WO2015183047A1 - Pharmaceutical preparation containing bepotastine and glyceryl behenate - Google Patents

Abstract

The present invention relates to a pharmaceutical composition containing bepotastine or a pharmaceutically acceptable salt thereof, and glyceryl behenate. The pharmaceutical preparation according to the present invention comprises an optically stable double-layer tablet preparation, which comprises: (a) a first layer containing bepotastine or a pharmaceutically acceptable salt thereof and having immediate-release characteristics; and (b) a second layer containing bepotastine or a pharmaceutically acceptable salt thereof and having sustained-release characteristics. The bepotastine sustained-release double-layer tablet preparation according to the present invention exhibits an excellent release pattern and bio-availability and has optically stability, and thus can be favorably used in the treatment of allergic rhinitis and pruritus.

Description

Pharmaceutical Formulations Including Bepotastine and GlycerylBehenate

The present invention relates to a pharmaceutical formulation comprising bepotastine or a pharmaceutically acceptable salt thereof and glyceryl behenate.

Bepotastine is a '(S) -4- [4-[(4-chlorophenyl) -pyridin-2-ylmethoxy] piperidin-1-yl] butanoic acid having a structural formula Phosphorus compound.

<Formula 1>

Bepotastine has an antiallergic activity and is an excellent drug as a therapeutic drug for anaphylactic airway stenosis, asthma or allergic rhinitis. Bepotastine in the (S) -array differs from the (R) -array in its pharmacological activity or safety, resulting in different metabolic rates and protein binding rates. In Japanese Patent Laid-Open Nos. 2-25465 and 10-237070, it is known that bepotastine of the (S) -array exhibits significantly higher pharmacological activity than the (R) -array.

Currently, bepotastine besylate has been developed as an immediate release formulation and is marketed by Mitsubishi Tanabe in Japan under the trade name "Talion". The dosage of the formulation is set at twice daily administration to maintain a constant therapeutic level.

Typically, when formulating (S) -arranged bepotastins, they are converted to low (R) -arranged bepotastins and readily racemized. That is why it is important to establish a formulation in which (S) -arranged bepotastine is included in high optical purity, in which bepotastine is not easily racemized and is optically stable.

Japanese Patent No. 3909998 discloses a bepotastine formulation having high storage stability. That is, to suppress the lamination of bepotastine or its pharmacologically acceptable salts to improve stability and at the same time to improve the preparation efficiency of the preparation, bepotastine or its pharmacologically acceptable salts, mannitol as a excipient, white sugar, Formulations are disclosed in combination with lactose, or mixtures thereof, and polyethylene glycol as a binder. However, the formulation has to be administered twice a day, so there is a problem in that the ease of taking patients.

Korean Patent Laid-Open Publication No. 2012-0083276 discloses independent release characteristics of the immediate release portion and the western release portion by separating the immediate release portion by applying the surface of the western portion including the active ingredient, the release control base and the pharmaceutically acceptable carrier with a water-insoluble polymer. There is disclosed a pharmaceutical composition having both fast-acting and long-lasting properties which can be prepared in a relatively simple process without any limitation on the amount and type of pharmaceutically active ingredients that can be used. However, the information disclosed in this patent does not reveal the optical stability of drugs such as bepotastine.

Korean Unexamined Patent Publication No. 2014-0052540 includes a water-insoluble basic substance in the formulation to adjust the pH to 7 or more, thereby effectively maintaining the optical stability of bepotastine and simultaneously containing a sustained release carrier. A possible bepotastine-containing sustained release pharmaceutical composition is disclosed. However, as shown in the PK experiment of Beagle dogs, in the case of general sustained-release drugs, the blood concentration of the drug gradually rises after taking the drug, and therefore, the rapid onset is an important antihistamine, bepotastine. Somewhat falling problem can be seen.

Korean Unexamined Patent Publication No. 2014-0016260 discloses an oral controlled release pharmaceutical composition comprising bepotastine having a bioavailability equivalent to that of an immediate release formulation by granulating bepotastine and a release modulator. However, there is a problem in that the preparation of the first drug layer, the bioadhesive layer preparation, the CR coating, the second drug layer preparation, the IR coating may be completed through a complex process of several steps.

