JP2018039749A - Semisolid preparation for oral administration, and production method thereof - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide semisolid preparations for oral administration in which the taste of a formulation is improved and in which decreased content and decreased thermal stability in an acidic drug preparation are suppressed, and to provide production methods thereof.SOLUTION: A semisolid preparation for oral administration contains (A) gelatin, (B) water, and (C) at least one drug selected from the group consisting of aspirin, ibuprofen, acetaminophen, loxoprofen, and salts thereof, having a pH of 1.0 to 3.5. A production method of a semisolid preparation for oral administration comprises gelating a liquid raw material in which the component (A) and (C) are dispersed into the component (B) and whose pH is 1.0 to 3.5.SELECTED DRAWING: None

Description

  The present invention relates to a semisolid preparation for internal use and a method for producing the same.

  In recent years, it has been desired to develop semi-solid preparations for internal use that are easy to take for elderly people who have poor swallowing function and children who are difficult to take tablets or liquids. Examples of semi-solid preparations for internal use include jelly preparations in which a drug is dispersed on a gel or sol base material. In general, in the semisolid preparation for internal use, the pH of the base material is adjusted to the acidic region for the purpose of suppressing the growth of microorganisms and the content of the drug in the preparation.

  If the pH of the substrate is in the acidic region, depending on the substrate, it may be difficult to maintain gel-like shape retention at high temperatures (eg, 50 ° C. or higher) (decrease in thermal stability). As a technique for improving the shape retention of a gel-like substrate at such a high temperature, a jelly containing micronized cellulose has been proposed (Patent Document 1).

JP-A-5-161460

However, in the technique of Patent Document 1, an unpleasant taste (bitterness) associated with a drug or micronized cellulose in a semisolid preparation for internal use may be strongly felt. In addition, the conventional techniques have not been sufficient to suppress the decrease in the content of the drug in the preparation and the decrease in the thermal stability.
Therefore, the present invention has an object of a semisolid preparation for internal use which improves the taste of the preparation and suppresses a decrease in the content of the drug in the preparation and a decrease in thermal stability, and a method for producing the same.

The present invention has the following aspects.
[1] Gelatin (A), water (B), and at least one drug (C) selected from the group consisting of aspirin, ibuprofen, acetaminophen, loxoprofen and salts thereof, and having a pH of 1 A semi-solid preparation for internal use which is 0.0 to 3.5.
[2] The semisolid preparation for internal use according to [1], wherein the component (A) has a weight average molecular weight of 30,000 to 270,000.
[3] The semisolid preparation for internal use according to [1] or [2], further containing a saccharide (D).
[4] The semisolid preparation for internal use according to any one of [1] to [3], further containing both or one of magnesium and aluminum or an inorganic metal salt (E).
[5] A method for producing a semi-solid preparation according to any one of [1] to [4], wherein the component (A) and the component (C) are dispersed in the component (B), and the pH is The manufacturing method of the semi-solid preparation for internal use which has the process of gelatinizing the raw material liquid which is 1.0-3.5.
[6] The semisolid preparation for internal use according to [5], comprising the step of dispersing the component (A) in the component (B) and then dispersing the component (C) to obtain the raw material liquid. Manufacturing method.

  According to the semisolid preparation for internal use of the present invention, the taste of the preparation can be improved, and the decrease in the drug content and the thermal stability in the preparation can be suppressed.

(Semi-solid preparation for internal use)
The semisolid preparation for internal use of this invention contains (A) component, (B) component, and (C) component, and pH is 1.0-3.5.
The semi-solid preparation for internal use in the present invention conforms to the oral jelly preparation and the jelly-like drop preparation in the tablet section in the 17th revision Japanese Pharmacopoeia General Rules for Preparations.
That is, the semi-solid preparation for internal use is obtained by dispersing the component (C) on a gel or sol base material in which the component (A) is dispersed in the component (B).
The semisolid preparation for internal use in the present invention is a preparation having a jelly property or a gummy property, and preferably has a jelly strength of 10 to 2000 g. The jelly strength of the semisolid preparation for internal use is more preferably 50 to 2000 g, and further preferably 100 to 1600 g. If the jelly strength of the semisolid preparation for internal use is not less than the above lower limit, the strength of the semisolid preparation for internal use will be improved, and the ingestibility will be improved. If the jelly strength of the semisolid preparation for internal use is not more than the above upper limit value, the strength will not be too high, and the ingestion will be improved.
According to JIS K6503, the jelly strength in the present invention is the weight when a semisolid preparation for internal use is loaded by a 12.7 mm plunger at 10 ° C. and the surface of the semisolid preparation for internal use is pushed down by 4 mm. (Unit: g).

