JPH0478615B2 - - Google Patents

Description

[Detailed description of the invention]

FIELD OF INDUSTRIAL APPLICATION The present invention relates to solid preparations of bile acids containing bile acids and β-cyclodextrin. More specifically, the present invention relates to bile acid powders, granules, and tablets that mask the bitter taste inherent in bile acids and contain a high concentration of bile acids. BACKGROUND ART Bile acids have been widely used as choleretic agents since ancient times, and their efficacy has been highly evaluated. In recent years, ursodeoxycholic acid and chenodeoxycholic acid, which are types of bile acids, have attracted attention as gallstone dissolving agents. When these bile acids are used as gallstone dissolving agents,
Adults require a daily dose of 300 to 400 mg, with a maximum dose of 600 mg. Bile acids inherently have a very strong bitter taste, so when taken in the form of powders, granules, or tablets, people feel pain and discomfort, and this is especially noticeable when they contain high concentrations of bile acids, making it very difficult to take. becomes. As a method for masking the bitter taste of bile acids, granules containing chenodeoxycholic acid and crystalline cellulose are disclosed in JP-A-59-190913, and granules containing chenodeoxycholic acid and crystalline cellulose are disclosed in JP-A-55-22616. Inclusion compounds with dextrins are disclosed. Generally used methods for masking bitter drugs include film coating, sugar coating for tablets, and addition of sweeteners. However, powders, granules, and tablets in which bitter taste is masked in a non-inclusion state by simply mixing ursodeoxycholic acid or chenodeoxycholic acid and β-cyclodextrin are not known. Problems to be Solved by the Invention Regarding the above-mentioned prior art, although the granules containing chenodeoxycholic acid and crystalline cellulose have alleviated bitterness to some extent, the effect is still insufficient, and moreover, there is no sensation of heat in the mouth. However, satisfactory effects such as a feeling of swelling were not obtained. Furthermore, since this granule contained a high concentration of crystalline cellulose, it took more than 30 minutes to disintegrate.
Inclusion of ursodeoxycholic acid or chenodeoxycholic acid with β-cyclodextrin is intended for water solubility, but concomitantly masks bitterness. However, in producing this clathrate compound, it is necessary to add β-cyclodextrin at a weight ratio of 3 or more to bile acid, and the solubility of both components in water is low, resulting in a dilute aqueous solution. The resulting clathrate compound after water is removed by concentration, freeze-drying, etc. becomes a very fine powder (apparent specific gravity, loose 0.04 g/cc) and has high scatterability (escape rate 38-45%). ), it is difficult to handle when preparing solid preparations such as powders, granules, and tablets. The production of clathrate compounds requires various steps such as solubilization, stirring, solvent removal, and freeze drying, which is very time consuming and troublesome. In addition, clathrate compounds are different drugs that differ from guest compounds in terms of pharmacological effects, absorption, excretion, etc. JP-A No. 55-22616, page 124, from the 3rd line to the last line of the bottom left column, there is a description of "a mixture of ursodeoxycholic acid and β-cyclodextrin (mixed in the absence of water)". This mixture was prepared experimentally as a comparison sample for thin layer chromatography, and there is no description of the blending ratio, effects, pharmaceutical properties, specific manufacturing method, etc. Therefore, it cannot be inferred from the disclosure of the publication that the mixture of ursodeoxycholic acid and β-cyclodextrin masks bitterness. In film coating of powders and granules, it is difficult to completely coat the surface of the particles, and it takes a long time to coat the particles as it must be coated repeatedly.Also, when film coating or sugar-coating tablets, it is difficult to completely coat the particle surface. There are inconveniences such as having to do so. The method of adding sweeteners does not fully achieve bitterness masking. Therefore, there is a need for a bile acid powder that sufficiently masks the bitter taste of bile acids, is simple to manufacture and formulate, is easy to handle as a finished preparation, and does not cause differences in pharmacological effects, absorption, excretion, etc. Granules and tablets are preferred. Particularly when bile acids are used as gallstone dissolving agents, it is necessary to take a high dose and contain a high concentration of bile acids, so a preparation having the above-mentioned characteristics is highly desirable. Means for Solving the Problems According to the above-mentioned Japanese Patent Application Laid-Open No. 190913/1989, it is stated that dextrin and β-cyclodextrin are not essential ingredients for masking bitterness, but the present inventors have conducted extensive research. Surprisingly, the inventors discovered that a solid preparation prepared by simply mixing bile acid and β-cyclodextrin at a certain mixing ratio masks the strong bitter taste of bile acid, and completed the present invention. A major feature of the solid preparation of the present invention is that the bile acid and β-cyclodextrin are in a non-clathrated