JP2831004B2 - Powdered pharmaceutical preparation - Google Patents

Description

The present invention relates to a powdered pharmaceutical preparation for oral administration.

Loperamide has the following structure, and is useful as an antidiarrheal agent for oral administration.

The hydrochloride salt of loperamide, loperamide hydrochloride, has a bitter taste and is very painful to take, especially for children.

On the other hand, JCRI pre-clinical research 5 , (1), 29-43, (1979)
Reported that physical dependence was observed when a large amount of loperamide hydrochloride was repeatedly administered to normal monkeys.

Under such circumstances, when preparing a formulation for oral administration containing loperamide, it is desired to mask the bitter taste and prevent a change in the administration route. In addition, there is no example in which such a change in the administration route is prevented by a pharmaceutical technique, not limited to the loperamide preparation.

The present inventors, when shaking with water, exhibit turbidity, the liquidity of which is neutral to alkaline, and preferably prepare a powdery granular pharmaceutical preparation for oral administration of loperamide hydrochloride so as to be slightly viscous. The inventors have found that the above-mentioned problems can be solved at the same time, and completed the present invention.

The present invention provides at least 0.01 to 1% by weight (hereinafter, simply referred to as%) of a salt of loperamide as a first component and a second component.
Aluminum, magnesium, calcium as ingredients
It contains a poorly water-soluble substance composed of at least one of zinc and titanium. When 1 g of the final preparation is shaken with 10 ml of water (hereinafter referred to as a shaking state), the liquid has a pH of 6 or less. 1010.

The second component here has a function of giving turbidity in a shaking state (turbidity function), and often has a function of adjusting the liquid property in a shaking state to pH 6 to 10 (pH adjusting function).

Specific examples of the second component include, for example, magnesium aluminate metasilicate, magnesium salt of stearic acid, aluminum salt, calcium salt or zinc salt, calcium salt or magnesium salt of silicic acid, magnesium aluminum silicate, talc, titanium oxide, Magnesium oxide, calcium or magnesium carbonate salts, substances such as magnesium aluminum hydroxide, aluminum, magnesium, calcium, zinc and titanium are included in any one or more substances, all of which are hardly soluble in water. is there. Of these, oxides have only a turbidity function, and others also have a pH adjustment function. The particle size of the second component is 0.1-100 μm, preferably 0.3-30 μm. The content of the second component is not limited unless there is a special reason that the pH value in the shaking state is out of the specified range or adversely affects the dissolution of loperamide from the final preparation.

The second component or components impart turbidity under shaking conditions and their pH is often adjusted to 6-10. It is better to use a plurality of second components little by little than to use a single second component. This is because adverse effects caused by using a large amount of a single second component, such as delay in adsorption and elution of loperamide as a main drug, are alleviated. With respect to the combination of the plurality of second components, for example, the presence or absence of a pH adjusting function, the degree of its strength, the duration of turbidity, and the effect of adsorption on loperamide are considered. These properties can be known by simple experiments. Regardless of the singular or plural, the total content of the second component is not particularly limited.
0.1% or more, preferably in the range of 0.2 to 5%.

Adjusting the pH of the liquid in a shaking state to pH 6 to 10 masks the bitterness of loperamide. Preferred pH under shaking conditions
The value is between 7 and 9.5, a particularly preferred range is between pH 7.5 and 9. Adjustment of the pH is preferably achieved by a second component, excluding oxides such as magnesium oxide. In addition, sodium (hydrogen) carbonate and sodium citrate may be contained for pH adjustment.

In order to stabilize turbidity in a shaking state, it is preferable to further include a thickener as a third component. Also, the thickener hinders the extraction of the main drug from the final preparation, and makes it difficult to perform one of the extraction operations, such as filtration. Examples of the thickener include synthetic polymer compounds such as hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, sodium carboxymethylcellulose, and polyvinylpyrrolidone, and natural polymer compounds such as pullulan, gelatin, gum arabic, pectin, guar gum, and glyloid. The content of the thickener is not particularly limited, but is 0.1% or more, usually 0.1 to 10%, preferably 0.5%.
５5%. The viscosity in a shaking state (20 ° C.) is about 100 cps or less, usually 1 to 50 cps, preferably
A thickener in an amount of 1.2 to 10 cps is contained.

In addition, excipients such as lactose and purified sucrose, lubricants such as light silicic anhydride, fragrances, coloring agents, lubricants and the like may be further blended.

The powdery pharmaceutical preparation of the present invention can be prepared by a method such as mixing each component well or pouring water or a binder-containing solution into the mixture and granulating the mixture, powders and fine granules, granules, Finished in dry syrup form.

The powdery pharmaceutical preparation for oral administration of the present invention thus obtained has a masked bitter taste, is easy to take, and becomes turbid and viscous when shaken with water. It is to prevent.

 Next, the present invention will be described in more detail with reference to examples.

Example 1 Formulation Loperamide hydrochloride 1 mg Lactose 976 mg Magnesium aluminate metasilicate 10 mg Magnesium stearate 5 mg Hydroxypropyl cellulose 10 mg Loperamide hydrochloride and magnesium stearate were put into a mixer, mixed for 5 minutes, and mixed with metasilicate After adding magnesium aluminate, lactose and hydroxypropylcellulose, mix for 10 minutes to obtain a powder.

When 250 mg of this powder is contained in the mouth, it does not feel bitter for about 30 seconds. In addition, when 1 g of the present powder was shaken with 10 ml of water, the powder turned cloudy, its pH was 8.1, and its viscosity was 1.3 cps.

