JPH0465051B2 - - Google Patents

Description

[Detailed description of the invention]

INDUSTRIAL APPLICATION FIELD The present invention relates to a bile acid oral solution containing bile acids and dextrins. The bile acid oral liquid preparation of the present invention is a clear liquid preparation in which bile acids are solubilized in water, and the extremely bitter taste peculiar to bile acids is masked, so that it can be used as a bile acid preparation that is easy to take internally. It is. Bile acids are frequently used as choleretic drugs and are highly evaluated for their efficacy and effectiveness, but they themselves have the property of being hardly soluble in water and having an extremely bitter taste. have. Therefore, it is extremely difficult to prepare a clear bile acid aqueous solution with no bitter taste, and the practical application of oral water preparations, which are absorbed much better in the gastrointestinal tract than solid preparations such as tablets or granules, has been greatly hindered. That is the reality. Conventional methods for obtaining bile acid aqueous solution preparations include:
For example, there is a method in which bile acids are solubilized by converting them into sodium salts (Japanese Patent Publication No. 17149/1983), and a method in which bile acids are converted into β-cyclodextrin inclusion compounds and solubilized (Japanese Patent Publication No. 17149/1983). −22616)
etc. have been reported. On the other hand, as a method of alleviating the bitterness of a bile acid aqueous solution, for example, a method using the sweetness of a flavoring agent such as white sugar or honey [Basic Course on Drug Development, Drug Manufacturing Methods (Part 2), p. 706, 1962
Published by Chijinshokan Co., Ltd. on November 15, 2017] is known. Problems to be Solved by the Invention However, the above-mentioned solubilization method using bile salts requires that the pH value of the aqueous solution be between 9.5 and 11.0, which necessitates careful pH adjustment.
Moreover, there is a problem in its application to internal water preparations for which liquid properties are preferably neutral or weakly acidic. In addition to this,
In this method, the bitter taste of the resulting bile acid aqueous solution does not disappear at all, and may even be enhanced in some cases. In addition, in the above-mentioned solubilization method using clathrate compounds, the clathrates obtained are extremely bulky (loose apparent specific gravity 0.04 g/cc, escape rate 38-45%) and are fine powders. When preparing a liquid medicine for internal use, handling is extremely troublesome, and there is concern that the scattering of bile acids may have an adverse effect on the health of the person in charge of manufacturing. On the other hand, in the method of alleviating bitterness using a flavoring agent, it has been pointed out that the bitterness of the bile acid aqueous solution cannot be sufficiently masked, resulting in a bad aftertaste after oral administration. In addition to this, syrups such as white sugar or honey,
A fatal drawback is that it has no effect on solubilizing bile acids. In addition, the present inventors have investigated pharmaceutical excipients commonly used in the solubilization or dispersion of poorly soluble drugs, such as polymeric compounds such as sodium carboxymethylcellulose, methylcellulose or hydroxypropylcellulose, or polyoxyl stearate 40 or Attempts were made to produce an aqueous bile acid solution using a surfactant such as polyethylene glycol, but none of the experiments yielded results that simultaneously satisfied both solubilization and bitterness mitigation. Measures to Solve the Problems However, when we prepared an aqueous bile acid solution using dextrins, which are often used as thickening agents or diluents for pharmaceutical preparations, we found that, surprisingly, bile acids were completely dissolved. The inventors discovered that the solution becomes a clear aqueous solution and that this aqueous solution has no bitter taste at all, leading to the present invention. According to the present invention, in a liquid medicine containing bile acids and dextrins, the weight ratio of dextrins to bile acids is 30 or more, and the concentration of dextrins is 35% (W/W) or less. Provided is a bile acid oral liquid preparation (hereinafter simply referred to as the liquid preparation of the present invention) characterized by the following. The content of bile acid, which is the main drug of the liquid preparation of the present invention, can be arbitrarily set as long as it is within the range in which the medicinal efficacy of bile acid can be expected. On the other hand, the amount of dextrins blended in the liquid medicine of the present invention is such that the weight ratio of the dextrins to bile acids is at least 30 and the content concentration is 35% (W/
