JPH02207A - Drug preparation containing bromhexine hydrochloride - Google Patents

Abstract

PURPOSE:To obtain the subject drug preparation free from the problems of the loss of bromhexine hydrochloride in the preparation caused by the adsorption to packaging material or container during storage and the lowering of the drug action by compounding bromhexine hydrochloride known as an excellent expectorant with a substance having surface activity. CONSTITUTION:The objective preparation can be prepared by compounding bromhexine hydrochloride with a substance having surface activity. The surface- active substance is preferably a sucrose fatty acid ester, glycerol monostearate, a polyethylene glycol fatty acid ester, etc., especially an ionic surfactant such as sodium laurylsulfate. The amount of the surfactant is 1-50pts.wt., especially 2-25pts.wt. per 1pt.wt. of bromhexine hydrochloride. The preparation can be prepared, e.g. in the case of a solid preparation, by mixing bromhexine hydrochloride with an excipient, a binder and a surface-active substance, kneading the mixture with a solvent and sieving the product after drying.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to a formulation containing bromhexine hydrochloride. More specifically, the present invention relates to a formulation in which bromhexine hydrochloride is prevented from adsorbing to the plastic packaging material or container during packaging and storage of the formulation.

[Prior art] Conventionally, bromhexine hydrochloride was used as starch, crystal cell mouth, -
Excipients 1, agents such as gas, hydroxypropylcellulose,
With a binder such as polyvinylpyrrolidone, it can be made into a solid preparation such as a powder, granule or tablet by a conventional method, or
．． Alternatively, it was dissolved in a solvent commonly used for manufacturing pharmaceuticals to form a solution preparation.

[Problems to be Solved by the Invention] However, as a result of research conducted by the present inventors, when these preparations are packaged and stored, bromhexine hydrochloride is adsorbed to the plastic of the packaging material or container, and It was found that the bromhexine hydrochloride content of

In particular, for granules, it is practical to store them in separate packages in plastic packaging materials or plastic laminated aluminum packaging materials, so plastics are often used as packaging materials, and these packaging materials are used in many cases. Since the area of contact with the fist is large, the reduction in bromhexine hydrochloride content is significant.

Bromhexine hydrochloride is a drug widely used as an excellent expectorant, but its dosage is 4 mg at a time.
It's only a small amount of 8 degrees.

Therefore, bromhexine hydrochloride in the preparation adsorbs to the packaging material or plastic of the container during storage, and reducing its content, even if only in a small amount, has a significant impact on the drug's efficacy.

[Means for Solving the Problems] As a result of various studies to solve the above problems, the present inventors have found that
The present invention was completed based on the discovery that by incorporating a substance with surfactant action into a bromhexine hydrochloride-containing preparation, it is possible to prevent the bromhexine hydrochloride in the preparation from being adsorbed to the packaging material or plastic of the container.

The present invention is a preparation in which bromhexine hydrochloride is blended with a substance having a surfactant effect.

In the present invention, substances having a surfactant action include sucrose fatty acid ester, glycerin fatty acid ester (glycerin monooleate, glycerin monostearate, glycerin dioleate, glycerin tristearate, etc.), propylene glycol fatty acid ester (propylene glycol monooleate, propylene glycol monostearate, propylene glycol dioleate, etc.), polyethylene glycol fatty acid esters (polyethylene glycol monooleate, polyethylene glycol monostearate, polyethylene glycol dioleate, etc.), polyoxy Ethylene hydrogenated castor oil derivatives (polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, etc.), sorbitan fatty acid esters (sorbitan monooleate, sorbitan monoisostearate, sorbitan monolaurate, sorbitan monostearate, sorbitan sesqui oleate, sorbitan trioleate, etc.), nonionic surfactants such as polyoxyethylene sorbitan fatty acid esters (e.g., polysorbate 80, etc.), and ionic surfactants with low toxicity suitable for oral administration (e.g., lauryl It is a substance that has both a hydrophilic group and a lipophilic group in its molecule, such as sodium sulfate, etc.) and hydroxypropyl cellulose, and these can be used alone or in combination.

Among these substances having surfactant action, ionic surfactants such as sodium lauryl sulfate are preferred.