The dimensions of the semisolid preparation for internal use of the present invention are not particularly limited, and can be appropriately determined in consideration of the blending amount and dose of the components (A), (B), and (C). From the viewpoint of easy handling of the semisolid preparation for internal use, the diameter of the semisolid preparation for internal use is preferably 5 to 40 mmφ, and more preferably 7 to 30 mmφ. Moreover, about 0.3-10g is suitable as a weight per semi-solid preparation for internal use.
The shape is not particularly limited, and examples thereof include a sphere, an ellipsoid, a cuboid, a cylinder, a prism, a cone, and a pyramid, and a sphere, an ellipsoid, a cuboid, a cylinder, and a prism are preferable. In the examples, an oval spherical semi-solid preparation for internal use having convex portions on the upper and lower sides was used.

The pH range of the semisolid preparation for internal use is preferably 1.0 or more and 3.5 or less, more preferably 1.0 or more and 3.3 or less, and further preferably 1.0 or more and 3.0 or less.
The pH is a value indicated after 1 minute has elapsed by directly immersing the glass electrode in a solution in which a semi-solid preparation for internal use is dissolved, using a glass electrode type pH meter (“HM-30R” manufactured by Toa DKK Corporation). .

<(A) component>
The component (A) is gelatin. By containing the component (A), the semisolid preparation for internal use of the present invention becomes a gel or a sol.
The weight molecular weight of gelatin is not particularly limited between tens of thousands and hundreds of thousands, but is preferably 30,000 to 270,000, more preferably 50,000 to 260,000, and further preferably 110,000 to 250,000. preferable. When the weight molecular weight of gelatin is not less than the lower limit, the strength of the semi-solid preparation for internal use is improved and the ingestibility is improved. When the weight molecular weight of gelatin is not more than the above upper limit, the strength does not become too high, and the dosage is improved.

(Molecular weight measurement method)
In the present invention, the weight average molecular weight (Mw) of gelatin can be calculated according to the method described in “20-1 Molecular Weight Distribution”, 10th edition of Photographic Gelatin Test Method (PAGI Method). Specifically, the PAGI method is a method for obtaining a chromatogram of gelatin by a gel filtration method using high performance liquid chromatography and estimating its molecular weight distribution. Specific operations are shown below.
As a device, a high performance liquid chromatograph, a column (2 Shodex Asahipak GS620 7G: manufactured by Showa Denko KK) and an ultraviolet absorption detector are used.
As a reagent, prepare (1) 0.1 mol / l potassium dihydrogen phosphate solution and (2) 0.1 mol / l sodium dihydrogen phosphate solution, mix them in equal amounts, and membrane filter with a pore size of 0.45 μm The eluent is filtered through 1).
The test solution was prepared by weighing 2.0 g of sample gelatin into a 100 ml volumetric flask, adding the eluent to swell for 1 hour, and heating to dissolve at 40 ° C. for about 60 minutes. And after cooling to room temperature, the eluent is added to the marked line. This solution is diluted exactly 10 times with an eluent to prepare a test solution. The test solution is filtered through a membrane filter having a pore size of 0.45 μm immediately before use.
As the measurement operation, two columns are mounted in series, and the eluent flow rate is 1.0 ml / min, the column temperature is 50 ° C., the injection amount of the test solution is 100 μl, and the absorbance is 230 nm. A molecular weight distribution curve of sample gelatin is prepared with the holding time on the horizontal axis and the corresponding absorbance at 230 nm on the vertical axis. In addition, evaluation is performed with the shape of the whole molecular weight distribution curve.

