JP6877923B2 - Semi-solid preparation for internal use and its manufacturing method - Google Patents

Description

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

In recent years, it has been desired to develop an easy-to-take semi-solid preparation for internal use for elderly people with impaired swallowing function and children who have difficulty in taking tablets and liquids. Examples of the semi-solid preparation for internal use include a jelly agent in which a drug is dispersed on a gel-like or sol-like base material. In general, in the semi-solid 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 suppressing the decrease in the content of the drug in the preparation.

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

Japanese Unexamined Patent Publication No. 5-161460

However, in the technique of Patent Document 1, the unpleasant taste (bitter taste) associated with the drug or the atomized cellulose in the semi-solid preparation for internal use may be strongly felt. Further, in the conventional technique, it is not sufficient to suppress the decrease in the content of the drug in the pharmaceutical product and the decrease in the thermal stability.
Therefore, an object of the present invention is a semi-solid preparation for internal use and a method for producing the same, 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.

The present invention has the following aspects.
[1] It contains gelatin (A), water (B), and at least one drug (C) selected from the group consisting of aspirin, ibuprofen, acetaminophen, loxoprofen and salts thereof, and has a pH of 1. .0 to 3.5, a semi-solid preparation for internal use.
[2] The semi-solid preparation for internal use according to [1], wherein the weight average molecular weight of the component (A) is 30,000 to 270,000.
[3] The semi-solid preparation for internal use according to [1] or [2], which further contains the saccharide (D).
[4] The semi-solid preparation for internal use according to any one of [1] to [3], which further contains an inorganic metal salt (E) of both magnesium and aluminum or one of them.
[5] The 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 adjusted. A method for producing a semi-solid preparation for internal use, which comprises a step of gelling a raw material liquid of 1.0 to 3.5.
[6] The semi-solid preparation for internal use according to [5], which comprises a 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 semi-solid preparation for internal use of the present invention, the taste of the preparation can be improved, and a decrease in the content of the drug in the preparation and a decrease in thermal stability can be suppressed.

(Semi-solid preparation for internal use)
The semi-solid preparation for internal use of the present invention contains the component (A), the component (B), and the component (C), and has a pH of 1.0 to 3.5.
The semi-solid preparation for internal use in the present invention is the same as the oral jelly agent and the jelly-like drop agent in the tablet section in the 17th revised Japanese Pharmacopoeia general formulation rules.
That is, the semi-solid preparation for internal use is a gel-like or sol-like base material in which the component (A) is dispersed in the component (B), and the component (C) is dispersed.
The semi-solid preparation for internal use in the present invention is a jelly-like or gummy-like preparation, and the jelly strength is preferably 10 to 2000 g. The jelly strength of the semi-solid preparation for internal use is more preferably 50 to 2000 g, and further preferably 100 to 1600 g. When the jelly strength of the semi-solid preparation for internal use is at least the above lower limit value, the strength of the semi-solid preparation for internal use is improved and the ingestibility is improved. When the jelly strength of the semi-solid preparation for internal use is not more than the above upper limit value, the strength does not become too high and the ingestibility is improved.
The jelly strength in the present invention is the weight when the surface of the semi-solid preparation for internal use is pushed down by 4 mm by applying a load to the semi-solid preparation for internal use with a plunger having a diameter of 12.7 mm at 10 ° C. according to JIS K6503. It means (unit: g).

The size of the semi-solid preparation for internal use of the present invention is 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 ease of handling of the semi-solid preparation for internal use, the diameter of the semi-solid preparation for internal use is preferably 5 to 40 mmφ, more preferably 7 to 30 mmφ. The appropriate weight of each semi-solid preparation for internal use is about 0.3 to 10 g.
The shape is not particularly limited, and examples thereof include a sphere, an ellipsoid, a rectangular parallelepiped, a cylinder, a prism, a cone, and a pyramid, and a sphere, an ellipsoid, a rectangular parallelepiped, a cylinder, and a prism are preferable. In the examples, an elliptical spherical semi-solid preparation for internal use with protrusions on the top and bottom was used.

