JP2002308762A - Preparation containing bisoprolol - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a bisoprolol-containing preparation having excellent storage stability. SOLUTION: The bisoprolol-containing preparation contains a granulated material containing (a) bisoprolol or its salt, (b) lactose and (c) a cellulose derivative selected from hydroxypropylcellulose and methylcellulose in non- molten state. It can be produced as a preparation containing granules produced by wet-granulation method (granule composed of e.g. 1-10 wt.% bisoprolol fumarate, 60-95 wt.% lactose and 1-10 wt.% cellulose derivative mentioned above).

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001] The present invention relates to a stable preparation containing bisoprolol, which is useful as a therapeutic and prophylactic agent for heart, circulatory and vascular diseases.

[0002]

2. Description of the Related Art Bisoprolol fumarate has a strong β-receptor blocking effect and is used clinically as a therapeutic / prophylactic agent for heart, circulatory and vascular diseases (trade name “Maintate Tablets”). "), Which has the disadvantage of being susceptible to hydrolysis. When excipients (such as lactose and crystalline cellulose) and binders (such as polyvinylpyrrolidone) used in the usual formulation process are blended with bisoprolol fumarate, the compound is hydrolyzed by moisture absorption and the active ingredient in the formulation There was a problem that the content was reduced.

[0003] In order to solve the above-mentioned problems, there has been proposed a preparation in which mannitol as an excipient and polyethylene glycol as a binder are blended with the compound (Japanese Patent Laid-Open Publication No. Hei.
No. 202131) discloses a method for producing a tablet by a melt granulation method utilizing thermal melting of polyethylene glycol. However, the tablets manufactured in this manner do not always have sufficient stability, and when a package in a less moisture-proof effect, for example, a PTP-packed or unpackaged tablet is allowed to stand under heated and humidified conditions, the tablet Roughness of the surface and decrease in tablet hardness are observed. For this reason, there is a problem that it is necessary to give due consideration to the management environment not only at the time of preparation of the preparation but also at the distribution stage and in the pharmacy. Although the above problem can be avoided to some extent by applying a film coating having high moisture resistance, there is a problem that an additional manufacturing step is required and the manufacturing cost is increased.

[0004]

SUMMARY OF THE INVENTION An object of the present invention is to provide a stable preparation containing bisoprolol. More specifically, it is an object of the present invention to provide a bisoprolol-containing preparation that is stable for a long time without requiring special storage conditions at the distribution stage or in a pharmacy. The present inventors have conducted intensive studies to solve the above problems, bisoprolol fumarate, lactose and a composition containing a specific cellulose derivative in a non-molten state have extremely excellent storage stability, It has been found that in the preparation containing this composition, the content of the active ingredient does not decrease even in a low moisture-proof packaging form, and roughening of the preparation surface and reduction in the preparation hardness do not occur. The present invention has been completed based on these findings.

[0005] That is, the present invention relates to a bisoprolol-containing preparation, comprising: (a) bisoprolol or a salt thereof, (b) lactose, and (c) a cellulose derivative selected from the group consisting of hydroxypropylcellulose and methylcellulose in a non-molten state. The present invention provides a preparation containing a granulated product.

According to a preferred embodiment of the present invention, 1 to 1
0% by weight bisoprolol, 60-95% by weight lactose,
And a granulation comprising 1 to 10% by weight of the cellulose derivative. This preparation is preferably prepared as a tablet, and preferably contains bisoprolol fumarate as an active ingredient. The above-mentioned preparation in the form of a tablet containing a granulated product prepared by a wet granulation method is also provided as a preferred embodiment of the present invention.

[0007]

BEST MODE FOR CARRYING OUT THE INVENTION Bisoprolol contained as an active ingredient in the preparation of the present invention may be in free form, but is preferably in the form of a physiologically acceptable salt. The kind of the salt is not particularly limited, and examples thereof include mineral salts such as hydrochloride and sulfate, and organic acid salts such as fumarate, maleate and tartrate. Of these, fumarate is most preferred. Hydroxypropylcellulose and methylcellulose are each widely used as a pharmaceutical additive, and commercially available products can be easily obtained. Cellulose derivatives may be used in combination of two or more.