There are no particular restrictions on the type of gelatin, such as those derived from bones and skins such as cows and pigs, whales and fish, among which cows, fish and pigs are preferred, and cows and pigs are more preferred. Preferably, it is derived from pigs. The gelatin may be acid-treated gelatin (isoelectric point pH 6-9) or alkali-treated gelatin (isoelectric point pH 4.8-5.2), but acid-treated gelatin is preferred.
The jelly strength of gelatin is preferably 100 g or more, more preferably 150 g or more, and even more preferably 200 g or more.
The viscosity of gelatin is preferably 1.0 to 8.0 mPa · s, more preferably 1.2 to 7.5 mPa · s, and most preferably 1.5 to 7.0 mPa · s.
In addition, the measuring method of a viscosity follows JISK6503-2001.
Although the compounding quantity of gelatin is not specifically limited, 2-50 mass% is preferable with respect to 100 mass% of semi-solid preparations for internal use, 3-40 mass% is more preferable, 4-30 mass% is further more preferable. If the content of the component (A) in 100% by mass of the semisolid preparation for internal use is not less than the above lower limit, the semisolid preparation for internal use is not easily broken into a powder and is not too hard, so that the ingestibility is improved. If the content of the component (A) in 100% by mass of the semisolid preparation for internal use is not more than the above upper limit value, it will not be deformed and divided when pinched the semisolid preparation for internal use. Ingestion improves. Moreover, the outstanding thermal stability is shown by setting it as this range.

<(B) component>
The component (B) is water. By containing the component (B), the semisolid preparation for internal use of the present invention becomes moderately flexible and easy to take. The water may be purified water, distilled water or tap water.
Although the compounding quantity of water is not specifically limited, 15-75 mass% is preferable with respect to 100 mass% of semi-solid preparations for internal use, 17-73 mass% is more preferable, 18-70 mass% is further more preferable. If the content of the component (B) in 100% by mass of the semisolid preparation for internal use is not less than the above lower limit, the semisolid preparation for internal use is not easily broken into a powder and is not too hard, so that the ingestibility is improved. If the content of the component (B) in 100% by mass of the semisolid preparation for internal use is not more than the above upper limit value, it is easy to handle because it is not deformed and divided when pinched the semisolid preparation for internal use. Ingestion improves.
The mass ratio represented by ([(A) component mass] / [(A) component mass + (B) component mass]) × 100 is preferably 5 to 40% by mass, and 6 to 35% by mass. % Is more preferable, and 7 to 30% by mass is more preferable.

<(C) component>
Component (C) is at least one drug selected from the group consisting of aspirin, ibuprofen, acetaminophen, loxoprofen and salts thereof. The component (C) is a drug component (active ingredient) in the semisolid preparation for internal use of the present invention, and the shape retention (thermal stability) of the semisolid preparation for internal use is maintained by containing the component (C). Is done. Among these components (C), aspirin is preferred from the viewpoint of improving the heat stability as a semisolid preparation for internal use.
These may be used individually by 1 type and may use 2 or more types together.
Content of (C) component is suitably determined according to the kind of (C) component, for example, 5-75 mass% is preferable with respect to 100 mass% of internal solid preparations, and 7-73 mass% is more preferable. 9 to 70% by mass is more preferable. By setting it within this range, an excellent thermal stability effect is exhibited.
In addition, the ratio of the mass of the component (C) to the mass of the component (A) (the mass of the component (C) / the mass of the component (A)) is preferably 0.1 to 10, and preferably 0.2 to 9.5. Is more preferable, and 0.4 to 9.0 is most preferable.

(aspirin)
Although the particle diameter of aspirin is not specifically limited, 0.5-500 micrometers is preferable, 1-400 micrometers is more preferable, 5-300 micrometers is further more preferable. By setting it within this range, an excellent thermal stability effect is exhibited.
The particle size distribution is measured with a laser scattering diffraction particle size distribution measuring apparatus (LS13320) manufactured by BECKMAN COULTER.

(Ibuprofen)
The particle diameter of ibuprofen is not particularly limited, but is preferably 0.5 to 200 μm, more preferably 1 to 150 μm, and further preferably 5 to 100 μm. By setting it within this range, an excellent thermal stability effect is exhibited. In addition, the measurement of a particle size distribution is based on aspirin.

(Acetaminophen)
The particle diameter of acetaminophen is not particularly limited, but is preferably 0.5 to 500 μm, more preferably 1 to 450 μm, and still more preferably 5 to 400 μm. By setting it within this range, an excellent thermal stability effect is exhibited. In addition, the measurement of a particle size distribution is based on aspirin.

