JPH05255120A - Bitterness-covering preparation - Google Patents

Abstract

PURPOSE:To provide the bitterness-covering preparation capable of covering the bitterness of slightly water-soluble physiologically active substances, especially clarithromycin, even when the pH of the saliva is deviated to the acidic side, and capable of being safely produced. CONSTITUTION:(B) An aqueous gel of a polyvinyl acetal diethylaminoacetate containing (A) a slightly water-soluble substance having bitterness, preferably clarithromycin, is compounded with (C) magnesium oxide and/or magnesium hydroxide to obtain the gastric juice-soluble oral preparation capable of covering the bitterness of the physiologically active ingredient A on the oral administration of the component A. When the component A is the clarithromycin, the components are compounded with each other in an A:B:C molar ratio of 1:1-10:0.1-20 (preferably 0.3-5). In the preparation, the component A is covered with the component B and the component C exists together with the component A and/or the component B.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a bitterness-masking preparation, and more particularly to a gastric-soluble oral preparation which masks the bitterness of oral administration of clarithromasin, which is a pharmacological ingredient.

[0002]

2. Description of the Related Art Conventionally, various oral preparations have been known which mask the unpleasant taste of a physiologically active substance which is a pharmacological component during oral administration to facilitate oral administration. The inventors of the present invention also disclose in JP-A-64-22816 that a drug having an unpleasant taste is treated with cold water.
Disclosed is a production method capable of safely producing a taste-masked oral preparation in which bitterness is masked by forming microcapsules covered with polyvinyl acetal diethylaminoacetate. Further, in Japanese Patent Application Laid-Open No. 2-505658, there is disclosed a method in which a suspension in which particles containing a drug exhibiting an unpleasant taste is dispersed is made into fine particles under humidified heating conditions and dried to obtain a taste-masked oral preparation. Disclosed.

[0003] All of these taste-masked oral preparations do not normally dissolve in the pH of the mouth, but utilize a gastric-soluble polymer compound that dissolves in the pH of gastric acid, using a safe manufacturing method that does not use organic solvents or the like. It is encapsulated.

However, in the case of extremely bitter drugs,
It is difficult to completely mask it, and there is a problem that bitterness develops, especially after several minutes have elapsed since the drug was taken. Furthermore, this problem is that (1) most of the ingested particles are swallowed immediately after ingestion and disappear from the mouth, but only a few particles are folds on the surface of the epithelium of the tongue, between teeth and between teeth, It remains in the space between the gingiva and (2) The pH in the mouth is not uniform for all people, especially oral bacteria such as plaque (eg streptococcus, lactobacillus, Str. Mutans, Veillonella).
Etc.) have a large number of survivors, so they are biased toward weak acidity,
The gastric soluble polymer compound, which is the coating substance of the taste-masked oral preparation, dissolves in the mouth, impairing the effect of masking bitterness,
(3) Microcapsules containing gastric-soluble polymer compounds, if left behind in the mouth, for example, in the back of the tongue, they are constantly exposed to acidic substances such as carbon dioxide in the exhaled breath, so they gradually dissolve, and the bitterness is also masked. It creates three new problems: the effect is lost.

In order to solve these problems, it is considered desirable to use a water-insoluble substance, such as ethyl cellulose or wax, or a substance, such as alginic acid, which is not soluble on the acidic side, as a wall agent. However, in practical use, since it does not dissolve in the acidic stomach, there is an adverse effect that bioavailability (bioavailability) decreases.

On the other hand, Japanese Patent Laid-Open No. 58-4714 discloses that
A pharmaceutical mixture is described which contains the gastric soluble polymer Eudragit® E100, polyvinyl acetate and the basic substance sodium hydrogen carbonate.

However, since Eudragit E100 and polyvinyl acetate are insoluble in water, it is necessary to use an organic solvent such as chloroform and acetone in order to contain a basic substance. There is a danger of inhalation of. Further, there are problems that environmental pollution is caused by solvent vapor discharged at the time of drying and facilities for completely recovering the solvent are large-scaled. Also in terms of bitterness masking, sodium hydrogen carbonate dissolves quickly in the mouth, so that the bitterness masking effect does not continue.

The present invention has been made based on the above circumstances. That is, an object of the present invention is to provide a bitterness-masking preparation that can mask the taste of a physiologically active substance and can be safely manufactured even if the pH in the mouth is biased to the acidic side.

[0009]

The bitterness-masking preparation of the present invention for achieving the above object comprises a polyvinyl acetal diethylaminoacetate aqueous gel containing a bitter water-insoluble substance, magnesium oxide and / or magnesium hydroxide. It is a bitterness-masking preparation characterized by comprising: The mixing ratio of each component constituting the bitterness masking preparation of the present invention is usually 1 to 10% by weight with respect to clarithromycin for polyvinyl acetal diethylaminoacetate, and clarithromycin for magnesium oxide and / or magnesium hydroxide. On the other hand, the molar ratio is 0.1 to 20, preferably 0.3 to 5. In this bitterness masking formulation, clarithromycin is coated with polyvinyl acetal diethylaminoacetate and magnesium oxide and / or magnesium hydroxide is present with clarithromycin and / or polyvinylacetal diethylaminoacetate.