The present inventors have studied the preparations including the release control additives and stabilizers, which improved the optical stability of bepotastine, and ensure the optical stability, and at the same time bepotastine or a pharmaceutical thereof that can prepare the preparation through an easy and simple manufacturing process The present invention has been completed by preparing a pharmaceutical formulation comprising a pharmaceutically acceptable salt and glyceryl behenate.

The present invention is to provide a bepotastine-containing formulation having an excellent sustained release pattern and bioavailability and at the same time optically stable.

In order to solve the above problems, the present invention provides a pharmaceutical formulation comprising bepotastine or a pharmaceutically acceptable salt thereof and glyceryl behenate.

The present invention also provides a pharmaceutical formulation comprising bepotastine or a pharmaceutically acceptable salt thereof and glyceryl behenate and an additive for controlling release.

As used herein, “pharmaceutically acceptable salts” means salts prepared according to conventional methods in the art, and such methods are known to those skilled in the art. Specifically, the pharmaceutically acceptable salts include, but are not limited to, salts derived from the following pharmacologically or physiologically acceptable inorganic and organic acids and bases. Examples of suitable acids include hydrochloric acid, bromic 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, citric acid, methanesulfuric acid Phonic acid, formic sand, benzoic acid, malonic acid, naphthalene-2-sulfonic acid, benzenesulfonic acid, and the like. Salts derived from suitable bases may include, but are not limited to, alkali metals such as sodium, or potassium, alkaline earth metals such as magnesium. Preferably the salt of bepotastine according to the invention may be bepotastine besylate.

As used herein, "release control additive" refers to a pharmaceutically available additive that allows the pharmacologically active ingredient, specifically bepotastine or a pharmaceutically acceptable salt thereof, to be slowly released or eluted in the formulation.

Release control additives that can be used in the present invention may be a hydrophilic polymer, a hydrophobic polymer and fatty acid, fatty acid esters, fatty acid alcohols, waxes and one or more of the magnesium aluminate silicate (UFL2, US2) or a combination thereof.

Hydrophilic polymers include polyvinylpyrrolidone, hydroxyethyl cellulose, hydroxypropyl cellulose, hypromellose, polyethylene oxide, polyethylene glycol, xanthan gum, guar gum, locust bean gum, sodium alginate, carrageenan, chitosan, carbopol, Sodium alginate can be reviewed and selected, and hydrophobic polymers can also be examined. Hydrophobic polymers include ethyl cellulose, cellulose acetate, cellulose propionate, cellulose acetate, cellulose triacetate, cellulose acetate phthalate, methacrylic acid copolymer, Ethylcellulose, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, and can also be selected from glyceryl palmitostearate, glyceryl stearate, glyceryl dise Fatty acids and fatty acid esters such as arate, cetyl palmitate, glyceryl monooleate, stearic acid, fatty acid alcohols such as cetostearyl alcohol, cetyl alcohol, stearyl alcohol, carnauba wax, beeswax, microcrystalline wax It may be selected from waxes. However, the above-mentioned release controlling additives are presented as examples of classification categories of hydrophilic polymers, hydrophobic polymers and fatty acids, fatty acid esters, fatty alcohols, waxes and the like, and are not limited to the above items.

In the present invention, the pharmaceutical preparation comprising bepotastine or a pharmaceutically acceptable salt thereof and glyceryl behenate includes (a) a first drug having beta release property by containing bepotastine or a pharmaceutically acceptable salt thereof. layer; And (b) a second layer having sustained release properties containing bepotastine or a pharmaceutically acceptable salt thereof.

In the present invention, bepotastine or a pharmaceutically acceptable salt thereof and glyceryl behenate may be included in a weight ratio of 1: 0.01 to 4. Preferably, bepotastine or a pharmaceutically acceptable salt thereof and glyceryl behenate may be included in a weight ratio of 1: 0.02 to 2, and more preferably bepotastine or a pharmaceutically acceptable salt thereof and glycerol. Rylbehenate may be included in a weight ratio of 1: 0.1 to 1.