The amount of the substance having a surfactant action added is 1 to 50 parts by weight, preferably 2 to 25 parts by weight, per 1 part by weight of bromhexine hydrochloride.

In the present invention, the term "preparation" refers to solid preparations such as powders, granules, and tablets, and solution preparations such as syrup.

The packaging material used in the present invention includes a plastic packaging material made of polyethylene, polypropylene, polyester, etc., a plastic laminated aluminum packaging material, or a packaging material in which the above-mentioned plastic is used as a part of the packaging material. In addition, the term "container" refers to a container made of the above-mentioned plastic, a container whose inside is covered with the above-mentioned plastic, or a container in which a portion of the container is made of the above-mentioned plastic. Even when packaged, the bromhexine hydrochloride in the formulation will not be adsorbed by the plastic. Furthermore, the formulation of the present invention has a strong adsorption run-up effect on bromhexine hydrochloride even when the plastic is used for the container lid, packing, etc. be. Among the bromhexine hydrochloride-containing preparations of the present invention, solid preparations are manufactured by a method generally used for manufacturing granules.

For example, it is produced by thoroughly mixing bromhexine hydrochloride, an excipient, a binder, and a substance having a surfactant action, adding a solvent, kneading well, drying, and sieving. When the solid preparation is a tablet, a lubricant is further added and then the tablet is compressed using a tablet machine.

The excipients and binders may be those commonly used; excipients include crystalline cellulose, starch, carboxymethyl cellulose, etc., binders include hydroxypropyl cellulose, polyvinylpyrrolidone, etc., and lubricants include , magnesium stearate, talc, hydrogenated castor oil, boric acid powder, and carnauba wax.

In addition, examples of the type of solvent used include solvents commonly used in pharmaceutical production, such as ethanol, water, and isopropyl alcohol.

On the other hand, a solution formulation is produced by dissolving or dispersing bromhexine hydrochloride and a substance having a surfactant effect in a solvent such as water.

In addition to the above-mentioned ingredients, the bromhexine hydrochloride-containing preparations exemplified above include drugs that do not interfere with the efficacy of bromhexine hydrochloride, such as ibuprofen, ethenzamide,
Acetaminophen, carbinoxamine maleate, noscapine hydrochloride, caffeine, dihydrocodeine phosphate,
0.1 to 80 parts by weight of various vitamins and the like can be added to 1 part by weight of bromhexine hydrochloride.

In addition, various additives commonly used in formulations, such as sweeteners (saccharin sodium, aspartame, xylitol, stevioside, glycyrrhizic acid, licorice extract, various sugars, etc.), pH adjusters (citric acid, tartaric acid,
Malic acid, succinic acid, benzoic acid, sodium phosphate,
disodium phosphate, etc.), preservatives (benzalkonium chloride, roseoxybenzoic acid esters, etc.), stabilizers (sodium bisulfite, ascorbic acid, etc.), disintegrants (starch, agar powder, gelatin, crystalline cellulose, carboxylic acid, etc.) Sodium methylcellulose, calcium carboxymethylcellulose, calcium carbonate, sodium hydrogen carbonate, etc.) can also be incorporated within the range that does not impair the effectiveness of the preparation.

[Effects of the Invention] As is clear from the test examples described later, the preparations of the present invention containing bromhexine hydrochloride and a substance having a surfactant action do not require the use of packaging materials or containers when these preparations are packaged and stored. Bromhexine hydrochloride is hardly adsorbed to plastic.

[Example] Hereinafter, the present invention will be explained in more detail by showing Examples and Test Examples.

(Example 1) After thoroughly mixing 4 g of bromhexine hydrochloride, 900 g of crystalline cellulose, 100 g of Sugar Ester S-370F [trade name of sucrose fatty acid ester, manufactured by Mitsubishi Chemical Industries, Ltd.] and 20 g of hydroxypropyl cellulose, 600 g of ethanol was added. The mixture was mixed in a mixing machine and sieved through a No. 12 sieve. Thereafter, it was dried in a fluidized bed (60° C., 1 hour) to obtain 950 g of a white dry product.

Of these, those that passed through a No. 12 sieve and remained on a No. 42 sieve were selected to obtain 803 g of granules.