Example 2 Formulation Loperamide hydrochloride 0.5 mg Purified sucrose 949.5 mg Calcium stearate 20 mg Sodium bicarbonate 10 mg Gum arabic powder 10 mg Carboxymethylcellulose Na 10 mg Loperamide hydrochloride, kneaded purified sucrose, calcium stearate, sodium hydrogencarbonate and sodium carboxymethylcellulose Mix for 10 minutes. A gum arabic powder solution dissolved in purified water of 7% by weight of the mixed powder is poured into the mixed powder and kneaded for 15 minutes. At 50 ° C
After drying for 20 hours, the mixture is sieved with a twin rotor to obtain a powder having a size of 32 mesh or less.

When 250 mg of this powder is contained in the mouth, it does not feel bitter for about 30 seconds. When 1 g of this powder was shaken with 10 ml of water, the powder turned cloudy, had a pH of 8.5 and a viscosity of 5 cps.

Example 3 A powder having the following formulation was obtained in the same manner as in Example 2, except that hydroxypropyl cellulose was dissolved in purified water and added to the mixed powder.

Prescription Loperamide hydrochloride 1 mg Mannitol 924 mg Titanium oxide 5 mg Magnesium stearate 30 mg Hydroxypropylcellulose 30 mg Saccharin Na 10 mg When this powder 250 mg is contained in the mouth, it does not feel bitter for about 30 seconds. When 1 g of this powder was shaken with 10 ml of water, the powder turned cloudy, had a pH of 8.6, and a viscosity of 1.5 cps.

Example 4 A powder having the following formulation was obtained in the same manner as in Example 2, except that hydroxypropyl cellulose was dissolved in purified water and added to the mixed powder.

Prescription Loperamide hydrochloride 0.5 mg Purified sucrose 964.5 mg Magnesium aluminate metasilicate 10 mg Magnesium stearate 5 mg Light anhydrous silicic acid 5 mg Carboxymethylcellulose Na 5 mg Hydroxypropylcellulose 10 mg Does not feel bitter. When 1 g of the present powder was shaken with 10 ml of water, the powder turned cloudy, had a pH of 8.7 and a viscosity of 5 cps.

Example 5 A powder having the following formulation was obtained in the same manner as in Example 2, except that hydroxypropylmethylcellulose was dissolved in purified water and added to the mixed powder.

Prescription Loperamide hydrochloride 1 mg Purified sucrose 929 mg Sodium citrate 20 mg Talc 30 mg Pullulan 10 mg Hydroxypropyl methylcellulose 10 mg When this powder 250 mg is taken in the mouth, it does not feel bitter for about 30 seconds. When 1 g of the present powder was shaken with 10 ml of water, the powder turned cloudy, had a pH of 7.8 and a viscosity of 1.4 cps.

──────────────────────────────────────────────────続 き Continued on the front page (72) Inventor, Yu Imazato 2-5-A3-202, Shinsenri-Higashi-cho, Toyonaka-shi, Osaka (56) References JP-A-60-161915 (JP, A) JP-A-57- 31610 (JP, A) PHYSCIANS 'DESK REFERENCE, 42nd edition, (1988), p. 1071-1072, 412 Sadao Iguchi, "New Comprehensive Development System Integrated Technology-Bases and Additives" (1985) R & D Planning 410-411, 413-415, 420-421, 427-428 (58) Fields investigated (Int.Cl. ⁶ , DB name) A61K 31/445 A61K 9/14 A61K 47/02 A61K 47/32 A61K 47 / 38 CA (STN)

Claims (6)

(57) [Claims] 1. At least (a) 0.01 to 1% by weight of loperamide hydrochloride as a first component; and (b) 0.2 to 5% by weight of magnesium aluminate metasilicate as a second component which is a poorly water-soluble component; stearic acid Magnesium, aluminum, causium or zinc salts; calcium or magnesium salts of silicic acid; magnesium aluminum silicate; talc; titanium oxide; magnesium oxide; calcium or magnesium salts of carbonic acid; or magnesium aluminum hydroxide; A powder or granular pharmaceutical preparation for oral administration containing these mixtures, which becomes turbid when 1 g of the final preparation is shaken with 10 ml of water and whose pH is adjusted to pH 6 to 10 if necessary. . 2. The powdery pharmaceutical preparation according to claim 1, wherein the pH of the liquid pharmaceutical preparation when 1 g of the pharmaceutical preparation is shaken with 10 ml of water is pH 7 to 9.5. 3. The granular pharmaceutical preparation according to claim 1, wherein the pH of the pharmaceutical preparation when shaking 1 g of the granular pharmaceutical preparation with 10 ml of water is pH 7.5 to 9. 4. A thickening agent as a third component, comprising 0.5 to 5% by weight of hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone, pullulan, gelatin, gum arabic, pectin, guar gum or glyloid or The powdery pharmaceutical preparation according to any one of claims 1 to 3, further comprising a mixture thereof. 5. A method according to claim 1, wherein the first component is loperamide hydrochloride in an amount of 0.03 to 0.3% by weight, and the second component is magnesium aluminate metasilicate, magnesium stearate, calcium stearate, talc or titanium oxide or a mixture thereof. The powdered pharmaceutical preparation according to any one of claims 1 to 4, wherein the component is hydroxypropylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, pullulan or gum arabic, or a mixture thereof. 6. A method according to claim 1, wherein the second component is a mixture of magnesium stearate and magnesium aluminate metasilicate, and the third component is sodium carboxymethylcellulose or hydroxypropylcellulose or a mixture thereof. The pharmaceutical preparation according to any one of the preceding claims.