JP2024055713A - Bilastine tablet and method for producing the same - Google Patents

Abstract

To provide a bilastine tablet that prevents tableting defects while exhibiting a reduced propensity for delayed dissolution, resulting in diminished solubility after storage, and a method for producing the same.SOLUTION: A bilastine tablet comprises bilastine or a pharmaceutically acceptable salt thereof, and sodium stearyl fumarate. The tablet preferably further comprises hydroxypropyl cellulose. A method for producing a bilastine tablet comprises the step for tableting a composition comprising bilastine or a pharmaceutically acceptable salt thereof, and sodium stearyl fumarate.SELECTED DRAWING: None

Description

The present invention relates to bilastine tablets and a method for producing the same.

Bilastine, i.e., 2-[4-(2-{4-[1-(2-ethoxyethyl)-1H-benzimidazol-2-yl]piperidin-1-yl}ethyl)phenyl]-2-methylpropanoic acid, is a therapeutic drug for allergic diseases, and preparations containing it are sold as "Bilanoa (registered trademark) tablets" and "Bilanoa (registered trademark) OD tablets."
Furthermore, Patent Document 1 discloses a bilastine orally disintegrating tablet having a specific formulation (composition) that has high hardness, rapid disintegration properties, and good storage stability.

JP 2022-097443 A

However, as the inventors further investigated tablets containing bilastine, they found that compositions containing bilastine are prone to tableting problems known as sticking, in which the bilastine adheres to the punch during tableting, and that tableting tends not to be stable.

The present invention has been made in consideration of the above-mentioned circumstances, and aims to provide a bilastine tablet that does not cause tableting problems and that also suppresses dissolution delay, which is a decrease in dissolution property after storage, and a method for producing the same.

The present inventors have conducted extensive research and found that, as described above, compositions containing bilastine tend to cause tableting problems. They also found that tablets that do not cause tableting problems and have suppressed delayed dissolution can be obtained by tableting using sodium stearyl fumarate as a lubricant, and thus completed the present invention.

The present invention has the following aspects.
[1] A bilastine tablet comprising bilastine or a pharma- ceutically acceptable salt thereof and sodium stearyl fumarate.
[2] The bilastine tablet of [1], further comprising hydroxypropyl cellulose.
[3] The bilastine tablet of [2], wherein the content of hydroxypropyl cellulose is 0.1 to 3 mass% in 100 mass% of the bilastine tablet.
[4] The bilastine tablet of [1] to [3], which is an orally disintegrating tablet.
[5] A method for producing bilastine tablets, comprising a step of tableting a composition containing bilastine or a pharma- ceutically acceptable salt thereof and sodium stearyl fumarate.

According to the present invention, it is possible to provide a bilastine tablet which does not cause tableting problems and which also suppresses delayed dissolution, and a method for producing the same.

The present invention will be described in detail below.
The bilastine tablet of the present invention (hereinafter sometimes simply referred to as "tablet") contains bilastine or a pharma- ceutically acceptable salt thereof, and sodium stearyl fumarate.

There is no particular limitation on the bilastine, and commercially available bilastine may be used, and it may be in a crystalline or amorphous form, or in a solvate or anhydrous form.
Pharmaceutically acceptable salts of bilastine include salts with inorganic acids such as hydrochloride and sulfuric acid, and organic acids such as acetic acid, citric acid, tartaric acid, and maleic acid; salts with alkali metals such as potassium and sodium; salts with alkaline earth metals such as calcium and magnesium; and salts with organic bases such as ammonium salts, ethylamine salts, and arginine salts.
The content of bilastine or a pharma- ceutically acceptable salt thereof in a bilastine tablet (100% by mass) is not particularly limited, but is preferably 1 to 30% by mass, more preferably 3 to 25% by mass, and even more preferably 10 to 20% by mass, in terms of bilastine.

