JPH0446118A - Compound composition - Google Patents

Abstract

PURPOSE:To prepare a compound composition of bromohexine chloride substantially not causing the adsorption of the bromohexine chloride on plastic packaging materials or containers when packaged and stored by mixing the bromohexine chloride with crystal cellulose and a specific amount of a solvent, kneading the mixture, drying, etc. CONSTITUTION:Bromohexine chloride, crystal cellulose and a solvent capable of dissolving >= 90% of the bromohexine chloride (e.g. water, methanol or ethanol) are mixed in an arbitrary order, kneaded and dried. Or the bromohexine is mixed with the crystal cellulose powder and subsequently ground until the bromohexine chloride is converted into an amorphous state.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention relates to a composite composition containing bromhexine hydrochloride, and more specifically, when a preparation containing bromhexine hydrochloride is packaged and stored, the bromhexine hydrochloride in the preparation is used as a packaging material. Or it relates to a composite composition for aiding adsorption to plastic containers.

Prior Art and Problems to be Solved by the Invention Conventionally, bromhexine hydrochloride is mixed with excipients such as starch and crystalline cellulose, and binders such as hydroxypropylcellulose and polyvinylpyrrolidone to form solids such as powders, granules, or tablets by conventional methods. It was either made into a formulation or dissolved in a solvent commonly used in the manufacture of pharmaceuticals to form a solution formulation.

However, as a result of research conducted by the present inventors, it has been found that when these preparations are packaged and stored, bromhexine hydrochloride is adsorbed to the plastic packaging material or container, resulting in a decrease in the bromhexine hydrochloride content in the preparations. did.

In particular, for granules, it is practical to store them separately in plastic packaging materials or plastic laminated aluminum packaging materials, so plastics are often used as packaging materials, and contact with these packaging materials is important. Since the area 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 only as small as 4 mg at a time.

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, the present inventors have found that when a composition consisting of bromhexine hydrochloride and crystalline cellulose is produced by a certain method, bromhexine hydrochloride and crystalline cellulose are different from normal ones. It was discovered that these substances exist in different states, and the present invention was completed based on this knowledge.

That is, the present invention is a composite composition characterized in that it is produced by mixing bromhexine hydrochloride, crystalline cellulose, and a solvent in an amount capable of dissolving bromhexine hydrochloride in any order, followed by kneading and drying (invention 1). ), and the present invention is a composite composition characterized in that it is produced by mixing powders made of bromhexine hydrochloride and crystalline cellulose, and then grinding the mixture until the bromhexine hydrochloride becomes amorphous (invention 2).

The present invention will be explained in detail below.

In invention 1, when the solvent is used in an amount that can completely dissolve bromhexine hydrochloride, adsorption of bromhexine hydrochloride to the packaging material or plastic of the container can be almost completely prevented,
More preferably, sufficient effects can be obtained by using an amount that dissolves 90% or more of bromhexine hydrochloride.

Moreover, methanol, ethanol, isopropyl alcohol, water, etc. can be used as a solvent, and a mixture thereof can also be used. The kneading method and time, drying method and time may be the same as those used for manufacturing the preparation, but when manufacturing the composite composition using an amount of solvent that is slightly less than the amount that can completely dissolve bromhexine hydrochloride, It is preferable that the kneading time be longer than usual.

In invention 2, whether or not bromhexine hydrochloride has become amorphous is confirmed by X-rays. Here, it is more preferable for bromhexine hydrochloride to be completely amorphous, but even if it is not completely amorphous, it is sufficient as long as the degree of crystallinity is 10% or less.6 For grinding, use a ball mill or an automatic mortar machine. , hybridizer, etc. can be used.

In Inventions 1 and 2, the blending ratio of bromhexine hydrochloride and crystalline cellulose is 10 parts or more of crystalline cellulose to 1 part bromhexine hydrochloride, preferably 20 parts or more of crystalline cellulose to 1 part bromhexine hydrochloride.

In addition to the above-mentioned essential ingredients, the composition of the present invention contains drugs that do not interfere with the efficacy of bromhexine hydrochloride, such as antipyretic analgesics (ibuprofen, ethenzamide, acetaminophen, etc.), antihistamines (carbinoxamine maleate, etc.), and antitussives. (noscapine hydrochloride, dihydrocodeine phosphate, etc.), various other vitamins, caffeine, etc. can be blended within an amount that does not interfere with the efficacy of bromhexine hydrochloride.

In addition, various additives commonly used in formulations, such as sweeteners (saccharin sodium, a'subaltame, xylitol, stevioside, glycyrrhizic acid, licorice extract, various sugars, etc.), disintegrants (starch, agar powder, gelatin, crystals, etc.), Cellulose, sodium carboxymethylcellulose, calcium carboxymethylcellulose, calcium carbonate, sodium hydrogen oxide, etc.) may also be incorporated within the range that does not impair the effectiveness of the preparation.

