JPH11310525A - Heavy granule containing glycyrrhizic acid - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a heavy granule preparation capable of displaying good elutability for glycyrrhizic acid in a low pH region by employing a modifying granulation method introducing solid particles as nuclei and using a binder consisting only of a solvent. SOLUTION: This heavy granule is obtained by employing a modifying granulation method in which (A) solid particles are introduced as nuclei, (B) a binder consisting only of solvents is sprayed and (C) a powdered medicine including glycyrrhizic acid or its salt is gradually added thereto so as to be accumulated. For example, the method in which component B as 99% methanol is sprayingly added to the component A as spherical granules of sucrose and starch, and the component C as the powdered medicine including dipotassium glycyrrhizinate is gradually added and accumulated. Consequently, good elutability for glycyrrhizic acid is secured and the resultant heavy granules are a preparation capable of using especially as an oral medicine for rhinitis, a medicine for cold, an antipyretic analgesic or the like.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention can be used in pharmaceutical preparations, especially oral medicine for rhinitis, cold medicine, antipyretic analgesic, antitussive expectorant, Chinese medicine preparations, etc., and ensures good dissolution of glycyrrhizic acid. Heavy granular preparations.

[0002]

2. Description of the Related Art Conventionally, glycyrrhizic acids have shown an anti-inflammatory effect when administered orally.
Attempts have been made to formulate it into cold medicines, antipyretic analgesics, antitussive expectorants, etc., and some of them have been commercialized and distributed on the market.
For example, in Japan, the “Regulation for the manufacture (import) of internal medicines for rhinitis” was notified on January 29, 1993, by the notice of the Chief of the Pharmaceutical Affairs Bureau No. 64, and glycyrrhizic acid and Its salts or licorice are recognized. Licorice has also been recognized as an active ingredient that can be combined with cold remedies, antipyretic analgesics, and antitussive expectorants. In addition, licorice is very often used as an active ingredient in Kampo preparations. Recently, application of poorly-absorbable pharmaceutical active ingredients as absorption enhancers for improving transmucosal absorbability has been studied.

[0003] By the way, the dissolution of the main drug component is rarely confirmed by a dissolution test so far, and at present, quality assurance is mostly performed by a disintegration test, but from the original idea of quality assurance. In this case, it is desirable to design the formulation of the drug with sufficient consideration of dissolution. When the dissolution property is evaluated, the dissolution test method of the Japanese Pharmacopoeia is generally adopted, and the dissolution test solution is varied in a low pH to neutral range such as pH 1.2, pH 4.0, and pH 6.8. Then, the dissolution of the active ingredient is evaluated.

[0004]

Since glycyrrhizic acid has relatively poor solubility in a low pH range, it does not disperse even in a dissolution test solution having a pH of 1.2 in an undissolved state. In some cases, the dissolution property is significantly deteriorated by the treatment. For example, as a method for producing heavy granules, a drug-containing sucrose / starch spherical granules are used as a core,
There is a method of laminating and granulating by gradually adding powder while spraying a binding liquid (modified granulation method, called layering). In this method, when an ethanol solution of povidone (K value: 30) is used as a binding solution and a powder containing dipotassium glycyrrhizinate is added, the obtained granules are very heavy, When evaluated by the test paddle method, the dissolution of glycyrrhizic acid at pH 1.2 was poor.

[0005] Since glycyrrhizic acid is an acidic compound,
Since the higher the H, the easier it is to dissolve, even if, for example, an attempt is made to add disodium phosphate to a powder containing dipotassium glycyrrhizinate, the dissolution property is not improved. As another method, for example, dispersing agents such as corn starch or carmellose calcium containing dipotassium glycyrrhizinate or polysorbate 8 as a surfactant in a binding solution are used.
Addition of 0 does not improve the dissolution. Accordingly, an object of the present invention is to provide a heavy granular preparation which ensures good dissolution of glycyrrhizic acid.