The pH range of the semi-solid 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 shown after 1 minute has passed 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 DKK-TOA CORPORATION). ..

<Ingredient (A)>
The component (A) is gelatin. By containing the component (A), the semi-solid 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 110,000 to 250,000. preferable. When the weight molecular weight of gelatin is at least the above lower limit value, 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 value, the strength does not become too high and the ingestibility 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 the 10th edition "20-1 molecular weight distribution" of the photographic gelatin test method (PAGI method). Specifically, the PAGI method is a method of obtaining a gelatin chromatogram by a gel filtration method using high performance liquid chromatography and estimating its molecular weight distribution. The specific operation is shown below.
As an apparatus, a high performance liquid chromatograph, a column (Shodex Asahipak GS620 7G 2 pieces: manufactured by Showa Denko KK), and an ultraviolet absorption detector are used.
As reagents, (1) 0.1 mol / l potassium dihydrogen phosphate solution and (2) 0.1 mol / l sodium dihydrogen phosphate solution are prepared, and they are mixed in equal amounts to form a membrane filter having a pore size of 0.45 μm. The eluent is filtered with.
To prepare the test solution, weigh 2.0 g of sample gelatin into a 100 ml volumetric flask, add an eluent to inflate it for 1 hour, and then heat it at 40 ° C. for about 60 minutes to dissolve it. Then, after cooling to room temperature, the eluate is added up to the marked line. This solution is diluted exactly 10 times with an eluent to prepare a test solution. The test solution is filtered with a membrane filter having a pore size of 0.45 μm immediately before use.
As a measurement operation, two columns are mounted in series, the flow rate of the eluent is 1.0 ml / min, the temperature of the column is 50 ° C., the injection amount of the test solution is 100 μl, and the absorbance is measured at a measurement wavelength of 230 nm. A molecular weight distribution curve of sample gelatin is created with the retention time on the horizontal axis and the corresponding absorbance at 230 nm on the vertical axis. The evaluation is performed on the shape of the entire molecular weight distribution curve.

The type of gelatin is not particularly limited, and examples thereof include those derived from bones and skins of cows and pigs, whales, and fish. Among them, cows, fish, and pigs are preferable, and cows and pigs are more preferable. It is preferably derived from pigs, most preferably derived from pigs. The gelatin may be acid-treated gelatin (isoelectric point pH 6 to 9) or alkali-treated gelatin (isoelectric point pH 4.8 to 5.2), but acid-treated gelatin is preferable.
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.
The method for measuring the viscosity follows JIS K 6503-2001.
The blending amount of gelatin is not particularly limited, but is preferably 2 to 50% by mass, more preferably 3 to 40% by mass, still more preferably 4 to 30% by mass, based on 100% by mass of the semi-solid preparation for internal use. When the content of the component (A) in 100% by mass of the semi-solid preparation for internal use is at least the above lower limit value, the semi-solid preparation for internal use does not easily crumble into powder and is not too hard, so that the ease of administration is improved. When the content of the component (A) in 100% by mass of the semi-solid 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 the semi-solid preparation for internal use is pinched. The ease of taking is improved. Further, in this range, excellent thermal stability is exhibited.

<Ingredient (B)>
The component (B) is water. By containing the component (B), the semi-solid 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.
The amount of water to be blended is not particularly limited, but is preferably 15 to 75% by mass, more preferably 17 to 73% by mass, still more preferably 18 to 70% by mass, based on 100% by mass of the semi-solid preparation for internal use. When the content of the component (B) in 100% by mass of the semi-solid preparation for internal use is at least the above lower limit value, the semi-solid preparation for internal use does not easily crumble into powder and is not too hard, so that the ease of administration is improved. When the content of the component (B) in 100% by mass of the semi-solid 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 the semi-solid preparation for internal use is pinched. The ease of taking is improved.
The mass ratio represented by ([mass of component (A)] / [mass of component (A) + mass of component (B)]) × 100 is preferably 5 to 40% by mass, preferably 6 to 35 mass. % Is more preferable, and 7 to 30% by mass is further preferable.