W) Requires the following: These requirements are such that if the blending weight ratio is less than 30,
This is because the solubilization of bile acids is insufficient and a clear bile acid aqueous solution cannot be obtained, and in addition, a sufficient bitter taste masking effect is not exerted, and the concentration of dextrins is 35% (W/W). If it exceeds
On the contrary, the solubilizing effect of bile acids decreases, and moreover, the aqueous solution becomes cloudy. Another advantage of incorporating dextrins in the liquid preparation of the present invention is that since the aqueous solution of dextrins is inherently weakly acidic, it is preferable that the solution be neutral or weakly acidic. The following conditions can be satisfied without any troublesome PH adjustment. Here, examples of bile acids that can be used include ursodeoxycholic acid and chenodeoxycholic acid. Moreover, examples of dextrins include amylodextrin, erythdextrin, and maltodextrin. The solution of the present invention contains bile acid, dextrins, and water as essential components, but depending on the manufacturing method, components other than these three components, such as a binder such as hydroxypropylcellulose or polyvinylpyrrolidone, stearic acid, etc. polyoxyl 40,
It may also contain surfactants such as poloxyethylene hydrogenated castor oil 60 or propylene glycol, or trace amounts of ethanol. In addition, other pharmaceutical excipients, such as preservatives to preserve bile acids,
If necessary, a flavoring agent or aromatic agent to adjust the taste and aroma, or a preservative aid to prevent spoilage may be contained. Here, as a preservative,
Examples include ethyl paraoxybenzoate, propyl paraoxybenzoate, butyl paraoxybenzoate or dehydroacetic acid. Flavoring agents include white sugar, glucose, sodium citrate or sodium phosphate as aromatic agents, menthol, orange flavor, strawberry flavor, vanilla flavor, cinnamon flavor or plum flavor. Examples of preservative aids include citric acid, hydrochloric acid, and phosphoric acid. Furthermore, the liquid preparation of the present invention contains other active ingredients that are expected to have a synergistic effect with bile acids, such as γ-oryzanol, tonics such as taurine or royal jelly, thiamine hydrochloride, riboflavin, pyridoxine hydrochloride, ascorbic acid, tocopherol, Vitamins such as biotin or calcium pantothenate, or gentian, cinnamon bark, licorice,
Herbal preparations such as fenugreek, ginseng, ginseng or chikum peel can also be included. The liquid medicine of the present invention is prepared by mixing 1 part by weight of bile acid and 30 parts by weight or more of dextrins in a fluidized bed, spraying an appropriate binding liquid onto the mixture, and granulating it under air blowing conditions at 50 to 80°C. Then, the obtained granules were added to water for 15~
It can be adjusted by stirring and dissolving at 70°C and adjusting the final concentration of dextrins to 35% (W/W) or less with water at the same temperature (hereinafter abbreviated as fluidized bed granulation method). ). Suitable binding liquids include water or aqueous or aqueous ethanolic solutions of binders such as hydroxypropylcellulose or polyvinylpyrrolidone, or surfactants such as polyoxyl stearate 40, polyoxyethylene hydrogenated castor oil 60 or propylene glycol. . In the granulation step of this fluidized bed granulation method, granules with extremely low scattering properties, that is, granules with a loose apparent specific gravity of 0.35 to 0.61 g/cc and an escape rate of 8 to 13%, are obtained. be able to. In addition, the liquid medicine of the present invention can be prepared by uniformly dispersing 1 part by weight of bile acids in water, adding 30 parts by weight or more of dextrins to this dispersion, stirring and dissolving at 15 to 70°C, and then dissolving at the same temperature. This can be adjusted by adjusting the final concentration of dextrins to 35% (W/W) or less with water (hereinafter abbreviated as the dispersion method). In the step of obtaining a bile acid dispersion liquid using this dispersion method, bile acids are used as bulk powder (loose apparent specific gravity 0.18 to 0.25).