In the preparation of the present invention, (a) bisoprolol or a salt thereof, (b) lactose, and (c) a cellulose derivative selected from the group consisting of hydroxypropylcellulose and methylcellulose are substantially non-melted. Contained in the granules. The proportion of the above components contained in the above granulated product is not particularly limited. For example, 1 to 10% by weight of bisoprolol, 60 to 95% by weight of lactose, and a cellulose derivative selected from the group consisting of hydroxypropylcellulose and methylcellulose The proportion is preferably 1 to 10% by weight (the ratio is% by weight based on the total weight of the composition).

The form of the preparation of the present invention is not particularly limited, but is preferably prepared as a solid preparation for oral administration, particularly preferably in the form of a tablet. In the preparation of the preparation of the present invention, in addition to the above-mentioned granulated substance, other additives for preparation can be used as needed. The type of the pharmaceutical additive is not particularly limited, and can be appropriately selected by those skilled in the art according to the type of the pharmaceutical preparation, desired properties, and the like.For example, an excipient, a disintegrant, a lubricant, and the like can be used. . It is preferable that these pharmaceutical additives are not incorporated into the above-mentioned granulated product.

[0010] The types of additives for pharmaceutical preparations such as excipients, disintegrants and lubricants are not particularly limited, and any of those usually used for the preparation of solid preparations, preferably tablets, can be used. For example, mannitol as an excipient, starches,
Calcium hydrogen phosphate or the like can be used, and is preferably used in the range of 10 to 20% by weight based on the weight of the composition. Disintegrators include, for example, low-substituted hydroxypropylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellose, sodium carboxymethyl starch, crosslinked polyvinylpyrrolidone, and the like. These disintegrants are 1 to
It is preferable to use it in the range of 10% by weight. Lubricants include magnesium stearate, calcium stearate, stearic acid, talc, waxes and the like. The lubricant is preferably used in the range of 0.5 to 5% by weight.

[0011] The method for producing the preparation of the present invention is not particularly limited, and the components (a) to (c) may be used in the composition contained in the granulated product.
Any method may be employed as long as it can be manufactured so as to exist in a non-molten state. For example, it is preferable to produce a granule comprising the above composition by a wet granulation method to produce a preparation containing the granule. As a wet granulation method,
For example, a fluidized bed granulation method, a high-speed stirring granulation method, an extrusion granulation method, a stirring fluidized granulation method and the like can be mentioned. Flow coater (Freund Industrial) for fluidized bed granulation, high speed mixer (Fukae Sangyo) for high-speed stirring granulation, vertical granulator (Pourek), twin dome (Fuji Paudal) for extrusion granulation, stirring fluidization In the granulation method, it is possible to use a granulator generally used for the production of a solid agent, such as a spiral flow (Freund Corporation) and a multiplex (Powrex).

For example, a granulated product composed of the above components (a) to (c) is prepared by wet granulation using bisoprolol fumarate as an active ingredient and lactose and a cellulose derivative. It can be compressed to produce tablets in the form of tablets. Operations such as mixing and granulation are all widely used in this technical field, and can be appropriately performed by those skilled in the art. For example, a suitable granulated product can be obtained by subjecting a mixed powder of bisoprolol fumarate and lactose to fluidized bed granulation with a 5% solution of hydroxypropylcellulose. The type of solvent used in the granulation is not particularly limited, and examples thereof include methanol, ethanol, methylene chloride, water, and a mixture thereof. After granulation thus obtained is sized to a desired particle size, a disintegrating agent, a lubricant and the like are further added as necessary, and tablets are obtained by compression molding with a tableting machine or the like. it can.

The preparation of the present invention is stable even when stored for a long period of time in a packaging form under low moisture-proof conditions (generally, a form in which the permeability of outside air and moisture is not considered when packaging tablets). For example, a form in which tablets are packed in a bag in which a polyethylene film is heat-sealed,
Packaging form, aluminum pillow package opened form,
Rigid vinyl chloride single layer sheet (for example, Sumilite VSS110
PT using 1,1104, both made by Sumitomo Bakelite)
In a package form under low moisture-proof conditions such as a P-package form, even if the formulation of the present invention is stored at 60 ° C. for one month, a decrease in the content of the active ingredient is hardly recognized. Also, at 40 ° C, 75
Even when stored for 1 month under% RH, there is a feature that the hardness of the tablet does not decrease and the appearance does not change. Therefore, the preparation of the present invention, preferably the tablet of the present invention can secure long-term stability in the form of a naked tablet without applying a film coating having high moisture resistance.