As the sodium stearyl fumarate, those available on the market for pharmaceutical use can be used.
By using sodium stearyl fumarate as a lubricant, it is possible to suppress the sticking phenomenon (tabletting trouble) in which the tableting composition adheres to the punch, and also to produce tablets in which the so-called dissolution delay, in which dissolution property decreases after a certain period of storage, is suppressed. When sodium stearyl fumarate is not used but another lubricant is used, dissolution delay tends to occur when an amount of lubricant that can suppress tableting trouble is added, and it is difficult to achieve both tableting trouble and dissolution delay as good results.
The content of sodium stearyl fumarate in 100% by mass of the bilastine tablet is preferably 1 to 5% by mass, more preferably 1 to 3% by mass, and even more preferably 1.5 to 2.5% by mass.
In addition to using sodium stearyl fumarate as a lubricant, other lubricants (for example, metal stearates such as magnesium stearate and calcium stearate, fatty acid esters such as glycerol fatty acid esters and sucrose fatty acid esters, talc, etc.) can also be used as necessary, but from the viewpoint of preventing tableting problems and delayed dissolution, it is preferable to use only sodium stearyl fumarate as a lubricant.
Furthermore, the mass ratio of sodium stearyl fumarate to bilastine [sodium stearyl fumarate/bilastine] is preferably 0.1 to 1, more preferably 0.1 to 0.5, even more preferably 0.1 to 0.2, and particularly preferably 0.1 to 0.15, because this can effectively suppress tableting problems and delayed dissolution.

In addition to bilastine or a pharma- ceutically acceptable salt thereof and sodium stearyl fumarate, the tablet of the present invention may contain, as necessary, any of the additives usable for pharmaceutical use, such as excipients, binders, disintegrants, colorants, sweeteners, and flavors.

Examples of the excipient include D-mannitol, crystalline cellulose, lactose hydrate, anhydrous lactose, refined sucrose, potato starch, pregelatinized starch, etc., and one or more of these can be used as necessary, but it is preferable to use at least one of D-mannitol and crystalline cellulose. D-mannitol is preferable because it is easy to obtain tablets with excellent swallowing sensation, and crystalline cellulose is excellent as an excipient because of its low reactivity with other components. Furthermore, when D-mannitol and crystalline cellulose are used in combination, the effects of excellent moldability and handling during tablet molding are obtained, and this is preferable in combination with the effect of the present invention of suppressing tableting problems.
The content of the excipient is preferably 60 to 90% by mass, more preferably 70 to 90% by mass, and even more preferably 75 to 85% by mass, based on 100% by mass of the tablet.
When D-mannitol is used, the content thereof is preferably 55 to 85% by mass, more preferably 60 to 80% by mass, and even more preferably 65 to 75% by mass, based on 100% by mass of the tablet.
When crystalline cellulose is used, its content is preferably 1 to 30% by mass, more preferably 2 to 20% by mass, and more preferably 5 to 15% by mass, based on 100% by mass of the tablet.
When these are used in combination, the mass ratio of D-mannitol to crystalline cellulose [D-mannitol/crystalline cellulose] is preferably 3-15, and more preferably 5-10.

Examples of binders include hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinyl alcohol, polyvinylpyrrolidone, stearyl alcohol, ammonio methacrylate copolymer, polyvinyl acetal diethyl amino acetate, dextrin, and starch syrup. One or more of these can be used, but the use of hydroxypropyl cellulose is preferable in that it can provide tablets with more suppressed dissolution delay. Hydroxypropyl cellulose can be used from the market as a pharmaceutical product, and for example, hydroxypropyl cellulose can be used with an aqueous solution viscosity (viscosity when made into a 2% aqueous solution at 20°C) specified in the Japanese Pharmacopoeia of 100 mPa·s or less, more preferably 1 to 50 mPa·s, and even more preferably 1 mPa·s or more and less than 3 mPa·s. The content of the binder in 100% by mass of bilastine tablets is preferably 0.1 to 3% by mass, more preferably 0.1 to 1% by mass, and even more preferably 0.1 to 0.5% by mass.
Furthermore, the mass ratio of the binder to bilastine [binder/bilastine] is preferably 0.01 to 0.1, more preferably 0.01 to 0.07, even more preferably 0.01 to 0.04, and particularly preferably 0.01 to 0.02, since this allows for more effective suppression of dissolution delay.
Furthermore, the mass ratio of the binder to sodium stearyl fumarate [binder/sodium stearyl fumarate] is preferably 0.05 to 2, more preferably 0.1 to 1, and even more preferably 0.1 to 0.6, from the viewpoint of suppressing tableting problems and delayed dissolution.