state and yet mask the bitter taste. Bile acids in the present invention refer to ursodeoxycholic acid and chenodeoxycholic acid, which are important as pharmaceuticals. The solid preparation of the present invention has essential characteristics and achieves the purpose in powders, granules, and tablets (particularly bare tablets) in which it is difficult to completely coat the particle surface. The term "powder" as used herein also includes fine granules. The blending amount of bile acid and β-cyclodextrin in the solid preparation of the present invention is such that the weight ratio of β-cyclodextrin to bile acid is 0.8 to 3.0, and the content of bile acid per 1 g of solid preparation is within the range of 250 to 550 mg. arbitrarily determined. Since this solid preparation contains a high concentration of bile acid, the number of administrations can be reduced, and it is particularly effective when used as a gallstone dissolving agent that requires high doses. In the solid preparation of the present invention, the powder contains bile acids and β-
Granules are obtained by mixing bile acid and β-cyclodextrin with a binder such as hydroxypropyl cellulose using a general granulator.
Tablets are prepared by compressing these powders and granules. In addition, depending on the dosage form, conventional additives such as talc,
Lubricants such as magnesium stearate, calcium stearate, silicic anhydride, starch, lactose, sucrose, mannitol sugar excipients, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, gum arabic powder,
Binders such as sodium carboxymethylcellulose and gelatin, surfactants such as polyoxyl 40 stearate, propylene glycol, and polyethylene glycol, and disintegrants such as carboxymethylcellulose, calcium carboxymethylcellulose, and low-substituted hydroxypropylcellulose are appropriately selected, and bile Acid content per 1g of solid preparation
It may be added within a range maintained at 250 to 550 mg. The solid preparation of the present invention is produced, for example, as follows. 100 parts by weight of ursodeoxycholic acid or chenodeoxycholic acid and 80 parts by weight of β-cyclodextrin
~300 parts by weight are placed in a V-type mixer and mixed for 10-60 minutes to obtain a powder. Add a binder to this powder for 5~
Add 45 parts by weight, granulate using water or water-containing ethanol using a crushing granulator, extrusion granulator, fluidized bed granulator, etc., and sieve to a desired particle size to obtain granules. Tablets are obtained by compressing the powder or granules thus obtained by a conventional method. The apparent specific gravity (loose) of the powder is 0.21 to 0.34 g/cc, and the escape rate is 8.5 to 15.1%, and the apparent specific gravity (loose) of the granule is 0.44 to 0.57 g/cc, and the escape rate is 7.2 to 7.2. 9.2
%, and both were easy to handle. Further, the disintegration time of the granules was 4 to 10 minutes, indicating that the preparations had good disintegration properties. The fact that the bile acids contained in the powders, granules, and tablets thus obtained is not included in β-cyclodextrin is due to the melting point of the Examples and Comparative Examples described below.
This is clear from the results of thin layer chromatography, infrared absorption spectroscopy (IR), and the determination of bile acids in solid preparations using neutralization titration. Effect The bitter taste masking effect of the solid preparation of the present invention will be explained below. A test sample for bitterness masking effect was prepared as follows. Ursodeoxycholic acid or chenodeoxycholic acid and β-cyclodextrin are blended in a predetermined weight ratio, and the powder is prepared using a V-type mixer [Model VFS: manufactured by Sanei Seisakusho Co., Ltd.]. same as below. ] at 30
For granules, add hydroxypropyl cellulose [HPC] to the above powder.
-L: Manufactured by Nippon Soda Co., Ltd. same as below. ] was added in a quick kneader [manufactured by Daiwa Kako Co., Ltd.]. same as below. ], kneaded with 50% hydrated ethanol, crushed and sized using a granulator [speed mill; Daiwa Kako Co., Ltd.]
Made in 3mm basket. same as below. ] and granulated at
It was then classified and prepared using No. 12 and No. 42 sieves.
A comparative sample was prepared by blending a predetermined amount of bile acid and crystalline cellulose [Avicel PH-101; manufactured by Asahi Kasei Corporation], adding 50 parts by weight of hydroxypropylcellulose-L as a binder, and preparing a powder in the same manner as above.
Granules were prepared. The bitterness mask effect was evaluated by 10 panelists (5 men, 5 women).
Judgment was made by a bitterness sensory test conducted by When each panelist held 1 g of sample in their mouth for 20 seconds, 10
A case where none of the 100 panelists felt bitterness was indicated by ○, a case where 1 to 7 panelists felt bitterness was indicated by △, and a case where 8 or more panelists felt bitterness was indicated by ×. The measurement results of bitterness masking effect, apparent specific gravity, and escape rate are shown in Table 1 (powders of ursodeoxycholic acid and chenodeoxycholic acid) and Table 2 (granules of ursodeoxycholic acid and chenodeoxycholic acid). The escape rate is sample 2
Using the method of Aoki et al. (Pharmacology, p. 27, 103,
(1967). The compounding ratio in each table represents the weight ratio of β-cyclodextrin or crystalline cellulose to bile acid.