[0014]

EXAMPLES Hereinafter, the present invention will be described more specifically with reference to Examples, but the scope of the present invention is not limited to the following Examples. Example 1 After mixing 200 g of bisoprolol fumarate and 3560 g of lactose, the mixture was placed in a fluid bed granulator (WSG-5: manufactured by Powrex), and hydroxypropyl cellulose (trade name: HP) was added thereto.
CL) 2000 g of a 5% ethanol solution was sprayed. After the spraying, the fluidized bed was dried and sieved with a 22-mesh sieve. To 3860 g of the sized product, 100 g of low-substituted hydroxypropylcellulose and 40 g of magnesium stearate were mixed, and a rotary tableting machine (AQU) was used.
A0518: manufactured by Kikusui Seisakusho), 6.5 mm in diameter, 1
100 mg tablets were obtained.

Example 2 After mixing 10 g of bisoprolol fumarate and 178 g of lactose, the mixture was placed in a fluidized bed granulator (Flow Coater Mini: manufactured by Freund Corporation), and methylcellulose (trade name: SM-
15) 100 g of a 5% ethanol / methylene chloride mixed solution (mixing ratio 5: 5) was sprayed. After spraying,
The fluidized bed was dried and sieved with a 22 mesh sieve. 5 g of low-substituted hydroxypropylcellulose and 2 g of magnesium stearate were mixed with 193 g of the sized product, and the diameter was 6.5 with a single-shot tableting machine (6B-2: Kikusui Seisakusho).
100 mg tablets were obtained.

Example 3 After mixing 100 g of bisoprolol fumarate and 3280 g of lactose, the mixture was placed in a fluidized bed granulator (WSG-5: manufactured by Powrex), and 2,000 g of a 5% ethanol solution of hydroxypropylcellulose was sprayed on the mixture. After the spraying, the fluidized bed was dried and sieved with a 22 mesh sieve. Granulated product 3
To 480 g, 80 g of low-substituted hydroxypropylcellulose and 40 g of magnesium stearate were mixed, and a tablet having a diameter of 6.0 mm and a tablet of 90 mg was obtained using a rotary tableting machine (AQUA0518: manufactured by Kikusui Seisakusho).

Example 4 After mixing 10 g of bisoprolol fumarate and 178 g of lactose, the mixture was placed in a mortar, and 100 g of a 5% ethanol solution of hydroxypropylcellulose was added thereto. About 5 in a mortar
After kneading for a minute, the mixture was dried in a fluidized bed and sieved and sized with a 22 mesh sieve. For 193 g of the sized product, 5 g of low-substituted hydroxypropylcellulose and 2 g of magnesium stearate
Were mixed and a single tablet press (6B-2: Kikusui Seisakusho) was used to obtain a tablet having a diameter of 6.5 mm and a tablet of 100 mg.

[0018]

[Table 1]

Comparative Example 1 10 g of bisoprolol fumarate, 152 g of mannitol,
30 g of polyethylene glycol 6000 was mixed and placed in a flow coater mini. This is about 1 at the intake temperature of 90 ° C.
It was fluidized for 5 minutes and melt granulated. Then turn off the heater,
After cooling, the granulated product was taken out and sized with a 22 mesh sieve. 2 g of magnesium stearate and 6 g of talc were added to 192 g of the sized product and mixed, and then a tablet having a diameter of 6.5 mm and a tablet of 100 mg was obtained using a single-shot tableting machine.

Comparative Example 2 10 g of bisoprolol fumarate, 154 g of lactose and 28 g of crystalline cellulose (Avicel PH101) were mixed and placed in a flow coater mini. An ethanol solution containing 6 g of polyvinylpyrrolidone was sprayed on this at an intake air temperature of 50 ° C. After drying the fluidized bed, the particles were sized with a 22 mesh sieve.
2 g of stearic acid was added to 198 g of the sized product and mixed, and then 6.5 mm in diameter and 100 tablets per tablet were obtained using a single-shot tableting machine.
mg tablets were obtained.