Examples of disintegrants include croscarmellose sodium, carmellose calcium, carmellose, low-substituted hydroxypropyl cellulose, crospovidone, corn starch, sodium starch glycolate, partially pregelatinized starch, hydroxypropyl starch, and the like. One or more of these can be used, but crospovidone is preferred since it gives tablets with excellent disintegrability.
The content of the disintegrant in 100% by mass of the bilastine tablet is preferably 0.1 to 5% by mass, more preferably 1 to 5% by mass, and even more preferably 1 to 4% by mass.

Examples of coloring agents include yellow ferric oxide, ferric oxide, Food Yellow No. 4, Food Yellow No. 5, Food Red No. 2, Food Red No. 3, Food Red No. 102, and the like, and one or more of these can be used.

Examples of sweeteners include acesulfame potassium, aspartame, sucralose, thaumatin, sucrose, erythritol, saccharin or a salt thereof, glycyrrhizic acid or a salt thereof, stevia or a salt thereof, etc., and one or more of these can be used. However, acesulfame potassium and aspartame are preferred in terms of obtaining tablets that have a good taste, and it is even more preferred to use these in combination.
Examples of flavorings include lime flavor, peach flavor, grape flavor, orange essence, orange oil, caramel, camphor, cinnamon oil, spearmint oil, strawberry essence, chocolate essence, cherry flavor, spruce oil, pine oil, peppermint oil, vanilla flavor, bitter essence, fruit flavor, peppermint essence, mixed flavor, mint flavor, 1-menthol, lemon powder, lemon oil, rose oil, and the like. One or more of these can be used, but lime flavor, peach flavor, and grape flavor are preferred from the viewpoint of suppressing the bitterness of bilastine or a pharma- ceutically acceptable salt thereof.

Other additives include, as necessary, a film coating substrate (hydroxypropyl cellulose, hydroxypropyl methyl cellulose, etc.), light anhydrous silicic acid, titanium oxide, carnauba wax, etc., and one or more of these can be used. The coating substrate may contain additives such as a colorant.

The form of the tablet of the present invention is not particularly limited, and examples thereof include immediate-release tablets (regular tablets), orally disintegrating tablets, and sustained-release tablets, which are produced through a tableting process. The tablet may consist of only a plain tablet or may be a coated tablet having a coating such as a film coat, but an orally disintegrating tablet consisting of a plain tablet is preferred.

The method for producing tablets of the present invention includes a step of tableting a composition containing bilastine or a pharma- ceutically acceptable salt thereof, sodium stearyl fumarate, and additives used as necessary (tabletting step). The front stage of the tableting step may include a granulation step of granulating at least a part of bilastine or a pharma- ceutically acceptable salt thereof, sodium stearyl fumarate, and additives added as necessary. In this case, the composition subjected to the tableting step will contain a granulated material. The front stage of the tableting step may not include a granulation step, in which a composition containing bilastine or a pharma- ceutically acceptable salt thereof, sodium stearyl fumarate, and additives as necessary is tableted without granulation, which is a so-called direct tableting step. The tablet tableted by the direct tableting step does not include a granulated material. The rear stage of the tableting step may include a coating step of coating the plain tablet obtained by tableting.
The granulation step, the tableting step and the coating step can each be carried out by a known method.
According to the present invention, tableting problems can be effectively suppressed, and therefore the present invention is effective when a direct tableting process, which is prone to tableting problems, is employed.