[0006]

The inventors of the present invention have conducted intensive studies, and as a result, solid particles were used as a nucleus, and a dispersion containing glycyrrhizic acid or a salt thereof was gradually added while spraying a binding solution to form a layer. In the modified granulation method,
As a binding liquid, without blending a polymer binder at all,
The inventors have invented that it is possible to produce a heavy granule capable of ensuring good dissolution of glycyrrhizic acid when composed only of a solvent. That is, in the modified granulation method of the present invention, in which solid particles are used as nuclei, and a dispersion containing glycyrrhizic acid or a salt thereof is gradually added while spraying a binding solution to form a laminate, only a solvent is used as the binding solution. And a method for producing heavy granules characterized by the following.

[0007] The present invention will be described in more detail as follows. The nucleus of the solid particles to be used is not particularly limited, and is composed of additives that can be used in pharmaceutical preparations, crystal grains of bulk drug substances, or granules thereof. The salts of glycyrrhizic acid are not particularly limited, and examples thereof include dipotassium glutyrrhizinate, monopotassium glycyrrhizinate, trisodium glycyrrhizinate, and diammonium glycyrrhizinate. Further, even when licorice extract or licorice powder is used as containing glycyrrhizic acid, it is naturally within the scope of the present invention. The powder containing glycyrrhizic acid or a salt thereof is not particularly limited, though it is composed of the above-mentioned additives and drug substances other than the water-soluble polymer which can be used in pharmaceutical preparations.

[0008] For example, the active pharmaceutical ingredients include aspirin, aspirin aluminum, acetaminophan, isopropylantipyrine, ibuprofen, indomethacin, etenzamid, sazapyrine, salicylamide, sodium salicylate, allyl isopropylacetyl urea, bromvalerylurea, lactyl phenetidine, and L hydrochloride. -Ethyl cysteine, isotipendyl hydrochloride, iproheptin hydrochloride, diphenylpyraline hydrochloride, diphenhydramine hydrochloride, dipheterol hydrochloride, triprolidine hydrochloride, tripelenamine hydrochloride, trimethokinol hydrochloride, phenylpropanolamine hydrochloride, methoxyphenamine hydrochloride, tondylamine hydrochloride, phenylpropanolamine hydrochloride, Phenylephrine hydrochloride, phenetazine hydrochloride, promethazine hydrochloride,
Metzirazine hydrochloride, meclizine hydrochloride, cyclidine hydrochloride,
Methylephedrine hydrochloride, methylephedrine saccharin salt, diphenhydramine salicylate, carbinoxamine diphenyldisulfonate, alimemazine tartrate, diphenhydramine tannate, phenetazine tannate,
Diphenylpyraline theoculate, mebuhydroline napadylate, promethazine methylene disalicylate, carbinoxamine maleate, chlorpheniramine maleate,
Mequitazine, Promethazine methylene disalicylate, Dipheterol phosphate, Allocramide hydrochloride, Cloperastine hydrochloride, Carbetapentane citrate, Tipepidine citrate, Sodium dibunate, Dextromethorphan hydrobromide, Dextromethorphan phenolphthalin salt, Hibenzanic acid Tipepidine, cloperastine fendizoate, codeine phosphate, dihydrocodeine phosphate, noscapine hydrochloride, noscapine, potassium cresol sulfonate, potassium guaiacol sulfonate, guaifenesin, bromhexine hydrochloride, clemastine fumarate, caffeine sodium benzoate, caffeine, anhydrous caffeine , Aminophylline, diprofylline, theophylline,
Proxifylline, lysozyme chloride, bromelain, serrapiopeptidase, semi-alkali proteinase, ethylcysteine hydrochloride, methylcysteine hydrochloride, cerylpyridinium chloride, decalinium chloride, chlorhexidine hydrochloride, carbocysteine, tonanexamic acid, dimorphone hydrochloride, vitamin B1 and its derivatives and Their salts, vitamin B2 and its derivatives and their salts,
Vitamin C and its derivatives and their salts, hesperidin and its derivatives and their salts, aminoacetic acid, magnesium silicate, synthetic aluminum silicate, synthetic hydrotalcite, magnesium oxide, dihydroxyaluminum aminoacetate, aluminum hydroxide gel , Dried aluminum hydroxide gel, mixed dried gel of aluminum hydroxide and magnesium carbonate, co-precipitated product of aluminum hydroxide and sodium hydrogen carbonate, co-precipitated product of aluminum hydroxide and calcium carbonate, magnesium carbonate,
Coprecipitation product of magnesium hydroxide and potassium aluminum sulfate, magnesium carbonate, magnesium metasilicate aluminate, isopropamide iodide, ephedra, nantenjitsu, spruce, onji, kyokyo, kyonin, shazenshi, shazensou, shikiru, sexan, senega, tokon ,
Bimo, Asenyaku, Fennel, Obak, Ogon, Karonin, Gejutsu, Chamomile, Cahi, Kaguyi, Gentian, Gooh, Beast, Saishin, Shion, Musk, Shajin, Shokyo, Shinjo, Zenko, Choji, Chimpi, juniper, juniper, earth dragon, chikusetsu carrot, carrot, peonies, botanical, valerian, salamander, hange, orange, shokyo, pheasant, chikujo, engosaku, bukuro, borei, shukusha, ryokyo, sansonin, Psycho, ginger, rhubarb, cuckoo, sis, senkyu, ryogannik, ougi, sanshin, mokko, cuckoo,
Daifukuhi, Kouboku, Gaiyou, Akyo, Forsythia, Oak, Mint, Bowfish, Goboushi, Kyoukatsu,
Gypsum, Geom, Processed Bushi End, Ryukotsu, Kobushi, Kankyo, Karakon, Chimo, Hamabofu, Dokkatsu, Gomushi, Lennik, Zikoppi, Saicha, Kikuka, Tonin, Mokutsu, Dokatsu, Irisen, Koubei, Kaseki, Yokonin, Kokonin Hot water, Keishi-to, Koso-to, Saiko-keishi-to, Sho-saiko-to, Sho-seiryu-to, Bakumondo-to, Hange-koboku-to, Maoto-to, Datsura extract, Belladonna alkaloid, Belladonna extract, Roth extract, etc. .

