consisting of a diluent, a surfactant, a lubricant, a flavoring agent, and a coating agent . (a) bepotastine or a pharmaceutically acceptable salt thereof; A swellable polymer; At least one release controlling agent selected from the group consisting of citric acid, succinic acid, tartaric acid, oxalic acid, glutamic acid, ascorbic acid, malic acid, maleic acid, lactic acid, fumaric acid, formic acid, acetic acid, alginic acid and polyacrylic acid; And a diluent; And
(b) mixing the mixture obtained in step (a) with a lubricant, and then calibrating the resulting mixture.
A method for the preparation of a controlled release single matrix tablet for once-a-day dosing. (a ') bepotastine or a pharmaceutically acceptable salt thereof; A swellable polymer; At least one release controlling agent selected from the group consisting of citric acid, succinic acid, tartaric acid, oxalic acid, glutamic acid, ascorbic acid, malic acid, maleic acid, lactic acid, fumaric acid, formic acid, acetic acid, alginic acid and polyacrylic acid; diluent; Preparing a dry granulate of a mixture of a lubricant and a lubricant; And
(b ') mixing the dry granules obtained in step (a') with a lubricant, and then calibrating the resulting mixture.
A method for the preparation of a controlled release single matrix tablet for once-a-day dosing. The method of claim 11 or 12, wherein the swelling polymer is selected from the group consisting of polyvinyl alcohol, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, methylcellulose, carboxymethylcellulose, polyethylene oxide, polyvinylpyrrolidone , Xanthan gum, guar gum, chitosan, carbomer, carrageenan, carboxymethyl cellulose, and sodium alginate. The process according to claim 11 or 12, wherein the swelling polymer is a mixture of hydroxypropyl methylcellulose and polyvinyl alcohol. 15. The method of claim 14, wherein the weight ratio of hydroxypropyl methylcellulose to polyvinyl alcohol in the mixture of hydroxypropylmethylcellulose and polyvinyl alcohol is 1: 1-2. The process according to claim 11 or 12, wherein the swellable polymer is used in an amount of from 20 to 80% by weight based on the total weight of the tablet. 13. The process according to claim 11 or 12, wherein the release controlling agent is at least one selected from the group consisting of citric acid, fumaric acid, tartaric acid, succinic acid, malic acid and alginic acid. The process according to claim 11 or 12, wherein the release control agent is used in an amount of 5 to 30% by weight based on the total weight of the tablet. The process according to claim 18, wherein the release control agent is used in an amount of 7 to 20% by weight based on the total weight of the tablet.

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