(Loxoprofen)
The particle diameter of loxoprofen is not particularly limited, but is preferably 0.5 to 400 μm, more preferably 1 to 350 μm, and still more preferably 5 to 300 μm. By setting it within this range, an excellent thermal stability effect is exhibited. In addition, the measurement of a particle size distribution is based on aspirin.

<(D) component>
(D) A component is saccharides. (D) By containing a component, the content fall in the semisolid formulation for internal use of an acidic drug can further be suppressed.
As the component (D), sucrose, powdered malt reducing sugar syrup, xylitol, sorbitol, maltose, trehalose, mannitol, and lactose are preferable, and sucrose, powdered malt reducing sugar syrup, xylitol, and sorbitol are more preferable.
These may be used individually by 1 type and may use 2 or more types together.
Although the particle diameter of (D) component is not specifically limited, 1-700 micrometers is preferable, 1-650 micrometers is more preferable, 1-600 micrometers is the most preferable. By making it within this range, an excellent effect of suppressing a decrease in drug content is exhibited.
Although the compounding quantity of (D) component is not specifically limited, 5-60 mass% is preferable with respect to 100 mass% of semi-solid preparations for internal use, 10-55 mass% is more preferable, 15-50 mass% is further more preferable.
By making it in this range, an excellent inhibitory effect on decrease in drug content is exhibited. In addition, a particle size distribution is measured with the measuring apparatus similar to (C) component.

<(E) component>
The component (E) is an inorganic metal salt. By containing the component (E), the taste of the semisolid preparation for internal use of the present invention can be further improved.
As the component (E), both of magnesium and aluminum or one of the inorganic metal salts is preferable. Specific examples include dry aluminum hydroxide gel, magnesium oxide, synthetic hydrotalcite, magnesium carbonate, magnesium aluminate metasilicate, and a coprecipitation product of aluminum hydroxide / calcium carbonate / magnesium carbonate. Among these, dry aluminum hydroxide gel is preferable.
Although the particle diameter of (E) component is not specifically limited, 1-500 micrometers is preferable, 10-350 micrometers is more preferable, 20-300 micrometers is more preferable. By making it within this range, an excellent effect of improving taste and texture is exhibited.
(E) Although the compounding quantity of a component is not specifically limited, 0.5-20 mass% is preferable with respect to 100 mass% of semi-solid preparations for internal use, 1-15 mass% is more preferable, 1.5-10 mass% Is more preferable. By making it within this range, an excellent effect of improving taste and texture is exhibited. In addition, a particle size distribution is measured with the measuring apparatus similar to (C) component.

<Optional component>
The semi-solid preparation for internal use may optionally contain other physiologically active ingredients and additives as long as the physical properties and storage stability of the preparation are not impaired.
As the physiologically active ingredient, for example, an antacid other than the component (E) and an antipyretic analgesic component other than the component (C) (for example, diclofenac, piroxicam, meloxicam, ampiroxicam, celoxixib, rofecoxib, thiaramide, etenzaamide, sulpyrine) Sedative hypnotic components (for example, allylisopropylacetylurea, bromvalerylurea, etc.), antihistamine components (for example, isothipentyl hydrochloride, diphenylpyraline hydrochloride, diphenhydramine hydrochloride, dipheterol hydrochloride, triprolidine hydrochloride, tripelamine amine hydrochloride, tonsilamine hydrochloride, phenetazine hydrochloride, hydrochloric acid Methodirazine, diphenhydramine salicylate, carbinoxamine diphenyldisulfonate, alimemazine tartrate, diphenhydramine tannate, diphenylpyraline teocrate, Mebhydroline padicylate, promethazine methylene disalicylate, carbinoxamine maleate, dl-chlorpheniramine maleate, chlorpheniramine maleate, dipheterol phosphate, etc.), central excitatory components (for example, sodium caffeine benzoate, caffeine benzoate) , Anhydrous caffeine, etc.), antitussive expectorant component (codeine phosphate, dextromethorphan hydrobromide, dimemorphan phosphate, tipepidine hibenzate, methoxyphenamine hydrochloride, trimethquinol hydrochloride, carbocysteine , Acetylcysteine, ethylcysteine, dl-methylephedrine, bromhexine hydrochloride, serrapeptase, lysozyme chloride, ambroxol, theophylline, aminophylline), vitamin components (eg vitamin B1 and its Conductors and salts thereof, vitamin B2 and derivatives thereof, and salts thereof, vitamin C and its derivatives and their salts, hesperidin and its derivatives and salts thereof, etc.) and the like. These medicinal components can be used singly or in appropriate combination of two or more. Of these, diphenhydramine hydrochloride, allylisopropylacetylurea, dl-chlorpheniramine maleate, anhydrous caffeine, dextromethorphan hydrobromide, and dl-methylephedrine are preferable.