The composite composition of the present invention can be prepared into various solid preparations (tablets, granules, powders, etc.) by conventional methods. In preparations prepared in this manner, bromhexine hydrochloride is not adsorbed to the plastic of the packaging or container.

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 container includes a container made of the above-mentioned plastic, a container whose inside is covered with the above-mentioned plastic, and a container in which a portion of the container is made of the above-mentioned plastic. Even if the preparation produced using the composite composition of the present invention is packaged with these packaging materials or containers, the bromhexine hydrochloride in the preparation will not be adsorbed to the plastic. The effect of the present invention to prevent adsorption of bromhexine hydrochloride is effective even when the plastic is used for container lids, packing, etc.

Effects of the Invention As is clear from the test examples described later, the composition of the present invention has the following effects:
When this product is packaged and stored, almost no bromhexine hydrochloride is adsorbed to the packaging material or plastic of the container.

EXAMPLES Hereinafter, the present invention will be explained in more detail with reference to Examples and Test Examples.

Example 1 A powder mixture of 4 g of bromhexine hydrochloride and 700 g of Avicel PHIOL (trade name of crystalline cellulose, manufactured by Asahi Kasei Corporation) was mixed with methanol 6001IL1! in a mortar. was added to completely dissolve bromhexine hydrochloride, which was then kneaded and dried in a conventional manner to obtain a powder.

Example 2 A powder was obtained in the same manner as in Example 1 except that 200 d of methanol was used instead of 600 d of methanol.

Example 3 A powder was obtained in the same manner as in Example 1 except that methanol 100D was used instead of methanol 60M.

Example 4 A powder was obtained in the same manner as in Example 1 except that 900 d of ethanol was used instead of 600 d of methanol.

Example 5 700 g of Avicel PHIOI was placed in a mortar, a solution of 4 g of bromhexine hydrochloride dissolved in 600 d of methanol was added thereto, and the mixture was kneaded and dried in a conventional manner to obtain a powder.

Example 6 In Example 5, methanol 20011IL1 was used instead of methanol 600ae! A powder was obtained in the same manner as in Example 5, except that .

Example 7 In Example 5, methanol 10011 was used instead of methanol 600-! ! A powder was obtained in the same manner as in Example 5, except that .

Example 8 Bromhexine hydrochloride 0.1g and Avicel PHIOI 3
．． A mixed powder of 9 g was ground in an automatic mortar machine for 20 hours to obtain a powder with a crystallinity of θ%.

Example 9 A powder with a crystallinity of 6% was obtained in the same manner as in Example 8, except that the powder was crushed for 10 hours instead of 20 hours using an automatic mortar machine.

Control example 1 [8 Bromhexine 4g and Avicel PI (101700
A powder was obtained by mixing g.

Comparative Example 2 A powder was obtained in the same manner as in Example 1 except that methanol 50- was used instead of methanol 600 ae.

Comparative Example 3 A powder was obtained in the same manner as in Example 1 except that methanol 50rne was used instead of methanol 600d(7) in Example 5.

Control Example 4 A powder was obtained in the same manner as in Example 8, except that the powder was ground for 5 hours instead of 20 hours using an automatic mortar machine.

Note) 4 g of bromhexine hydrochloride is dissolved in 105 me of methanol.

Test Examples The powders obtained in Examples 1 to 8 and Control Examples 1 to 4 were taken in an amount equivalent to 4+ ng of bromhexine hydrochloride, each packaged in an aluminum packaging material with polyethylene laminated on the inside, and heated under heating conditions (60 ng). ``C), and after 5 days,
The content of bromhexine hydrochloride in the packaging material after 10 days and 15 days was determined 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 60°C for 130 minutes.

Quantification conditions (1) Pump; HITACHI 655A-12■ Detector, HITACHI [Newly manufactured by Hitachi Seisakusho Co., Ltd.] 55A [Newly manufactured by Hitachi Seisakusho Co., Ltd.] (3) Operating conditions; Detector measurement wavelength Detector Sensitivity column Column Temperature ultraviolet absorption photometer 10 nm 0.04 AUFS Inner diameter 4 mm, length d 150 mm stainless steel tube,
Fill with ophtadecylsilyl gel as a filler.

Constant temperature moving bed flow rate around 50°C (4) Injection amount Mixture of acetonitrile and 1/15M potassium dihydrogen phosphate solution of sodium lauryl sulfate (mixing ratio 520:480) Constant flow rate of about 1-per minute; Hydrochloric acid Bromhexine with a concentration of about 20μg/d
〇－Injection

Claims (2)

[Claims] (1) A composite composition produced by mixing bromhexine hydrochloride, crystalline cellulose, and a solvent in an amount capable of dissolving 90% or more of bromhexine hydrochloride in any order, followed by kneading and drying. (2) A composite composition characterized in that it is produced by mixing powders made of bromhexine hydrochloride and crystalline cellulose and then pulverizing the mixture until the bromhexine hydrochloride becomes amorphous.