【table】

【table】

【table】

[Table] As is clear from each table, powders and granules containing ursodeoxycholic acid or chenodeoxycholic acid and β-cyclodextrin were tested by all panelists when the weight ratio of β-cyclodextrin was in the range of 0.8 to 3.0. It was found that it did not taste bitter and completely masked the bitterness of bile acids. Furthermore, tablets prepared from these powders and granules did not taste bitter. On the other hand, in the control formulation containing crystalline cellulose instead of β-cyclodextrin, 1 to 7 people felt bitterness at blending weight ratios of 2.5 and 4.0, and the masking effect was insufficient. In addition, samples No. 11, 12, 13, 14 containing crystalline cellulose,
On 25, 26, 27, and 28, all panelists felt a sensation of heat in the mouth (the tongue felt numb and hot) and a swelling sensation (the mucous membranes in the mouth felt like they were being compressed). Next, production examples of the solid preparation of the present invention will be specifically explained with reference to Examples. In Examples and Comparative Examples, neutralization titration and thin layer chromatography (hereinafter referred to as TLC) were performed as follows, and infrared absorption spectra (hereinafter referred to as IR) were measured by the KB _r disc method. (Neutralization titration method) This was carried out in accordance with the method for determining ursodeoxycholic acid under the Japanese Pharmacopoeia Law (11th Bureau). 50 ml of acetone was added to a sample equivalent to 500 mg of bile acid, stirred for 10 minutes at room temperature, and then centrifuged. The supernatant was collected and dried under reduced pressure. 40 ml of neutralized ethanol and 20 ml of water were added to the resulting residue to dissolve it, then 2 drops of phenolphthalein test solution were added, and the mixture was titrated with 0.1N sodium hydroxide solution. This allows the amount of bile acids mixed in the sample in an acetone-soluble state to be quantified. (TLC) The acetone supernatant prepared by the above neutralization titration method was spotted on a thin layer plate of silica gel 60F 254 (manufactured by Merck & Co., Ltd.), and a mixed solvent of ethyl acetate: cyclohexane: glacial acetic acid (50:13:3) was used. It was developed and detected by heating after spraying with concentrated sulfuric acid. Example 1 125 g of ursodeoxycholic acid and 375 g of β-cyclodextrin were placed in a V-type mixer and mixed at 30 rpm.
A powder was obtained by mixing for 30 minutes. When the content of ursodeoxycholic acid in the powder was measured by neutralization titration method, it was found to be 248.5 ± 0.2 mg per 1 g (theoretical content 250 mg,
The extraction rate was approximately 99.4%). The escape rate was 9%, there was little dust, and it was easy to handle. Melting point 196-202℃
(melting), 260-274℃ (carbonization). TLC showed one spot at Rf0.6 as in sample No. 6 in FIG. IR
The spectrum is shown in Figure 2. When 1 g of this powder was subjected to a bitterness sensory test by 10 panelists, none of them felt any bitterness. Example 2 Put 300 g of chenodeoxycholic acid and 300 g of β-cyclodextrin into a V-type mixer, and mix at 30 rpm for 30 min.
A powder was obtained by mixing for a minute. The content of chenodeoxycholic acid in the powder was determined by neutralization titration and was 498 ± 0.6 mg per 1 g (theoretical content 500 mg, extraction rate approx.
99.6%). It had an escape rate of 9.3% and was easy to handle with little dust. Melting point 118℃ (melting), 265
~275℃ (carbonized). TLC showed one spot at Rf0.6 as in sample No. 7 in FIG. The IR spectrum is shown in Figure 3. When 1 g of this powder was subjected to a bitterness sensory test by 10 panelists, none of them felt any bitterness. Example 3 300 g of ursodeoxycholic acid, 600 g of β-cyclodextrin, 70 g of carboxymethyl cellulose calcium and 30 g of hydroxypropyl cellulose were placed in a quick kneader and mixed for 3 minutes, and then 210 g of ethanol was added and kneaded. This kneaded material was granulated using a crushing and sizing granulator, dried at 60°C, and then sized using 12 mesh and 42 mesh sieves to obtain ursodeoxycholic acid-containing granules. The content of ursodeoxycholic acid in the granules was determined by neutralization titration method and was found to be per gram.