  Examples of the gelling agent or thickener of the present invention include alginic acid, agar, carrageenan, sodium alginate, guar gum, locust bean gum, tamarind gum, pectin, gum arabic, tragand gum, carboxymethylcellulose, hydroxycellulose, polyvinyl alcohol, xanthan gum, pullulan. , Casein, and carboxymethyl starch. Of these, alginic acid, agar, carrageenan, pectin, carboxymethylcellulose, and hydroxycellulose are preferable.

Examples of additives include excipients, disintegrants, fragrances, lubricants, sweeteners, sour agents , pH adjusters and the like. Specifically, as the excipient, crystalline cellulose, light anhydrous silicic acid, L-cysteine or the like can be used.
Examples of the fragrances include menthol, limonene, plant essential oil (mint oil, mint oil, lychee oil, orange oil, lemon oil, etc.) and the like.
Examples of the sweetener include saccharin sodium, aspartame, stevia, dipotassium glycyrrhizinate, acesulfame potassium, thaumatin, sucralose and the like.
As the sour agent , citric acid, tartaric acid, malic acid, succinic acid, fumaric acid, lactic acid, or a salt thereof can be used.
Examples of the pH adjuster include hydrochloric acid, phosphoric acid, lactic acid, tartaric acid, citric acid, malic acid, and butyric acid, and hydrochloric acid, phosphoric acid, citric acid, and malic acid are preferable.
These pH adjusters may be used alone or in combination of two or more.
In addition, the sum total of (A) component-(E) component and arbitrary components does not exceed 100 mass%.

(Production method)
The method for producing a semi-solid preparation for internal use according to the present invention comprises a step of gelling a raw material liquid having a pH of 1.0 to 3.5 in which the component (A) and the component (C) are dispersed in the component (B). Step).
For example, in the method for producing a semisolid preparation for internal use, the (A) component and the optional component are added to the gelatin solution obtained by the heating and dissolving step in which the component (A) is heated and dissolved in the component (B). A mixing step of mixing to obtain a raw material liquid and a forming step.
Furthermore, in this invention, it has the process of adding (D) component and (E) component in the said mixing process, and can improve the taste of a formulation and the fall of a drug content. Regarding the component (D), it may be added as a powder or may be added after being dissolved in the component (B), but it is preferably added in a state dissolved in an appropriate amount of the component (B).
Hereinafter, each step will be specifically described.

<Heat dissolution process>
In the heating and dissolving step, the component (A) is swollen with the component (B) and then heated to obtain a gelatin solution.
The heating temperature is preferably 40 to 90 ° C, more preferably 50 to 80 ° C, and further preferably 60 to 70 ° C.

<Mixing process>
In the mixing step, the components (D) to (E) are mixed with the gelatin solution, the pH is adjusted to 1.0 to 3.5 with a pH adjuster, and the component (C) is mixed. This is a step of obtaining a raw material liquid.
In the present invention, the method for mixing the above components is not particularly limited, but the components (A) to (E) can be mixed by hand or using a known stirrer. In addition, when mixing each component of (B)-(E), what is necessary is just to mix the raw powder of each component on normal conditions, but about (D) component, the state melt | dissolved in (B) component Is preferred.
Specific examples of the mixer (stirrer) that can be used in the present invention include a stirrer such as a three-one motor. In the present invention, among these, a three-one motor can be suitably used from the viewpoint of obtaining good mixing properties.