This bitterness-masking preparation is an emulsifier (for example, glycerin fatty acid ester, dioctyl sodium sulfosuccinate, polyoxyl stearate 40, gelatin, glyceryl monooleate, lecithin, cholesterol, etc.) as long as the object of the present invention is not impaired. , Suspending agents (eg, gum arabic, tragacanth, crystalline cellulose, glycerin, methyl cellulose, etc.), surfactants (sodium lauryl sulfate, polysorbate 80, cetyl alcohol, etc.), thickeners (eg, carboxymethyl cellulose sodium) , Polyvinylpyrrolidone, sucrose, sodium alginate, etc.), binders (hydroxypropylcellulose, starch etc.), plasticizers (Macrogol 6000, Pluronic F68 etc.), pH adjusters (citric acid, charcoal) Sodium hydrogen, etc., preservatives (ethyl paraoxybenzoate, butyl paraoxybenzoate, etc.), lubricants (talc, magnesium aluminometasilicate, etc.), flavoring agents (sorbitol, sodium saccharin, cinnamon oil, malic acid, mono-fumarate) It may also contain additives such as sodium), fragrances and pigments.

The bitterness-masking preparation of the present invention is preferably spherical fine particles. This is because the spherical fine particles do not give a feeling of foreign matter when contained in the mouth. The particle size is usually 300 μm or less, preferably 50 to 20.
It is 0 μm. This bitterness-masking preparation is prepared by adding clarithromycin, polyvinyl acetal diethylaminoacetate, magnesium oxide and / or water or an aqueous antifreeze solution.
Alternatively, magnesium hydroxide and, if necessary, a suspension containing the additive is dropped from a nozzle hole, and the dropped droplet is heated using steam or the like to form an aqueous gel,
It can be produced by aging with warm water at 20 to 90 ° C, preferably 40 to 80 ° C, and then drying.

The water used as the suspension is not particularly limited, but purified water is preferable. As the aqueous antifreeze liquid, polyhydric alcohol such as glycerin and propylene glycol can be added to water, preferably purified water, so as not to freeze even if the temperature is 0 ° C or lower. Further, depending on the case, a water-soluble organic solvent such as acetone or ethanol can be added. The particle size of the solid component in the suspension is
Fine particles are preferable, and the particle size is 30 μm.
The following is preferably 0.1 to 10 μm. In addition, clarithromycin may be subjected to a pretreatment such as coating with silicic acid or solid oil and fat, if necessary. The content of clarithromycin in the suspension is usually 40% by weight or less, preferably 10 to 30% by weight.

The content of polyvinyl acetal diethylaminoacetate in the suspension is usually 10% by weight or less, preferably 4 to 8% by weight. The content of magnesium oxide and / or magnesium hydroxide in the suspension is usually 0.1 to 20, preferably 0.3 to 5, in molar ratio with respect to clarithromycin. The content of the additive in the suspension is a suitable amount that does not impair the object of the present invention.

The diameter of the nozzle holes provided in the nozzle is usually 50 to 300 μm, preferably 75 to 150 μm, and the number of nozzle holes is usually 1 to 10,000, preferably 100 to 1,000. As the mixing method of each component described above, a conventionally known mixing method, mixing time and mixing device can be adopted. For example, using a commonly used propeller type, turbine type, etc. stirrer,
A suspension can be prepared by mixing the above components while cooling in the range of -10 to 10 ° C, preferably in the range of -5 to 5 ° C.

When the suspension is dropped from the nozzle hole, a spherical particle close to a true sphere can be produced by applying vibration to the suspension extruded from the nozzle hole. The frequency of the applied vibration is 1,000 to 10,000 Hz.
As a vibration method for applying vibration to the suspension flowing out of the nozzle, the nozzle may be regularly vibrated, or the suspension may be directly vibrated by a diaphragm or a vibrating rod.
As a means for applying vibration, a conventionally known method, for example, a vibrator can be adopted. By applying regular vibration to the suspension flowing out in a smooth flow, the flowing out suspension is regularly divided to generate a group of particulate droplets having a uniform particle size distribution.

The droplet group formed by flowing out from the nozzle hole usually falls in the air. The atmosphere in which the droplet group falls is not particularly limited, and may be air or an inert gas. In the present invention, dry air is preferred.

The droplets dropped from the nozzle holes can be heated by various means such as steam, hot water, hot air, a heater, or a combination of these various means. The heating temperature is usually preferably 20 to 80 ° C.

Specifically, for example, the suspension is made to flow out and fall into the air from a nozzle, and heated steam or warm air is blown to the droplet group generated by applying the vibration to the flowing out suspension, Then, a heating means for dropping the droplet group into the warm water tank can be mentioned. The drop distance from the nozzle to the hot water tank is preferably adjusted so that the residence time of the liquid droplets in the air is 1 second or less. The warm water tank may be a tank filled with still water heated to a constant temperature, but is preferably a tank filled with horizontally swirling warm water. The temperature of the hot water in the hot water tank is the same as the heating temperature. By using a hot water tank having hot water flowing in this horizontal swirling flow, it is possible to obtain aqueous gel particles having no difference in temperature history from each other, and the aqueous gel particles that have fallen collide with the vessel wall. As a result, the aqueous gel particles are not deformed.