299.2±0.4mg (theoretical content 300mg, extraction rate approximately 99.7%)
It was hot. The disintegration time was 4.6 minutes. Melting point 196~
201℃ (melting), 260-275℃ (carbonization). TLC is
One spot is shown at Rf0.6 (figure omitted). The IR spectrum is shown in Figure 4. When 1 g of this granule was subjected to a bitterness sensory test by 10 panelists, none of them felt any bitterness. Example 4 400 g of chenodeoxycholic acid, 500 g of β-cyclodextrin, 60 g of carboxymethyl cellulose calcium and hydroxypropyl cellulose
After putting 30g into a quick kneader and mixing for 3 minutes, 180g of 50% aqueous ethanol was added and granulated. After drying at 60°C, the granules were sized using a 12-mesh sieve to obtain 920 g of granules. 9.3 g of magnesium stearate was added to the obtained granules to prepare granules for tabletting. Melting point 118-119℃ (melting), 264-271℃
(Carbonization). TLC showed one spot at Rf0.6 (figure omitted). The granules were weighed using a tablet press [Clean Press Collect 12TV-AWC [manufactured by Kikusui Seisakusho Co., Ltd.]].
A tablet containing 250 mg of chenodeoxycholic acid was obtained by molding it into a mold with a diameter of 8 mm. The content of chenodeoxycholic acid in the tablets was determined by neutralization titration method.
99.7±0.1mg per tablet (250mg) (theoretical content 100mg,
The extraction rate was approximately 99.7%). This is per 1g
Equivalent to 398.8±0.4mg. 4 tablets (approximately 400 mg of chenodeoxycholic acid)
When a bitter sensory test was conducted on 10 panelists (equivalent amount), none of them felt any bitterness. Example 5 500 g of ursodeoxycholic acid, 470 g of β-cyclodextrin and 30 g of hydroxypropyl cellulose were placed in a quick kneader and mixed for 3 minutes, then 185 g of ethanol was added and kneaded.
This kneaded product was granulated in the same manner as in Example 3 to obtain ursodeoxycholic acid-containing granules. The content of ursodeoxycholic acid in the granules was determined by neutralization titration and was found to be 497.6±0.2 mg/g (theoretical content 500 mg, extraction rate approximately 99.5%). The disintegration time was 8.8 minutes. Melting point 195-197℃ (melting),
265-274℃ (carbonization). TLC showed one spot at Rf0.6 (figure omitted). When 1 g of this granule was subjected to a bitterness sensory test by 10 panelists, none of them felt any bitterness. [Comparative Example] In order to prove that bile acids are not included in β-cyclodextrin in the solid preparation of the present invention, ursodeoxycholic acid, chenodeoxycholic acid and β were prepared according to the method described in JP-A-55-22616. - We produced clathrate compounds with cyclodextrin and compared their melting points, TLC, IR, etc. (a) 1.0 g of ursodeoxycholic acid was suspended in 300 ml of water, and 4.05 g of anhydrous β-cyclodextrin was added little by little while stirring well, and dissolved to form a colorless and transparent solution. Pour this solution under low pressure to approx.
Water was distilled off at 60° C., and the resulting residue was washed with acetone and dried to obtain about 5 g of an clathrate compound of ursodeoxycholic acid and β-cyclodextrin. Melting point 285-291℃. (The melting point of β-cyclodextrin is 267-272°C.). TLC did not show any spots like sample No. 4 in FIG. This indicates that the clathrate is not dissolved at all in acetone.
(β-cyclodextrin is insoluble in acetone). The IR spectrum is shown in Figure 5. (b) Approximately 5 g of an inclusion compound of chenodeoxycholic acid and β-cyclodextrin was obtained in the same manner as in (a) except that chenodeoxycholic acid was used instead of ursodeoxycholic acid. Melting point 272-278
℃. TLC did not show any spots like sample No. 5 in FIG. This indicates that the clathrate is not dissolved at all in acetone.
The IR spectrum is shown in Figure 6. The differences between the solid preparation of the present invention and the clathrate compound are as follows.