The first layer having immediate release in the bilayer tablet preparation according to the present invention includes a disintegrant in granules, and the disintegrant includes crospovidone, croscarmellose sodium, sodium starch glycolate, pregelatinized starch, microcrystalline cellulose, Polyvinylpyrrolidone, low-substituted hydroxypropylcellulose (L-HPC), calcium and sodium salts of carboxymethylcellulose, colloidal silicon dioxide, guar gum, magnesium aluminum silicate, methylcellulose, powdered cellulose, starch, It may be selected from the group consisting of alginic acid and sodium alginate, but is not limited to the above items.

The first layer and the second layer granules of the present invention may further include a diluent or a lubricant. Diluent of the present invention means all excipients commonly used in the pharmaceutical field. For example, lactose, mannitol, microcrystalline cellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone, starch, pregelatinized starch, methylcellulose, copolyvidone, and the like, and mixtures thereof. The diluent allows the preparation to be of a size sufficient to be taken and provides sufficient binding force during tableting. In addition, glidants may include magnesium stearate, calcium stearate, glyceryl behenate, stearic acid, talc, aerosil, castor oil, sodium stearyl fumarate, etc., which provide sufficient fluidity when tableting and bond between punch and die. Serves to prevent.

In the present invention, the process for producing the first layer and the second layer granules can be generally used in pharmaceutical processes such as direct blow method, wet granulation method, dry granulation method, melt granulation method, compression granulation method, spray drying method, fluidized bed granulation method. It can be selected as one of the granule recipe.

The bilayer tablet formulation according to the present invention can be prepared very easily through the following process.

1) Apples are mixed with excipients including bepotastine and glyceryl behenate, disintegrant and diluent to prepare a first granule.

2) Apples are mixed with excipients including bepotastine and glyceryl behenate, excipient for controlling release and diluent to prepare a second granule.

3) Pass each granule through a suitable sieve and add lubricant.

4) The first and second granules are compressed into bilayer tablets.

5) If necessary, further tablets are film coated.

The pharmaceutical preparation comprising bepotastine or a pharmaceutically acceptable salt thereof and glyceryl behenate of the present invention secures optical stability, thereby reducing the pharmacological activity due to racemization to the (R) -configuration. It can be prevented and shows excellent dissolution pattern and bioavailability.

In addition, the present invention can improve the ease of taking patients by lowering the dosage of bepotastine twice daily from the conventional daily dosing, and may be useful for treating allergic rhinitis and pruritus. .

In addition, the present invention can be manufactured by a common and simple manufacturing method to meet the manufacturer's convenience and at the same time can be expected to reduce the industrial high production yield and production cost.

1 is a graph showing the dissolution profiles of Examples 7 and 8 of the present invention.

2 is a graph showing the dissolution profiles of Examples 9 to 13 of the present invention.

3 is a graph showing the dissolution profile of Examples 14 to 16 of the present invention.

4 is a graph showing the dissolution profile of Examples 17 to 19 of the present invention.

5 is a graph showing the dissolution profile of Examples 20 to 23 of the present invention.

FIG. 6 is a graph comparing example 12 of the present invention with a commercially available tarione-defined plasma concentration change. FIG.

Hereinafter, the present invention will be described in detail by way of examples. However, the scope of the present invention is not limited by these examples. Embodiments of the present invention are provided to more fully describe the present invention to those skilled in the art.

<Example 1> Preparation of Bepotastine and Glycerylbehenate Pharmaceutical Compositions of the Invention

Bepotastine and glyceryl behenate were mixed in a 1: 1 ratio to prepare bepotastine and glyceryl behenate pharmaceutical compositions.

<Comparative Examples 1 to 15> Preparation of Bepotastine and Common Excipient-Containing Pharmaceutical Compositions

A bepotastine-containing pharmaceutical composition was prepared by mixing the excipients commonly used in the tablet preparation with the bepotastine bepotastine in a 1: 1 ratio to prepare Comparative Examples 1 to 15, respectively.