[0009] The solvent composition of the binding solution used is not particularly limited.
Examples thereof include ethanol, methanol, water, acetonitrile, acetone, isopropanol, and methylene chloride. Ethanol and water are also preferable from the viewpoint of work. In the production method of the present invention, for example, 9 g
A method of obtaining a heavy granule by laminating by gradually adding a powder containing dipotassium glycyrrhizinate while spray-adding 9% ethanol, followed by drying. Manufacturing equipment for performing this modified granulation is a centrifugal flow device,
Although it is not particularly limited, such as a tumbling granulator and a stirring granulator, it is obvious that a production apparatus having few elements that destroy the core of the solid particles to be used is preferable.

The heavy granules in the present invention are, for example, those having a bulk specific gravity of 0.5 g / mL or more, but are not particularly limited because they vary depending on the composition, the surface condition of the granules, and the like. The heavy granular preparation obtained by the present invention may be used as a preparation as it is, may be mixed with other granules and powders, may be tablet-formed as it is, or may be filled in a capsule. Furthermore, another layer may be formed as the upper layer, and may be subjected to usual pharmaceutical modification, which is not particularly limited.

[0011]

EXAMPLES Next, the present invention will be described more specifically with reference to Examples, Comparative Examples and Test Examples, but the present invention is not limited thereto.