【table】

[Table] As described above, bile acids and β-
It can be seen that cyclodextrin, unlike clathrate compounds, is simply in a mixed state. Effects of the Invention The solid preparation of the present invention contains ursodeoxycholic acid or chenodeoxycholic acid, which is a bile acid useful as a choleretic agent and gallstone dissolving agent, and β-cyclodextrin at a blending weight ratio of β-cyclodextrin to bile acid of 0.8. Regarding the powders, granules, and tablets prepared by mixing ~3.0, these preparations completely mask the strong bitter taste of bile acids even though the bile acids are in a non-inclusion state, so they are easy to take and extremely useful as pharmaceuticals. It is useful for Moreover, the solid preparation of the present invention has g
Since it contains bile acids at a high concentration of 250 to 550 mg per serving, the number of administrations can be reduced, and it is particularly effective when used as a gallstone dissolving agent that requires high doses.

[Brief explanation of drawings]

Figure 1 shows TLC, samples 1 and 2 are acetone solutions of standard products of ursodeoxycholic acid and chenodeoxycholic acid, respectively, samples 3, 4 and 5 are standard products of β-cyclodextrin, comparative example (a) and (b) The clathrate compound is treated with acetone, and 6 and 7 are the acetone treatment solutions of the powders of Examples 1 and 2, respectively. Figures 2 to 6 are IR spectra; Figure 2 is for each solid preparation of Example 1, Figure 3 is for Example 2, Figure 4 is for each solid preparation of Example 3, and Figure 5 is for the comparative example (A). FIG. 6 shows each clathrate compound of Comparative Example (b).

Claims (1)

[Scope of Claims] 1. In a solid preparation containing bile acid and β-cyclodextrin, the blending weight ratio of β-cyclodextrin to bile acid is 0.8 to 3.0, and the content of bile acid per 1 g of the solid preparation is A solid preparation of bile acids, characterized in that the amount is 250 to 550 mg. 2. The solid preparation of bile acid according to claim 1, wherein the bile acid is ursodeoxycholic acid or chenodeoxycholic acid. 3. The solid preparation of bile acid according to claim 1, wherein the solid preparation is a powder, granule, or tablet.