<Ingredient (C)>
The 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 semi-solid preparation for internal use of the present invention, and by containing the component (C), the shape retention (heat stability) of the semi-solid preparation for internal use is maintained. Will be done. Among these components (C), aspirin is preferable from the viewpoint of improving thermal stability as a semi-solid preparation for internal use.
These may be used alone or in combination of two or more.
The content of the component (C) is appropriately determined according to the type of the component (C). For example, the content of the component (C) is preferably 5 to 75% by mass, more preferably 7 to 73% by mass, based on 100% by mass of the semi-solid preparation for internal use. , 9-70% by mass is more preferable. Within this range, an excellent thermal stability effect is exhibited.
The ratio of the mass of the component (C) to the mass of the component (A) (mass of the component (C) / mass of the component (A)) is preferably 0.1 to 10, and is 0.2 to 9.5. Is more preferable, and 0.4 to 9.0 is most preferable.

(aspirin)
The particle size of aspirin is not particularly limited, but is preferably 0.5 to 500 μm, more preferably 1 to 400 μm, and even more preferably 5 to 300 μm. Within this range, an excellent thermal stability effect is exhibited.
The particle size distribution is measured by a laser confusion diffraction method particle size distribution measuring device (LS13320) manufactured by BECKMAN COULTER.

(Ibuprofen)
The particle size of ibuprofen is not particularly limited, but is preferably 0.5 to 200 μm, more preferably 1 to 150 μm, and even more preferably 5 to 100 μm. Within this range, an excellent thermal stability effect is exhibited. The particle size distribution is measured according to aspirin.

(Acetaminophen)
The particle size of acetaminophen is not particularly limited, but is preferably 0.5 to 500 μm, more preferably 1 to 450 μm, and even more preferably 5 to 400 μm. Within this range, an excellent thermal stability effect is exhibited. The particle size distribution is measured according to aspirin.

(Loxoprofen)
The particle size of loxoprofen is not particularly limited, but is preferably 0.5 to 400 μm, more preferably 1 to 350 μm, and even more preferably 5 to 300 μm. Within this range, an excellent thermal stability effect is exhibited. The particle size distribution is measured according to aspirin.

<Ingredient (D)>
The component (D) is a saccharide. By containing the component (D), it is possible to further suppress a decrease in the content of the acidic drug in the semi-solid preparation for internal use.
As the component (D), sucrose, powdered malt-reducing sugar starch syrup, xylitol, sorbitol, maltose, trehalose, mannitol, and lactose are preferable, and sucrose, powdered malt-reducing sugar starch syrup, xylitol, and sorbitol are more preferable.
These may be used alone or in combination of two or more.
The particle size of the component (D) is not particularly limited, but is preferably 1 to 700 μm, more preferably 1 to 650 μm, and most preferably 1 to 600 μm. Within this range, an excellent effect of suppressing a decrease in drug content is exhibited.
The blending amount of the component (D) is not particularly limited, but is preferably 5 to 60% by mass, more preferably 10 to 55% by mass, still more preferably 15 to 50% by mass, based on 100% by mass of the semi-solid preparation for internal use.
Within this range, an excellent effect of suppressing a decrease in drug content is exhibited. The particle size distribution is measured by the same measuring device as the component (C).