In addition, the order which mixes (C) component is not specifically limited, You may make it disperse | distribute to (B) component with (A) component in the heating melt | dissolution process mentioned above, The state previously disperse | distributed with the appropriate amount of (B) component May be added.
In consideration of the solubility of the component (C) in the component (B), it is preferable to mix the component (C) after the heating and dissolving step described above.

<Molding process>
The molding step is a step of obtaining the semi-solid preparation for internal use by pouring the above raw material liquid into a mold and cooling. The material of the mold is not particularly limited, and corn starch, plastic, stainless steel, iron and the like can be used, and corn starch is preferable.
The cooling time is preferably 1 hour to 24 hours, more preferably 2 hours to 18 hours, and even more preferably 3 hours to 12 hours.
The cooling temperature is preferably −5 to 30 ° C., more preferably −3 to 29 ° C., and still more preferably 0 to 28 ° C.

Hereinafter, the present invention will be described in more detail using examples, but the present invention is not limited to these examples.
The raw materials used in this example are as shown in <Used raw materials> below.

<Raw materials>
Gelatin: “AP-270”, molecular weight 110,000, manufactured by Nippi.
Aspirin: “RODINE3220” (particle size: 89 μm).
Ibuprofen: “IBUPROFEN25” (particle size: 26 μm) manufactured by BASF
Loxoprofen sodium hydrate: “Loxoprofen sodium hydrate” (particle size: 195 μm), manufactured by Daiwa Pharmaceutical Co., Ltd.
Acetaminophen: “Acetaminophen” (particle diameter: 114 μm) manufactured by Marincklot Japan Co., Ltd.
Ketoprofen: “Ketoprofen” (particle size: 20 μm) manufactured by Mutual Yakuhin Co., Ltd.
Dry aluminum hydroxide gel: “S-100” (particle diameter: 112 μm), manufactured by Kyowa Chemical Industry Co., Ltd.
Magnesium oxide: manufactured by Tomita Pharmaceutical Co., Ltd., “Magnesium oxide NK” Japanese Pharmacopoeia (particle size: 35 μm).
Synthetic hydrotalcite: “Alkamak VF” (particle diameter: 35 μm), manufactured by Kyowa Chemical Industry Co., Ltd.
Calcium carbonate: “Precipitated calcium carbonate” (particle size: 3 μm), manufactured by Bihoku Flour Industries.
Magnesium carbonate: manufactured by Tomita Pharmaceutical Co., Ltd., particle size (163 μm).
Sucrose: “Sucrose” manufactured by Mitsui Sugar Co., Ltd. (particle size: 560 μm).
Powdered malt reducing sugar syrup: “Amarty MR-50” (particle diameter: 52 μm), manufactured by Mitsubishi Corporation Foodtech.
Xylitol: “Xylit” (particle size: 210 μm), manufactured by Mitsubishi Corporation Foodtech.
Sorbitol: “Sorbit” (particle size: 152 μm), manufactured by Mitsubishi Corporation Foodtech.
Hydrochloric acid: Wako Pure Chemical, “special grade reagent”.
Malic acid: “DL Malic acid” manufactured by Wako Pure Chemical Industries.

<Thermal stability evaluation method>
The semisolid preparation for internal use in each case was placed in a tray, and the entire tray was packaged with an aluminum gusset. This was stored in a thermostat at 50 ° C. for 4 days. The mass of the semisolid preparation for internal use before and after storage was measured, and the ratio (residual rate (mass%)) of the semisolid preparation for internal use after storage to the mass of the semisolid preparation for internal use before storage was determined. Thermal stability was evaluated according to the following evaluation criteria.
(Evaluation criteria)
5 points: 90% by mass or more of solid content remains.
4 points: Solid content of 80 or more and less than 90% by mass remains.
3 points: Solid content of 70 or more and less than 80% by mass remains.
2 points: Solid content of 50 or more and less than 70% by mass remains.
1 point: dissolved more than 50% by mass.
In addition, it was set as the pass with 3 points or more.

<Taste evaluation method>
The semi-solid preparation for internal use in each case was taken, and the taste was evaluated in the following 5 stages. The semi-solid preparation for internal use was not swallowed, but was discharged when the evaluation was completed. The subjects were nine healthy men, rounded to the first decimal place.
(Evaluation criteria)
5 points: No unpleasant taste is felt.
4 points: Unpleasant taste is hardly felt.
3 points: A little unpleasant taste is felt.
2 points: Uncomfortable taste is felt, but can be taken.
1 point: A strong unpleasant taste is felt, and taking is encouraged.
In addition, it was set as the pass with 2 points or more.