Experimental Example 1 Evaluation of stability of bepotastine-containing pharmaceutical composition

To confirm the effect of excipients on the optical stability of bepotastine besylate, the pharmaceutical compositions of Examples 1 and Comparative Examples 1-15 described in Table 1 were stored at 60 ° C. in 75% RH for 1 month, and S-array bepotas The degree of conversion of Stine to the isomer of the R-configuration is shown in Table 2 as follows.

<Analysis method>

Add 20 mg of each sample to 50 mL of mobile phase, mix vigorously for 10 minutes, and filter this solution. 10 ul of the test solution was tested according to HPLC under the following conditions to obtain peak areas Ar and As of the R and S forms.

<Analysis Condition>

-Detector: ultraviolet visible absorbance photometer (wavelength: 225 nm)

Column: Ultron ES-OVM (4.6 mm inner, 15 cm long)

Column temperature: 40 ° C

Flow rate: 0.5 mL / min

Mobile phase: 2.7 g of potassium dihydrogen phosphate is dissolved in 1000 mL of water and adjusted to pH 5.5 using 0.2 mol / L sodium hydroxide solution. To 500 mL of this solution add 75 mL of acetonitrile.

<Calculation>

Amount of R-array (%) = As / (Ar + As) X 100

As can be seen in Table 2, it was found that betayl bepotastine alone (control) was converted to R-array having 8.55% of low pharmacological activity when stored at 60 ° C for 75% RH for one month. The excipients of Comparative Examples 1 to 15, which are commonly used in pharmaceuticals, also influenced the stability of bepotastine, and especially by magnesium stearate (Comparative Example 8), which is commonly used as a lubricant, changed by 34.45%. It became.

In contrast, for the glyceryl behenate-containing pharmaceutical composition according to the present invention, the besylate bepotastine converted to R-array was only 0.16% despite the 60 ° C 75% RH 1 month storage period. Glyceryl behenate was an excipient mainly used as a lubricating agent, such as magnesium stearate, but in the present invention, it was found that glyceryl behenate significantly improved the photochemical stability of befolate phosphate.

<Examples 2 to 4> Preparation of pharmaceutical composition according to the ratio of bepotastine and glyceryl behenate

Bepotastine and glyceryl behenate ratios shown in Table 3 below, and uniformly mixed at about 80 ℃ at a rate of 20 mesh apples to prepare a bepotastine and glyceryl behenate pharmaceutical composition Examples 2 to 4 It was set as.

Experimental Example 2 Besyl acid bepotastine: glyceryl behenate ratio stability evaluation

In order to confirm the stability effect of glyceryl behenate in more detail, the stability evaluation was performed about Examples 2-4 described in Table 3. The test is shown in Table 3 to evaluate the degree of conversion of bepotastine of the S-array to the R-array after storage at 60 ° C 75% RH for one month.

As can be seen in Table 3, as the glyceryl behenate ratio increases, it was confirmed that the amount of besylate bepotastine converted to R-array decreased, through which glyceryl behenate was stable in besylate bepotastine. It can be seen that to improve.

Accordingly, the present invention is essential for pharmaceutical preparations containing bepotastine or a pharmaceutically acceptable salt thereof so as to prevent the problem of betastatin racemization into the (R) -configuration resulting in lowered pharmacological activity. Glyceryl behenate.

Example 5 Preparation of Bepotastine-Containing Immediate Release Tablet According to the Present Invention

Mix well with bepsyl acid bepotastine, microcrystalline cellulose, mannitol and glyceryl behenate in the composition shown in Table 4, and then, magnesium stearate was sieved through a 40 mesh and compressed into tablets of 8 to 12 KP using a tableting machine. Potastine-containing immediate-release tablets were prepared.