Comparative Examples 1 to 7, Examples 1 and 2 Nonpareil-101 (24-32) (registered trademark: manufactured by Freund Corporation) was charged into a tumbling granulator, and 10% povidone K30 was used as a binding liquid. Of ethanol (Comparative Examples 1 to 7) or only a solvent (Examples 1 and 2) while spray-adding dipotassium glycyrrhizinate (Gly).
K2), d-chlorpheniramine maleate (abbreviated as d-MCP), isopropamide iodide (abbreviated as TY), anhydrous caffeine (abbreviated as CAFF), phenylpropanolamine hydrochloride (abbreviated as PPA) ) Is gradually added and laminated, and dried to produce spherical heavy granules. In addition, the prescription composition of the used powder and binding solution is as shown in Tables 1-3.
The powder used was a well-mixed raw material, pulverized by a hammer mill, and then mixed well again before use. Example 1
The bulk specific gravity of the granules prepared in the above was about 0.7 g / mL.

[0013]

[Table 1] Formulation composition of Comparative Examples 1-3 Aerosil 200 (registered trademark; light silicic anhydride manufactured by Nippon Aerosil Co., Ltd.), Neusilin UFL2 (magnesium aluminate metasilicate manufactured by Fuji Chemical Industry Co., Ltd.) ECG505 (carboxymethyl cellulose calcium manufactured by Nichirin Chemical Industry Co., Ltd.)

[0014]

[Table 2] Table 2. Formulation composition of Comparative Examples 4 to 6

[0015]

[Table 3] Formulation composition of Comparative Example 7, Examples 1 and 2 Carplex 80 (registered trademark, hydrous amorphous silicon dioxide handled by Shionogi Pharmaceutical)

Test Examples 1 to 9 The heavy granules obtained above were quantified by the dissolution test paddle method in Japan under the following conditions. The elution rate was 100% when 15 mg of dipotassium glycyrrhizinate was eluted. Dissolution test conditions ・ JP Paddle method ・ Eluent 13 JP 900mL of the first solution (pH about 1.2) ・ Liquid temperature 37 ℃ ・ Paddle rotation speed 100rpm ・ Sample amount: 15mg equivalent of glycyrrhizin Granules containing dipotassium acid. The results of Test Examples 1 to 9 are as shown in Table 4.

[0017]

[Table 4] Results of Test Examples 1 to 9

[0018]Test results Test example 1  This is an example in which povidone K30 was contained as a binding solution.
The rate was as bad as 66% after 30 minutes.Test example 2  Example containing povidone K30, glycyrrhizic acid
Is an acidic compound.
The acid agent Neusilin UFL2 was added, but the dissolution rate was
Thirty minutes later it was 21% bad.Test example 3  This is an example containing povidone K30, and
Starch and ECG505, but the dissolution rate
After 30 minutes, it was 20% bad.Test example 4  Example containing povidone K30, glycyrrhizic acid
Is an acidic compound.
Na as an impactor₂HPO₄Was dissolved, but the dissolution rate was 30
A minute later, it was 55% bad.Test example 5  This is an example containing povidone K30, which is a surfactant.
Polysorbate 80 was added, but the dissolution rate was 30 minutes later.
It was bad at 51%.Test Examples 6 and 7  Example containing povidone K30 in a similar formulation to Test Example 8
As in Comparative Example 1, the dissolution rate was poor.Test Examples 8 and 9  Examples of the present invention using only a solvent as a binding solution
After 5 minutes, a dissolution rate exceeding 90% has already been secured.
This is a good result.

[0019]

The heavy granular preparation containing glycyrrhizic acid or a salt thereof provided by the present invention comprises a solid particle as a nucleus, and gradually disperses the dispersion containing glycyrrhizic acid or a salt thereof while spraying a binding solution. In the modified granulation method of adding and laminating, as a result of manufacturing by using only a solvent as a binding solution, an excellent effect of dissolution in a low PH region is obtained.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁶ Identification code FI A61K 31/70 ACG A61K 31/70 ACG ACH ACH

Claims (1)

[Claims] 1. A modified granulation method in which solid particles are used as nuclei, and a dispersion containing glycyrrhizic acid or a salt thereof is gradually added while spraying a binding solution to form a layer, and only a solvent is used as the binding solution. A method for producing heavy granules, characterized by comprising: