JP2841857B2 - Long-term stable oral pharmaceutical preparation - Google Patents

Description

Description: TECHNICAL FIELD The present invention relates to a long-term stable oral pharmaceutical preparation containing bisoprolol.

(Prior art)

Bisoprolol [chemical name: 1- [p-[(2-isopropoxyethoxy) methyl] phenoxy] -3-isopropylamino-2-propanol] (hereinafter referred to as bisoprolol) has a strong β-receptor blocking action. Has,
It is an excellent drug for treating and preventing heart, circulatory and vascular diseases (Japanese Patent Publication No. 62-10220).

However, this compound is easily hydrolyzed, and when formulated using excipients or binders commonly used in this field, the compound is hydrolyzed by moisture absorption and the content in the formulation decreases. There is a problem of doing.

[Problem to be solved by the present invention] An object of the present invention is to provide a stable oral preparation containing bisoprolol.

[Means for solving the problem]

The present invention relates to a long-term stable oral pharmaceutical preparation comprising bisoprolol or a pharmaceutically acceptable salt thereof and annit and polyethylene glycol, and a method for producing the same.

Conventionally, mannitol is a known substance as an excipient, and polyethylene glycol is a known substance as a binder.However, when bisoprolol is combined with these substances, it is completely known that the hydrolysis of the pharmaceutically active ingredient is suppressed. That was not.

In the present invention, bisoprolol which is a pharmaceutically active ingredient may be a free base or may be an acid addition salt such as an inorganic acid or an organic acid. Examples of the inorganic acid addition salts include sulfate, nitrate, hydrochloride, hydrobromide and orthophosphate, and examples of the organic acid addition salts include formate, acetate, propionate, and pivalic acid. Salt, diethyl acetate, malonate, succinate, pimelate,
Fumarate, maleate, lactate, tartrate, malate, benzoate, salicylate, 2-phenylpropionate, citrate, gluconate, ascorbate, nicotinate, isoform Nicotinate, methanesulfonate, ethanesulfonate, ethanedisulfonate, 2
-Hydroxyethanesulfonate, benzenesulfonate, p-toluenesulfonate or naphthalene monosulfonate naphthalenedisulfonic acid salt.

The mannitol used in the present invention is not particularly limited as long as it is one usually used in a preparation for oral administration.

In addition, polyethylene glycol may be any one that is usually used in a formulation for oral administration, and is not particularly limited.For example, the average molecular weight is 1,000 to 20,000, preferably 4,0.
Those having a size of from 00 to 6,000 can be suitably used.

Mannitol, polyethylene glycol and the pharmaceutically active ingredient are each about 50-90% by weight, especially about 60-80% by weight, polyethylene glycol about 5-30% by weight, especially about 8-15% by weight, pharmaceutically active ingredient. About 1 to
It is preferred that the amount be 30% by weight, especially about 2 to 20% by weight.

In the preparation of the present invention, other excipients or lubricants can be used depending on the dosage form. As the excipient, any of those usually used in oral preparations can be used. Examples of these excipients include lactose, starch, sorbit, crystalline cellulose, dibasic calcium phosphate, calcium citrate, sucrose, calcium sulfate and the like. And sorbit is particularly preferably used. These excipients are preferably used in the range of about 10 to 25% by weight. Also, the lubricant may be any one which can be usually used in an oral preparation, and examples thereof include talc, magnesium stearate, calcium stearate, stearic acid, and wax. Lubricants are preferably used in the range of about 0.1-3.0% by weight.

The preparation of the present invention is produced by blending mannitol and polyethylene glycol with a pharmaceutically active ingredient bisoprolol or a pharmacologically acceptable salt thereof, granulating the mixture, and, if necessary, further molding it into a desired dosage form. be able to. Any of the above operations can be performed by a conventional method in this technical field, for example, a heating granulation method, a wet granulation method, or a dry granulation method. In the case of the heat granulation method, it can be carried out by mixing a pharmaceutically active ingredient, mannitol and polyethylene glycol, appropriately heating and mixing, cooling, and, if necessary, pulverizing. The heating temperature is preferably about 60-90 ° C, especially about 70-85 ° C. When an excipient other than mannitol is further used, it may be added at the same time as the above mixing. In the case of wet granulation, it can be carried out by kneading a pharmaceutically active ingredient and mannitol or a mixture thereof with a polyethylene glycol-containing solution, granulating the mixture with a commercially available granulating apparatus or the like, and drying. Examples of the solvent used in kneading include methanol, ethanol, water, and mixtures thereof. Furthermore, when using the dry granulation method, it can be carried out using a commercially available dry granulator.

The solidified product thus obtained is pulverized using a commercially available pulverizer or the like so as to have a desired particle size. The particle size varies depending on the purpose of use, but is generally about 50 to 1,500 μm, especially about 100 to 80 μm.
0 μm is appropriate.

The pulverized product thus obtained can be further made into a desired dosage form by a conventional method such as sizing and tableting, if necessary. Further, it is preferable to use a lubricant as needed at the time of formulation such as tableting. Thus, a formulation suitable for oral administration can be obtained. Such dosage forms include, for example, powders, granules, fine granules,
Tablets and the like, and furthermore, these final products include coloring agents,
Auxiliaries such as fragrances can optionally be included.

Hereinafter, the present invention will be further described with reference to Experimental Examples and Examples.

Experimental Example Stability was tested when bisoprolol 1/2 fumarate was combined with the excipients, binders and lubricants shown in Table 1 below.

In the experiment, each substance was mixed at a predetermined ratio, tablets prepared by a conventional method were stored at 60 ° C. for one month, and the residual amount of the active drug after storage was measured to calculate the residual ratio. The results are as shown in Table 1.

Example 1 5 parts by weight of bisoprolol 1/2 fumarate and 84 parts by weight of mannitol were mixed, and the mixture was placed in a stirring granulator (Shinagawa mixer), and polyethylene glycol (average molecular weight: 6000) was added thereto.
Ethanol containing 10 parts by weight (dissolved by heating at 60 ° C.) is added and kneaded. The kneaded material is treated with a 20 mesh JIS standard sieve, and the material that has passed through the sieve is dried at 40 ° C. for 2 hours. After drying, add and mix 1 part by weight of magnesium stearate,
The mixture is compressed on a rotary tablet press (6.5 mm diameter) to give 100 mg tablets per tablet.

Example 2 5 parts by weight of bisoprolol 1/2 fumarate and 76 parts by weight of mannitol were mixed, and the mixture was placed in a stirring granulator (Shinagawa mixer), and polyethylene glycol (average molecular weight 6000) was added thereto.
15 parts by weight of ethanol (dissolved by heating at 60 ° C.) is added and kneaded. The kneaded material is treated with a 20 mesh JIS standard sieve, and the material that has passed through the sieve is dried at 40 ° C. for 2 hours. After drying, 1 part by weight of magnesium stearate and 3 parts by weight of talc are added and mixed. Thereafter, a tablet of 100 mg per tablet is obtained in the same manner as in Example 1.

Example 3 10 parts by weight of bisoprolol 1/2 fumarate, 99 parts by weight of mantonit and polyethylene glycol (average molecular weight
6000) 10 parts by weight are mixed, put into a high-speed stirring granulator (high-speed mixer), and heat-granulated at an external bath temperature of 75 ° C.
The granulated product was cooled to room temperature, treated with a 20-mesh JIS standard sieve, and passed through a sieve with magnesium stearate 1
Add parts by weight and mix. The mixture is turned on a rotary tablet press (diameter
7 mm) to give tablets of 120 mg per tablet.

Example 4 5 parts by weight of bisoprolol 1/2 fumarate, 144.5 parts by weight of mannitol and 30 parts by weight of sorbite were mixed, and the mixture was placed in a stirring granulator (Shinagawa mixer), and polyethylene glycol (average molecular weight: 6000) was added thereto. ) Add 20 parts by weight of ethanol (dissolved by heating at 60 ° C) and knead. Kneaded material
After drying at 40 ° C. for 15 minutes, the kneaded material is crushed. Again at 40 ° C 2
After drying for an hour, it is treated with a 32 mesh JIS standard sieve. 0.5 parts by weight of hydrous silicon dioxide is added to the mixture that has passed through the sieve, and mixed to obtain a powder.

Example 5 The granules obtained in Example 4 are filled into hard gelatin capsules to obtain capsules.

Example 6 5 parts by weight of bisoprolol 1/2 fumarate, 164.5 parts by weight of mannitol and 30 parts by weight of polyethylene glycol (average molecular weight: 6000) were mixed, and the mixture was placed in a high-speed stirring granulator (high-speed mixer), followed by an external bath. Heat granulation at a temperature of 75 ° C. The granulated product is cooled to room temperature and treated with a 12 mesh JIS standard sieve. Water-containing silicon dioxide 0.5
The parts by weight are added and mixed to obtain granules.

〔The invention's effect〕

The oral pharmaceutical preparation of the present invention thus obtained can stably exist the active agent for a long period of time by blending mannitol and polyethylene glycol with bisoprolol, which is a pharmaceutically active ingredient, or a pharmaceutically acceptable salt thereof. It has excellent properties as a pharmaceutical preparation.

In addition, the preparation of the present invention, particularly a tablet, has the advantage that the active ingredient elutes from the tablet in the gastrointestinal tract very quickly, so that it is not necessary to use a disintegrant, which is usually required in tablets. .

Furthermore, according to the present invention, since bisoprolol serves as a binder, polyethylene glycol which is apt to cause tableting troubles such as mannitol and sticking, which is conventionally considered to be inferior in moldability, is used. Since a good formulation can be obtained without any obstacles during the preparation, a simple and economically stable oral pharmaceutical formulation can be obtained for a long period of time.

Continued on the front page (58) Fields surveyed (Int.Cl. ⁶ , DB name) A61K 31/135 A61K 47/26 A61K 47/34 C07C 215/00 A61K 31/045 A61K 31/765 CA (STN) REGISTRY ( STN) WPIDS (STN)

Claims (4)

(57) [Claims] 1. A long-term stable oral pharmaceutical preparation comprising mannitol and polyethylene glycol mixed with bisoprolol or a pharmaceutically acceptable salt thereof. 2. 1-30% by weight of bisoprolol 1/2 fumarate, 50-90% by weight of mannitol and 5-30% by weight
2. The preparation according to claim 1, which comprises polyethylene glycol. 3. The polyethylene glycol having an average molecular weight of 1,
The preparation according to claim 2, wherein the amount is from 000 to 20,000. 4. A long-term stable oral preparation characterized by blending mannitol and polyethylene glycol with bisoprolol or a pharmacologically acceptable salt thereof and granulating the mixture and, if necessary, further molding it into a desired dosage form. Of pharmaceutical preparations for medical use.