<Ingredient (E)>
The component (E) is an inorganic metal salt. By containing the component (E), the taste of the semi-solid preparation for internal use of the present invention can be further improved.
As the component (E), an inorganic metal salt of both magnesium and aluminum or one of them is preferable. Specific examples thereof include dry aluminum hydroxide gel, magnesium oxide, synthetic hydrotalcite, magnesium carbonate, magnesium aluminometasilicate, and co-precipitated products of aluminum hydroxide, calcium carbonate, and magnesium carbonate. Among these, dry aluminum hydroxide gel is preferable.
The particle size of the component (E) is not particularly limited, but is preferably 1 to 500 μm, more preferably 10 to 350 μm, and even more preferably 20 to 300 μm. Within this range, an excellent effect of improving taste and texture is exhibited.
The blending amount of the component (E) is not particularly limited, but is preferably 0.5 to 20% by mass, more preferably 1 to 15% by mass, and 1.5 to 10% by mass with respect to 100% by mass of the semi-solid preparation for internal use. Is even more preferable. Within this range, an excellent effect of improving taste and texture is exhibited. The particle size distribution is measured by the same measuring device as the component (C).

<Arbitrary ingredient>
Other physiologically active ingredients and additives may be optionally added to the semi-solid preparation for internal use as long as the physical properties and storage stability of the preparation are not impaired.
Physiologically active ingredients include, for example, antiseptic agents other than the component (E) and antipyretic and analgesic components other than the component (C) (for example, diclofenac, pyroxicum, meroxycam, ampyroxycam, serocoxib, lofecoxib, thialamide, etenzamid, sulpyrine, etc.) , Soothing and hypnotic components (eg, allylisopropylacetylurea, bromvalerylurea, etc.), antihistamine components (eg, isotipendyl hydrochloride, diphenylpyraline hydrochloride, diphenhydramine hydrochloride, dipheterol hydrochloride, triprolidin hydrochloride, triperenamine hydrochloride, tonzilamine hydrochloride, phenetazine hydrochloride, hydrochloric acid Metodilazine, diphenhydramine salicylate, carbinoxamine diphenyldisulfonate, alimemazine tartrate, diphenhydramine tannate, diphenylpyraline theocrate, mebuhydroline napadisylate, promethazine methylene disalicylate, carbinoxamine maleate, dl-chlorpheniramine maleate Lamine, dipheterol phosphate, etc.), central excitatory components (eg, sodium benzoate caffeine, caffeine, anhydrous caffeine, etc.), antitussive sputum components (codein phosphate, dextrometholphan hydrobromide, dimemorphan phosphorus, etc.) Acid salt, tipepidin hibenzate, methoxyphenamine hydrochloride, trimetquinol hydrochloride, carbocysteine, acetylcysteine, ethylcysteine, dl-methylephedrine, bromhexine hydrochloride, therapeptase, lysozyme chloride, ambroxol, theophylline, aminophilin ), Vitamin components (for example, 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, etc.) and the like. Be done. These medicinal ingredients may be used alone or in combination of two or more. Of these, diphenhydramine hydrochloride, allylisopropylacetylurea, dl-chlorpheniramine maleate, caffeine anhydrous, dextromethorphan hydrobromic acid, 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, arabic gum, tragand gum, carboxymethyl cellulose, hydroxycellulose, polyvinyl alcohol, xanthan gum, and purulan. , Casein, carboxymethyl starch and the like. Of these, alginic acid, agar, carrageenan, pectin, carboxymethyl cellulose, and hydroxy cellulose are preferable.

Excipients Examples of additives are disintegrants, fragrances, lubricants, sweetening agents, sour agents, and pH adjusting agents. Specifically, as the excipient, crystalline cellulose, light silicic anhydride, L-cysteine and the like can be used.
Examples of the fragrance include menthol, limonene, vegetable essential oil (mentha oil, mint oil, lychee oil, orange oil, lemon oil, etc.) and the like.
Examples of the sweetener include sodium saccharin, aspartame, stevia, dipotassium glycyrrhizinate, acesulfame potassium, thaumatin, sucralose and the like.
The sour agent, citric acid, tartaric acid, malic acid, succinic acid, fumaric acid, may be used lactic acid or their salts.
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.
The total of the components (A) to (E) and the optional components does not exceed 100% by mass.