<Drug content evaluation method>
The semisolid preparation for internal use in each case was placed in a tray, and the entire tray was packaged with an aluminum gusset. This was stored in a constant temperature bath at 50 ° C. and 75% RH for 4 days. The content of the drug before and after storage was measured, and the ratio of the content of the drug after storage to the content of the drug before storage (vs. the initial content (mass%)) was calculated. The drug versus initial content was evaluated as follows. The quantitative tests for aspirin, ibuprofen, and ketoprofen were conducted in accordance with the quantitative test methods for aspirin, ibuprofen, and ketoprofen described in the 17th revision Japanese Pharmacopoeia.
(Evaluation criteria)
5 points: The initial value content is 90% by mass or more.
4 points: The initial value content is 85 or more and less than 90% by mass.
3 points: The initial value content is 80 or more and less than 85% by mass.
2 points: The initial value content is 75 or more and less than 80% by mass.
1 point: The content relative to the initial value is less than 70% by mass.
-: No drug is contained.
Three or more points were accepted.

(Examples 1-4, Comparative Examples 1-2)
According to the blending amount in Table 1, the gelatin as component (A) is swollen with purified water as component (B), dissolved at 60 ° C., and then the pH of the gelatin solution is adjusted to 2.5 with hydrochloric acid. did. Aspirin or ibuprofen, loxoprofen dihydrate, and acetaminophen were added as component (C) to this gelatin solution to obtain a raw material solution. This raw material liquid is poured into a corn starch mold (hemispherical shape with a radius of 8 mm) so as to have the blending amount shown in Table 1, covered, cooled in a refrigerator at 5 ° C. for 7 hours, and elliptically spherical with protrusions on the top and bottom. A semi-solid preparation for internal use was obtained. The obtained semisolid preparation for internal use was evaluated for heat stability, taste, and content with respect to initial value of the drug (Table 1).
As a result, when aspirin or ibuprofen, loxoprofen dihydrate, or acetaminophen as component (C) was added, the heat stability of the semisolid preparation for internal use was improved.
On the other hand, as shown in Comparative Example 1, the semisolid preparation for internal use in which the component (C) was not added was dissolved by 50% by mass or more at 50 ° C. for 4 days. Moreover, as shown in Comparative Example 2, even when ketoprofen, which is a pharmaceutical ingredient other than the component (C), was added, the semisolid preparation for internal use was dissolved by 50% by mass or more.

(Examples 5 to 8, Comparative Example 3)
According to the blending amounts in Table 2, the raw material solution was adjusted in the same manner as in Example 1 except that the blending amount of hydrochloric acid as a pH adjusting agent was changed to obtain oval spherical semisolid preparations for internal use having different pHs. In the same manner as in Example 1, the semi-solid preparation for internal use after storage was evaluated for heat stability, taste, and content with respect to the initial value of the drug (Table 2).
As a result, it showed thermal stability when the pH of the gelatin solution was 1.4 to 3.3. Moreover, there was no problem with respect to taste and drug content even when the pH of the gelatin solution was 3.3.
On the other hand, as shown in Comparative Example 3, the semi-solid preparation for internal use in which the pH of the gelatin solution was 4.5 had no problem with heat stability, but a decrease in the aspirin content was observed.

(Examples 9 to 16)
According to the blending amount in Table 3, the raw material liquid was prepared in the same manner as in Example 1 except that the blending amount of the aspirin of the component (C) and the purified water of the component (B) were changed. The obtained oval spherical semi-solid preparation for internal use was evaluated for the thermal stability after storage, taste, and content with respect to the initial value of the drug in the same manner as in the above Examples (Table 3).
As a result, when the component (C) was added in an amount of 14% by mass or more with respect to 100% by mass of the semisolid preparation for internal use, thermal stability was exhibited. In particular, when the component (C) was added in an amount of 26% by mass or more with respect to 100% by mass of the semisolid preparation for internal use, good thermal stability was exhibited. The taste and drug content were in a range where there was no problem, and the taste was particularly good when the component (C) was 57% by mass or less with respect to 100% by mass of the semisolid preparation for internal use. Also, good thermal stability when the mass ratio represented by ([(A) component mass] / [(A) component mass + (B) component mass]) × 100 mass ratio is 9.0% by mass or more. Showed sex.