<Example 6> Preparation of Bepotastine-Containing Sustained-Release Tablet According to the Invention

In the composition shown in Table 5, besylate besylate, microcrystalline cellulose, glyceryl behenate, and hypromellose, an additive for controlling release, were mixed well, and magnesium stearate was sieved through a 40 mesh and mixed using a tablet press. Bepotastine-containing sustained-release tablets were prepared by compression to 12 KP.

<Examples 7 and 8> Preparation of Bepotastine-Containing Bilayer Tablets According to the Present Invention

In the composition shown in Table 6, bepotyl acid bepotastine-containing bilayer tablet according to the present invention was prepared as Examples 7 and 8.

Examples 7 and 8 according to the present invention are prepared by the following preparation method.

IR granules

① The beta vesyl acid vesitol, mannitol, microcrystalline cellulose, and glyceryl behenate were put into the fluidized bed granulator, and the granules were prepared under the following conditions.

<Fluid bed granulator conditions>

● Inlet Air Temperature: 85 ℃

● Outlet Air Temperature: Above 70 ℃

● Product Air Temperature: 70 ℃

Compressed air source: 6 kgf / cm ²

② Magnesium stearate was sieved through 40 mesh in the prepared granules to prepare IR granules.

2. SR granule manufacture

① Fluid Bed Granulator Bepotastine, microcrystalline cellulose, glyceryl behenate, and hypromellose were put into a fluid bed granulator, and granulated by the following conditions.

<Fluid bed granulator conditions>

● Inlet Air Temperature: 85 ℃

● Outlet Air Temperature: Above 70 ℃

● Product Air Temperature: 70 ℃

Compressed air source: 6 kgf / cm ²

② Magnesium stearate was sieved through 40 mesh in the prepared granules to prepare SR granules.

3. Two-Layered Tablet Manufacturing

The tablet was tableted at 60 parts by weight of IR, 200 parts by weight of SR, 200 mg, and 8 to 12 KP using a double tablet press to prepare a white tablet having 260 mg per tablet.

< Example  9 to 13> Additive for controlling release Hypromellose  Proportional Besylate Bepotastine  Preparation of Containing Two-Layered Tablets

In order to confirm the dissolution rate of besylate bepotastine according to the proportion of hypromellose, which is an additive for controlling release, a besylate bepotastine-containing bilayer tablet was prepared in the same manner as in Examples 7 and 8, respectively, and in Examples 9 to 8, respectively. It was set to 13.

<Examples 14 to 19> Preparation of Bepotastine Bepotastine Bilayer Tablet Further Containing Magnesium Aluminate Metasilicate

In the composition shown in Table 8, bepotyl acid bepotastine bilayer tablet further comprising magnesium metasilicate aluminate for emission control was prepared and used as Examples 14 to 19, respectively. The preparation method was prepared in the same manner as in Examples 7 and 8.

<Examples 20 to 23> Preparation of Bepotastine Bepotastine Double-Layered Tablet Comprising an Release Control Additive According to the Present Invention

Carrageenan, sodium alginate, polyethylene oxide and carbopol were used to prepare Examples 20 to 23 as additives for controlled release. The preparation method was prepared in the same manner as in Examples 7 and 8.

Comparative Example 16

A commercially available beryl acid bepotastine formulation, tarion tablets, 10 mg was used as Comparative Example 16.

Experimental Example 3 Evaluation of the stability of the preparations according to the invention

In order to confirm the effect of glyceryl behenate on bepotastine optical stability in the final tablets, stability evaluations of Examples 5, 6, 7, 7, 10, and Comparative Example 16 were conducted. The stability test assessed the amount of analogues (ethyl ester, piperizine, isopropyl ester and Unknown Impurity) and the optical isomer R-array after storing each tablet at 60 ° C. 75% RH for one month.

As a result, as shown in Table 10, the amount of the optical isomer R-array is significantly reduced in Examples 5, 6, 7 and 10 including glyceryl behenate as compared to Comparative Example 16. Through this, it was confirmed that the excellent stability effect of glyceryl behenate.