(Example 2) Ethanol TOIO-M [trade name of polysorbate 80,
[manufactured by Nikko Chemical Co., Ltd.]] to produce granules according to Example 1 to obtain 807 g of granules.

(Example 3) After thoroughly mixing 4 g of bromhexine hydrochloride, 900 g of crystalline cellulose, 10 g of Sugar Ester S-570 [trade name of sucrose fatty acid ester, manufactured by Mitsubishi Chemical Industries, Ltd.] and 20 g of hydroxypropyl cellulose, 600 g of ethanol was added. The mixture was added, kneaded in a kneader, and sieved through a No. 8 sieve. Then, it was dried in a fluidized bed (60°C for 11 hours).
850 white dried fish were obtained. This was passed through a No. 24 sieve, and 2 g of magnesium stearate was added to what passed through the sieve, and the tablets were compressed using a tablet machine so that the bromhexine hydrochloride content was 4 mg.
g (1088 tablets) was obtained.

(Example 4) Tablets were manufactured according to Example 3 using 10 g of ethanol TOIO-M [trade name of polysorbate 8o, manufactured by Nikko Chemical Co., Ltd.] instead of 10 g of Sugar Ester S-570, and 512 g of tablets were prepared. (1092 tablets) were obtained.

(Example 5) Granules 80 manufactured and processed in the same manner as in Example 1
0 g was crushed in a mortar and passed through a No. 42 sieve to obtain 771 g of powder.

(Example 6) Granules 80 manufactured and processed by the same method as Example 2
0 g was crushed in a mortar and passed through a No. 42 sieve to obtain powder 770 grade.

(Example 7) Bromhexine hydrochloride 4g 1 Ibuproftec 150g 1 Crystalline cellulose 800g Sodium lauryl sulfate 50g
After thoroughly mixing 5 g of hydroxypropyl cellulose, 600 g of ethanol was added and kneaded with a kneader,
It was sieved through a No. 12 sieve. Then fluidized bed drying (60°
C.) to obtain 940 g of a white dry product.

Of these, those that passed through a No. 12 sieve and remained on a No. 42 sieve were selected to obtain 796 g of granules.

(Example 8) Granules 8 were prepared in the same manner as in Example 7, except that the amount of ibuprofen added in Example 7 was changed from 150 g to 200 g, and the amount of sodium lauryl sulfate added was changed from 50 g to 10 g.
02g was obtained.

(Comparative Example 1) Granules were produced in the same manner as in Example 7 except that sodium lauryl sulfate was not added in Example 8, and 800 g of granules were obtained.

(Test Example) The granules produced in Example 7.8 and Comparative Example 1 were designated as Preparations 1 to 3, respectively. These were packaged in an aluminum packaging material laminated with Botethylene on the inside and heated under heating conditions (50°C).
), and the content of bromhexine hydrochloride in the packaging material after 1 week, 2 weeks, 3 weeks, and 4 weeks was quantified using high performance liquid chromatography under the following conditions. Bromhexine hydrochloride in the packaging material was determined using an extract obtained by refluxing the packaging material in chloroform at 50°C for 30 minutes.

Quantitative conditions (1) Pump; HITACHI ■Detector, HITACHI 655A-12 [Manufactured by Hitachi Seisakusho Co., Ltd.] 55A [Manufactured by Hitachi Ltd. Co0) Operating conditions; Detector measurement wavelength Detector sensitivity column Column temperature movement Layer UV absorption photometer 10 nm 0,04 AUFS A stainless steel tube with an inner diameter of 4 mm and a length of 150 mm is filled with 5 μm of ophtadecylsilylated silica gel as a filler.

A mixture of acetonitrile at a constant temperature of around 50°C and a 1/15M potassium dihydrogen phosphate solution (mixing ratio 520:480) with a lauryl sulfur flow rate (4) injection amount of sodium oxide (mixing ratio 520:480) 1ff per minute! ! constant flow rate; inject 10I4f1 of bromhexine hydrochloride with a concentration of approximately 201 tg/me. The results were expressed as a percentage, with the bromhexine hydrochloride content in the preparation immediately after preparation being 100% (Table 1)
.

Table 1

Claims (1)

[Claims] A preparation containing bromhexine hydrochloride and a substance with surfactant action.