The particles which have been subjected to the heat treatment are dried. As a drying device, a conventionally known drying method and drying device can be used for drying. Examples of the drying device include a fluidized bed drying device, a vacuum drying device, a vacuum fluidized drying device, a medium fluidized bed drying device, and a rotary aeration drying device.

By granulating or mixing the particles with an excipient, a binder, a thickener, a flavoring agent, a pH adjusting agent and the like by a usual method (eg, fluidized bed granulation), a completely bitter taste It is possible to obtain a formulation in which

Examples of the excipient mentioned here include starch, dextrin, dextran, talc, lactose, sucrose, sorbitol, xylitol, maltitol, aspartame, sodium saccharin and the like. Examples of the binder include pyridoxypropylmethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, carboxymethylcellulose, polyvinyl alcohol, pocivinylpyrrolidone and the like. Examples of the thickener include hydroxypropylmethyl cellulose, carboxymethyl cellulose, methyl cellulose, propylene glycol alginate and the like. Examples of the corrigent include sucrose, powdered sugar, sorbitol, maltitol, xylitol aspartame, sodium saccharin, paratenite, and various natural and synthetic flavors. pH
Examples of the regulator include sodium hydroxide, sodium bicarbonate, magnesium hydroxide, magnesium oxide, magnesium carbonate, calcium hydroxide, calcium carbonate, aluminum oxide, silicon dioxide, etc., and these may be used alone or in combination. You can By this method,
It is possible to obtain a bitterness-masking preparation of spherical particles in a large amount and at high speed.

[0022]

The bitterness-masking preparation of the present invention provides a bitterness-masking preparation which can mask the taste of a physiologically active substance and can be manufactured safely even if the pH in the mouth is biased to the acidic side. be able to.

[0023]

【Example】

(Example 1) To 94 parts by weight of purified water at 2 ° C, 5 parts by weight of polyvinyl acetal diethylaminoacetate was added with stirring and dissolved, and then 0.02 parts by weight of sodium lauryl sulfate and cetyl alcohol were further added. Add 0.005 parts by weight of clarithromycin (average particle size 2 μm) 1
Parts by weight, magnesium oxide 0.5 parts by weight,
A uniform suspension was prepared by stirring the whole.

The resulting suspension, the suspension is ejected from the nozzle to vibrate (nozzle hole diameter: 100 [mu] m, the nozzle hole number: 250 lines, the frequency of the nozzles is 7,200H _Z), uniform particle size Droplets.

The falling droplets are sprayed with steam at 70 ° C.,
The fallen aqueous gel particles were collected in a horizontal swirling warm water tank. The retention time from the nozzle to the hot water tank is
It was 0.54 seconds. The collected gel particles were aged in warm water at 52 ° C. for 14 hours and then dried using a fluidized bed dryer to obtain particles having a particle size distribution shown in FIG. At that time, the drying temperature was 70 ° C. and the drying time was 30 minutes.

A bitterness test was carried out on the obtained bitterness masking preparation in order to evaluate the degree of bitterness masking.

The method is to select 15 males and 20 females aged 20 to 30 in advance, and select 10 males and females with no taste abnormality by using taste blind test paper (Test Papers, manufactured by ADVANTEC).
It was used as a panelist for bitterness tests.

The test was conducted on all 10 men and women, one sample per day, after 2 hours from lunch. Preparation of syrup is 20W / W% for each sample 30 minutes before the start of the test.
1 part of clarithromycin was added to 2.5 ml of an aqueous solution of a sweetener (1 part by weight of sugar, 2 parts by weight of sorbitol, 2 parts by weight of xylitol, 0.02 parts by weight of sodium saccharin).
It was prepared to be 00 mg. For evaluation, each panelist had 2.5 ml of each sample syrup contained in the mouth for 1 minute, and then exhaled to the outside of the mouth. Immediately after the administration, 5 minutes, 15 minutes later, the degree of bitterness was evaluated according to the following 5 levels. I went separately.

Degree of bitterness; Stage 1 No bitterness. Second stage Almost no bitterness. Stage 3 Slightly bitter. Stage 4 Bitter. Stage 5 Very bitter. The evaluation results are shown in Table 1.

[0030]

[Table 1]

[Brief description of drawings]

FIG. 1 is a particle size distribution chart showing a particle size distribution of particles obtained in Example 1.

Claims (2)

[Claims] 1. A bitterness-masking preparation comprising a polyvinyl acetal diethylaminoacetate aqueous gel containing a bitter water-insoluble substance mixed with magnesium oxide and / or magnesium hydroxide. 2. The bitterness masking preparation according to claim 1, wherein the poorly water-soluble substance having bitterness is clarithromycin.