Experimental Example 4 Dissolution Test

A dissolution test was carried out with bilayer tablets prepared in Examples 7 to 23 and commercially available tarion tablets (Comparative Example 16) to measure the release pattern of besylate bepotastine as an active ingredient from these bilayer tablet formulations. Elution evaluation was carried out at pH 1.2 900 mL, Basket method 100 rpm, and the amount of bebetalate released was quantified by HPLC.

1 to 5 show the besylate bepotastine release pattern of the two-layered tablets prepared in Examples 7 to 23 and tarion tablets, which are commercially available products.

As shown in Figure 2, the besylate bepotastine release pattern was found that the release rate is slowed down as the content (%) of hypromellose as an additive for controlling release is increased. In addition, it was found that the release pattern of bepotastine was slow as the amount of magnesium aluminate silicate or glyceryl behenate increased. Through this, it was found that the release rate of bepotastine besylate can be freely controlled by controlling hypromellose, magnesium metasilicate aluminate, and glyceryl behenate.

In addition, it can be seen from Figure 5 that other release control additives other than hypromellose, carrageenan, sodium alginate, polyethylene oxide and carbopol can also control the release rate of bepotastine besylate.

Experimental Example 5 Pharmacokinetic Test in Beagle Dogs

10 mg tablets of tarrion tablets of Example 12 and Comparative Example 16 were administered orally once to each of 5 beagle dogs, followed by 20 minutes, 40 minutes, and 1 hour after administration of the control drug in cephalic vein. 3 mL of blood was collected at, 1.5, 2, 4, 6, 8, 10, 12, 24 hours, and in the case of Examples, 0.5, 1, 1.5, 2, 4, 6, 9, 12, 15 before and after administration. 3 mL blood was collected at 18, 24 hours. The collected blood was centrifuged to separate plasma and stored in the freezer for analysis. After the 7-day washout period, they were cross-tested in the same manner, and drug concentrations in plasma were analyzed by LC-MS / MS.

As a result, the besylate bepotastine bilayer tablet prepared in Example 12, as shown in Table 11 and FIG. 6, showed that the besylate bepotastine blood concentration profile rose rapidly similarly to the reference drug due to the initial rapid drug release. From this, it could be inferred that besylate bepotastine will be rapidly absorbed into the body to express the effect.

In addition, Example 12 maintains the blood concentration of bepotastine bepotastine for a long time compared to the tarion tablets administered once a day, and showed an AUC about twice as high as the tarion tablets AUC. Through this, besylate bepotastine bilayer tablet prepared through the present invention was confirmed to be effective as a preparation that can be taken once a day.

Claims (7)

1. A pharmaceutical formulation comprising bepotastine or a pharmaceutically acceptable salt thereof and glyceryl behenate.
2. The pharmaceutical formulation of claim 1 further comprising an additive for controlling release.
3. The formulation of claim 1, wherein the formulation comprising bepotastine or a pharmaceutically acceptable salt thereof and glyceryl behenate comprises: an immediate release layer comprising bepotastine and glyceryl behenate; And a sustained release layer comprising bepotastine, glyceryl behenate, and an additive for controlling release; Pharmaceutical formulations comprising a.
4. The pharmaceutical preparation according to any one of claims 1 to 3, wherein the bepotastine or a pharmaceutically acceptable salt thereof and glyceryl behenate are included in a weight ratio of 1: 0.02 to 2.
5. The pharmaceutical composition of claim 2 or 3, wherein the additive for controlling release is one or two or more selected from the group consisting of hypromellose, magnesium metasilicate aluminate, carrageenan, sodium alginate, carbopol and polyethylene oxide. Formulation.
6. The pharmaceutical formulation according to any one of claims 1 to 3, wherein the formulation is administered once daily.
7. Bepotastine or a pharmaceutically acceptable salt thereof, glyceryl behenate, and an excipient for controlling release. The active ingredient contained in the pH 1.2 eluate condition is 5 ~ 10 mg as bepotastine at 1 hour, 15 ~ at 12 hours. Formulations characterized in that they are administered in a once daily regimen of 25 mg release.

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