g/cc, escape rate 15 to 24%) may be used as is, but in order to improve dispersibility, the bulk powder may be dissolved in ethanol and used. Also,
If necessary, a surfactant such as polyoxyl stearate 40, polyoxyl ethylene hydrogenated castor oil 60, or propylene glycol may be further added. In both the fluidized bed granulation method and the dispersion method, the bile acid clathrate compound described in JP-A-55-22616 (loose apparent specific gravity 0.04 g/cc, escape rate 38-45%) is used. The risk of bile acid scattering is much lower than when preparing liquid medicines using
A clear bile acid oral solution can be obtained with simple handling. When the liquid preparation of the present invention contains the above-mentioned preservatives, flavoring agents, aromatics, or preservative aids, they may be added in the granulation step in the fluidized bed granulation method or in the step of obtaining the bile acid dispersion in the dispersion method. Pharmaceutical excipients may be added, or in both methods, in the subsequent step of stirring and dissolving the bile acids,
These pharmaceutical additives may also be added. When the above-mentioned other active ingredients that are expected to have a synergistic effect with bile acids are added to the liquid preparation of the present invention, it is desirable to add those active ingredients during the solubilization step of bile acids in both methods. The active ingredients to be added may be used as they are, but in the case of nutritional tonics or vitamins, their aqueous solutions or aqueous suspensions, and in the case of crude drugs, crude drug extracts, crude drug liquid extracts, crude drug tinctures, etc. It is preferable to use Actions and Effects of the Invention The bile acid solubilizing effect and bitter taste masking effect of dextrins in the liquid preparation of the present invention will be explained below. Tests on bile acid solubilization effect and bitterness masking effect were conducted using 70 different samples prepared. Each sample contained a predetermined amount of ursodeoxycholic acid (loose apparent specific gravity 0.24 g/cc, escape rate 17%).
or chenodeoxycholic acid (loose apparent specific gravity 0.19
g/cc, escape rate 22%) was uniformly dispersed in purified water, a predetermined amount of each of amylodextrin, erythdextrin, or maltodextrin was added thereto, stirred and mixed at 20 to 65°C, and then incubated at the same temperature. Adjustments were made by adjusting the total amount of each sample to 100 g with purified water. The composition of each sample prepared in this manner other than water was as described in the column of water formulation composition in Tables 1 and 2. In addition, when we investigated the liquid properties of each sample, the PH value was
It was within the range of 3.3 to 5.0, indicating weak acidity. The bile acid solubilization effect was determined by comprehensively determining the absorbance of each sample at a wavelength of 660 nm measured with a spectrophotometer and the clarity of each sample visually observed. The bitterness masking effect was judged by a bitterness sensory test conducted by 10 panelists. The results are shown in Tables 1 and 2 in the columns of solubilization effect and bitterness masking effect. In both tables, the visual clarity is expressed as + when it is cloudy, ± when it is slightly cloudy, and - when it is clear. The bitterness masking effect was determined when each panelist held 10g of each sample in their mouth for 20 seconds and then swallowed it, and all 10 panelists did not feel any bitterness. If 1 to 7 people felt bitterness, △
If 8 or more people felt the taste was bitter, they were marked with an x. In both tables, the compounding ratio means the ratio of the weight of dextrins to the weight of bile acids.