Comparative Example 3 10 g of bisoprolol fumarate, 154 g of lactose and 28 g of crystalline cellulose were mixed and placed in a mortar. An ethanol solution containing 6 g of polyvinylpyrrolidone was added thereto, and the mixture was kneaded in a mortar for about 5 minutes and dried in a fluidized bed. After drying the fluidized bed, the particles were sized with a 22 mesh sieve. After adding 2 g of stearic acid to 198 g of the sized product and mixing, a single-shot tableting machine was used to obtain a tablet having a diameter of 6.5 mm and a tablet of 100 mg.

Comparative Example 4 After mixing 10 g of bisoprolol fumarate and 178 g of lactose, the mixture was placed in a fluid bed granulator (Flow Coater Mini: manufactured by Freund Corporation), and polyvinylpyrrolidone (trade name: P)
(VP K-30) 100 g of a 5% ethanol solution was sprayed. After the spraying, the fluidized bed was dried and sieved with a 22 mesh sieve. To 193 g of the sized product, 5 g of low-substituted hydroxypropylcellulose and 2 g of magnesium stearate were mixed, and a single-shot tableting machine (6B-2: Kikusui Seisakusho) was used to make a tablet having a diameter of 6.5 mm and a tablet of 100 mg. Obtained.

Comparative Example 5 After mixing 10 g of bisoprolol fumarate and 178 g of lactose, the mixture was placed in a fluidized-bed granulator (Flow Coater Mini: manufactured by Freund Corporation), and 5% ethanol / hydroxypropylmethylcellulose (trade name: TC-5RW) was added. 100 g of a water mixed solution (1: 1) was sprayed. After the spraying, the fluidized bed was dried and sieved with a 22 mesh sieve. To 193 g of the sized product, 5 g of low-substituted hydroxypropylcellulose and 2 g of magnesium stearate were mixed, and a single-shot tableting machine (6B-2: Kikusui Seisakusho) was used to prepare a tablet having a diameter of 6.5 mm and a tablet of 100 mg. Obtained.

[0024]

[Table 2]

Test Example Each of the tablets obtained in Examples 1 to 4 and the tablets obtained in Comparative Examples 1 to 5 was put in a polyethylene bag and stored at 60 ° C. for one month, and then the content of bisoprolol fumarate was determined. The content was measured and the residual ratio was determined with the content before storage as 100%. Further, the tablet hardness and appearance change after storage at 40 ° C. under 75% RH for one month were confirmed and compared with those before storage. Table 3 shows the results.

Although the residual ratio of the active ingredient in the tablets of Examples 1 to 4 showed any high value, the residual ratios of the tablets of Comparative Examples 1 to 5 all decreased. In all of the tablets of Examples 1 to 4, the change in hardness was smaller than that before storage, but the hardness of the tablet manufactured by the melt granulation method using polyethylene glycol (Comparative Example 1) was significantly reduced. In addition, in the tablets of Examples 1 to 4, no change was observed in the appearance of the tablets as compared to before storage, but the tablets produced by the melt granulation method using polyethylene glycol (Comparative Example 1) The tablet surface changed to a rough state.

[0027]

[Table 3]

[0028]

EFFECTS OF THE INVENTION The preparation of the present invention is characterized by having excellent storage stability, the content of the active ingredient is not reduced even under a low moisture-proof packaging form, and the surface of the preparation is not roughened and the hardness of the preparation is not reduced. Have.

Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat II (reference) A61P 9/10 A61P 9/10 9/12 9/12 25/02 105 25/02 105 F term (reference) 4C076 AA36 BB01 CC11 CC12 CC13 DD41 DD66 EE32 FF36 FF65 GG02 GG14 4C206 AA01 FA21 KA01 KA15 MA03 MA05 MA28 MA55 MA72

Claims (3)

[Claims] 1. A granulated product containing bisoprolol in a non-molten state, which comprises (a) bisoprolol or a salt thereof, (b) lactose, and (c) a cellulose derivative selected from the group consisting of hydroxypropylcellulose and methylcellulose. A formulation containing 2. The formulation according to claim 1, comprising a granulate comprising 1 to 10% by weight of bisoprolol fumarate, 60 to 95% by weight of lactose and 1 to 10% by weight of said cellulose derivative. 3. The preparation according to claim 1, which is in the form of a tablet containing a granulated substance prepared by a wet granulation method.