(Examples 17 to 21)
According to the blending amount shown in Table 4, any one of (D) component sucrose, powdered malt reducing sugar syrup, xylitol, and sorbitol was dissolved in gelatin solution (50% of purified water described as (B) component) The diversion was used and dissolved.) The solution was adjusted to pH 2.5 with hydrochloric acid. Furthermore, aspirin was added as component (C) to obtain a raw material liquid. This raw material solution was prepared in the same manner as in Example 1 to obtain an oval spherical semi-solid preparation for internal use. In the same manner as in the previous examples, the thermal stability, taste, and drug content relative to initial value were evaluated (Table 4).
As a result, when any one of component (D), sucrose, powdered malt reducing sugar syrup, xylitol, and sorbitol was added, the decrease in drug content of the semisolid preparation for internal use was more effectively suppressed. In particular, when powdered malt reducing sugar syrup was added, a high effect was also obtained with respect to suppression of decrease in drug content.
On the other hand, when corn starch was blended as an optional component, the effect of suppressing the decrease in drug content was not confirmed. Even when the moisture ratio in the same preparation as in Example 1 was used, the effect of suppressing the decrease in drug content was confirmed by adding the component (D) in the same manner.

(Examples 22 to 27)
According to the blending amount of Table 5, any one of dry aluminum hydroxide gel, magnesium oxide, synthetic hydrotalcite, and magnesium carbonate was mixed as the component (E) in the gelatin solution. The solution was adjusted to pH 2.5 with hydrochloric acid. Furthermore, aspirin was added as component (C) to obtain a raw material liquid. This raw material solution was prepared in the same manner as in Example 1 to obtain an oval spherical semi-solid preparation for internal use. In the same manner as in the above-mentioned Examples, the thermal stability after storage, taste, and drug content versus initial value content were evaluated (Table 5).
As a result, even when any component (E) was added, there was an effect of improving the taste of the semisolid preparation for internal use. In particular, when dry aluminum hydroxide gel was added, a high effect was obtained.
On the other hand, when corn starch was blended as an optional component, the effect of improving the taste of the preparation was not confirmed. Furthermore, in Example 27 in which sorbitol was used as the component (D) and dry aluminum hydroxide gel was used as the component (E), the best results were obtained for all of the heat stability, taste, and drug content relative to the initial value.

(Example 28)
According to the blending amount in Table 6, malic acid was added to the gelatin solution as a powder to adjust the pH to 3.0. Furthermore, aspirin was added as component (C) to obtain a raw material liquid. This raw material solution was prepared in the same manner as in Example 1 to obtain an oval spherical semi-solid preparation for internal use.
As in the above-mentioned Examples, the thermal stability after storage, taste, and content with respect to the initial value of the drug were evaluated. As a result, even when the pH adjuster was changed to malic acid, good thermal stability was shown (Table 6). . In addition, the taste and drug content relative to the initial value were also good.

Claims (6)

  Gelatin (A), water (B), and at least one drug (C) selected from the group consisting of aspirin, ibuprofen, acetaminophen, loxoprofen and salts thereof, and having a pH of 1.0 to A semi-solid preparation for internal use which is 3.5. The weight average molecular weight of the component (A) is 30,000 to 270,000.
The semisolid preparation for internal use according to claim 1.   The semisolid preparation for internal use according to claim 1 or 2, further comprising a saccharide (D).   Furthermore, the semi-solid preparation for internal use as described in any one of Claims 1-3 containing the inorganic metal salt (E) of both or one of magnesium and aluminum. A method for producing a semisolid preparation for internal use according to any one of claims 1 to 4,
Manufacture of semi-solid preparation for internal use which has the process of gelatinizing the raw material liquid which said (A) component and said (C) component are disperse | distributed in said (B) component, and pH is 1.0-3.5. Method.   The method for producing a semisolid preparation for internal use according to claim 5, comprising the step of dispersing the component (A) in the component (B) and then dispersing the component (C) to obtain the raw material liquid. .