The present invention will now be described in more detail with reference to examples.
[Examples 1 to 9]
According to the formulation in Table 1 below, orally disintegrating tablets were produced by direct compression.
Specifically, the components other than the lubricant were mixed among the components listed as the composition for tableting in Table 1, and then the lubricant was added and mixed to obtain a composition for tableting. This composition was then compressed into tablets with a miniature tableting machine (VELA5) to produce tablets with a diameter of 7 mm and a mass of 125 mg.
The presence or absence of sticking during tableting and the average dissolution rate of the obtained tablets after storage under specified conditions were determined by the following method.
The hydroxypropyl cellulose used had an aqueous solution viscosity (viscosity of a 2% aqueous solution at 20° C.) of 2.0 to 2.9 mPa·s as specified in the Japanese Pharmacopoeia.
The results are shown in Table 1.

<Sticking>
In each example, when the composition for tableting was tableted for 5 minutes using a miniature tablet press (VELA5), if sticking did not occur, it was marked as "○", and if it did occur, it was marked as "×". These are listed in Table 1.

<Average dissolution rate>
The tablets obtained in each example were stored under the following three conditions.
Condition 1: 25°C, 85% relative humidity, 1 month Condition 2: 40°C, 75% relative humidity, 1 month Condition 3: 60°C, 1 month (humidity not controlled)
Using one tablet after storage under each condition and 900 mL of test solution at pH 6.8, a dissolution test was performed at 50 revolutions per minute by the paddle method. 15 minutes after the start of the test, 10 mL or more of the dissolution solution was collected and filtered through a membrane filter with a pore size of 0.45 μm or less. The first 5 mL of filtrate was removed, and the next 1 mL of filtrate was accurately measured, and 1 mL of acetonitrile/water mixture (1:1) for liquid chromatography was added accurately to prepare a sample solution.
Separately, dry the quantitative bilastine at 105°C for 3 hours, weigh out about 22 mg of it, and dissolve it in a 1:1 mixture of acetonitrile and water for liquid chromatography to make exactly 100 mL. Measure out 5 mL of this liquid accurately, and add a 1:1 mixture of acetonitrile and water for liquid chromatography to make exactly 50 mL. Measure out 1 mL of this liquid accurately, and add 1 mL of the test solution to make a standard solution.
The sample solution and the standard solution were tested by HPLC, and the ultraviolet absorption at a wavelength of 210 nm was measured to obtain a chromatogram. The dissolution rate (%) of each sample solution 15 minutes after the start of the dissolution test was calculated based on the peak area of the standard solution.
The above test was carried out for three tablets (n=3), and the average of these (average dissolution rate) was calculated and shown in Table 1.
The mobile phase was prepared as follows: 6.8 g of potassium dihydrogen phosphate and 2.5 g of sodium 1-octanesulfonate were dissolved in water to make 1000 mL. 400 mL of acetonitrile for liquid chromatography was added to 600 mL of this solution.

As shown in Table 1, the tablets containing sodium stearyl fumarate as a lubricant did not suffer from sticking and the delay in dissolution was suppressed. On the other hand, when magnesium stearate or glycerin fatty acid ester was used, it was difficult to achieve both of these goals. For example, in Example 7, although sticking did not occur, the delay in dissolution was significant.
Furthermore, the tablets further containing hydroxypropyl cellulose tended to further suppress the delay in dissolution.

Claims (5)

A bilastine tablet comprising bilastine or a pharma- ceutically acceptable salt thereof and sodium stearyl fumarate. 2. The bilastine tablet of claim 1, further comprising hydroxypropyl cellulose. The bilastine tablet according to claim 2, wherein the content of hydroxypropyl cellulose is 0.1 to 3% by mass based on 100% by mass of the bilastine tablet. The bilastine tablet according to any one of claims 1 to 3, which is an orally disintegrating tablet. A method for producing bilastine tablets, comprising a step of tableting a composition containing bilastine or a pharma- ceutically acceptable salt thereof and sodium stearyl fumarate.