【table】

【table】

【table】

【table】

【table】

【table】

[Table] As is clear from Tables 1 and 2, in bile acid oral solutions, the weight ratio of dextrins to bile acids is 30 or more, and the concentration of dextrins is 35% (W /W) If it is less than
It is observed that bile acids are significantly solubilized in water, forming a clear aqueous solution with an absorbance of approximately 0.1 or less, and at the same time, the bitterness inherent in bile acids is sufficiently masked. Therefore, the solution of the present invention can be used as a non-bitter internal solution in bile acid preparations. Although most of the samples described above correspond to examples of the present invention, other examples will be described in detail below in order to further explain the present invention. Example 1 10 g of ursodeoxycholic acid and 1 g of paraoxin benzoic acid were dissolved in ethanol, and the total volume was adjusted to exactly 100 ml. 1 ml of this ethanol solution was weighed out using a volumetric pipette, and poured into 80 g of sterile purified water for uniform dispersion. 3 g of amylodextrin was added to this dispersion, and the mixture was sufficiently stirred and mixed while heating to 60 to 65°C. By adding this amylodextrin, the cloudy white dispersion immediately became a clear aqueous solution, with no bitter taste at all. Next, add 350mg of licorice extract to the resulting aqueous solution.
0.8ml of Shokiyou style extract, Ukiyo tincture
1.5ml, cinnabar extract 0.5ml and carrot extract
130mg, plum flavor 0.1ml, glucose 10g and 0.5
60 g of polyoxyethylene hydrogenated castor oil was added and thoroughly stirred and mixed, and this was sterilized and filtered using a 0.45μ membrane filter, and the total amount was made up to 100 g with sterile purified water. This final solution was evenly divided and filled into five 20 ml drink bottles, which were sealed with metal caps to provide a liquid for gastrointestinal use. The ursodeoxycholic acid content in each bottle was determined by gas chromatography to be 19.8±
It was 0.3 mg. Example 2 5g of chenodeoxycholic acid (loose apparent specific gravity
0.18 g/cc, escape rate 24%) and 490 g of maltodextrin were each weighed and mixed in an FL0-1 fluidized bed granulator (manufactured by Freund Sangyo Co., Ltd.). While spraying 100 g of a 40% (W/W) aqueous ethanol solution containing 1% (W/W) hydroxypropylcellulose into this fluidized bed, fluidized bed granulation was carried out at an air blowing temperature of 60°C. The grains were sorted. The loose apparent specific gravity of this granule is 0.41 g/cc, and the escape rate is 10.
It was %. Next, 32 g of the granulated material was added to 80 g of sterilized purified water and thoroughly stirred, and a clear aqueous solution with no bitter taste and a slightly sweet taste was immediately obtained. Add 1% butyl paraoxybenzoate (W/
1 ml of the ethanol solution containing W) and 0.5 g of polyxyl stearate 40 were added, and after thorough stirring and mixing, the total amount was made up to 120 g with sterile purified water. This final solution was heat sterilized at 95°C for 1 hour, then heated to 60°C.
The mixture was allowed to cool to ℃, and the mixture was evenly divided and filled into four 30 ml drink bottles, sealed with metal caps, and administered internally. The chenodeoxycholic acid content in each bottle was determined by gas chromatography to be 79.5±0.8 mg per bottle. Example 3 5 g of ursodeoxycholic acid (loose apparent specific gravity 0.25 g/cc, escape rate 15%) and 395 g of erythdextrin were each weighed, placed in an FL0-1 type fluidized bed granulator, mixed, and then This was subjected to fluidized bed granulation at a blowing temperature of 60° C. while spraying 80 g of water, and sized to a size of 32 meshes. The loose apparent specific gravity of the granulated material is
It was 0.57 g/cc, and the escape rate was 9%. When 4 g of this granulated material was added to 70 g of sterile purified water and thoroughly stirred, a clear aqueous solution with no bitter taste was immediately obtained. This aqueous solution contains 20 mg of thiamine hydrochloride, 10 mg of tocopherol acetate, 5 mg of riboflavin phosphate, 50 μg of bithion, 1000 mg of taurine, and royal jelly.
After adding 250 mg of white sugar, 15 g of white sugar, 0.1 ml of propylene glycol, and 0.1 ml of orange flavor, and thoroughly stirring and mixing, the total amount was made up to 100 g with sterilized purified water. This was sterilized and filtered using a 0.45μ membrane filter, and the resulting final liquid was filled into five 20ml drink bottles in equal portions and sealed with metal caps to form a nourishing and tonic internal medicine. .
The ursodeoxycholic acid content in each bottle was determined by gas chromatography.
It was 9.9±0.2 mg.

Claims (1)

[Scope of Claims] 1. In a liquid medicine containing bile acids and dextrins, the weight ratio of dextrins to bile acids is 30 or more, and the concentration of dextrins is 35% (W/W) or less. A bile acid oral solution. 2. The bile acid oral solution according to claim 1, wherein the bile acid is ursodeoxycholic acid or chenodeoxycholic acid. 3. The bile acid oral solution according to claim 2, wherein the dextrins are amylodextrin, erythrodextrin, or maltodextrin. 4. In liquid medicines containing bile acids and dextrins, the weight ratio of dextrins to bile acids is 30 or more, and the concentration of dextrins is 35%.
(W/W) or less, and contains at least one or more components of a nutritional tonic, a vitamin, and a crude drug preparation. 5. The nutritional tonic is γ-oryzanol, taurine, or royal jelly, or two or more of these, and the vitamin is thiamine hydrochloride, riboflavin, pyridoxine hydrochloride, ascorbic acid, tocopherol, piotin, or calcium pantothenate, or two or more of these. The bile acid oral water according to claim 4, wherein the crude drug preparation is composed of gentian bark, cinnamon bark, blackberry, licorice, fenugreek, sagebrush, carrot, or chimney bark, or two or more of these. agent.