(Production method)
The method for producing a semi-solid preparation for internal use of the present invention is a step (molding) in which the components (A) and (C) are dispersed in the component (B) and the raw material liquid having a pH of 1.0 to 3.5 is gelled. Step).
For example, in the method for producing a semi-solid preparation for internal use, a heat-dissolving step of heat-dissolving the component (A) in the component (B) and a gelatin-dissolving solution obtained by the heat-dissolving step include the component (C) and an optional component. It has a mixing step of mixing to obtain a raw material liquid and a molding step.
Further, in the present invention, the step of adding the component (D) and the component (E) during the mixing step is provided, and the improvement of the taste of the preparation and the decrease of the drug content can be suppressed. The component (D) may be added as a powder or after being dissolved in the component (B), but it is preferably added in a state of being dissolved in an appropriate amount of the component (B).
Hereinafter, each step will be specifically described.

<Heat melting process>
The heat-dissolving step is a step of swelling the component (A) with the component (B) and then heating to obtain a gelatin solution.
The heating temperature is preferably 40 to 90 ° C, more preferably 50 to 80 ° C, still more preferably 60 to 70 ° C.

<Mixing process>
In the mixing step, each component (D) to (E) is mixed with the above gelatin solution, the pH is adjusted to 1.0 to 3.5 with a pH adjuster, and the component (C) is mixed. This is the process of obtaining the raw material liquid.
In the present invention, the method for mixing each of the above components is not particularly limited, but the components (A) to (E) can be mixed by hand or by using a known stirrer. When mixing the components (B) to (E), the bulk powder of each component may be mixed uniformly under normal conditions, but the component (D) is in a state of being dissolved in the component (B). Is preferable.
Specific examples of the mixer (stirring) machine that can be used in the present invention include a stirrer such as a three-one motor. In the present invention, the three-one motor can be preferably used from the viewpoint of obtaining good mixing properties among these.

The order in which the component (C) is mixed is not particularly limited, and the component (B) may be dispersed together with the component (A) in the above-mentioned heating and melting step, and the component (B) is dispersed in advance in an appropriate amount. May be added with.
Considering the solubility of the component (C) in the component (B), it is preferable to mix the component (C) after the above-mentioned heat-dissolving step.

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

Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited to these Examples.
The raw materials used in this example are as shown in <Raw materials used> below. Examples 1 to 3 and 5 to 28 are reference examples.

<Raw materials used>
Gelatin: Nippi, "AP-270" molecular weight 110,000.
Aspirin: "RODINE3220" (particle size: 89 μm).
Ibuprofen: "IBUPROFEN25" (particle size: 26 μm) manufactured by BASF.
Loxoprofen sodium hydrate: "Loxoprofen sodium hydrate" manufactured by Daiwa Yakuhin Kogyo Co., Ltd. (particle size: 195 μm).
Acetaminophen: "Acetaminophen" (particle size: 114 μm) manufactured by Marincrot Japan Co., Ltd.
Ketoprofen: "Ketoprofen" (particle size: 20 μm) manufactured by Mutual Yakuko Co., Ltd.
Dry aluminum hydroxide gel: "S-100" (particle size: 112 μm) manufactured by Kyowa Chemical Industry Co., Ltd.
Magnesium oxide: "Magnesium oxide NK" manufactured by Tomita Pharmaceutical Co., Ltd. Japanese Pharmacopoeia (particle size: 35 μm).
Synthetic hydrotalcite: "Alcamac VF" (particle size: 35 μm) manufactured by Kyowa Chemical Industry Co., Ltd.
Calcium carbonate: "Precipitated calcium carbonate" manufactured by Bihoku Powder Industry Co., Ltd. (particle size: 3 μm).
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 starch syrup: "Amalti MR-50" (particle size: 52 μm) manufactured by Mitsubishi Corporation Food Tech.
Xylitol: "Xylitol" (particle size: 210 μm) manufactured by Mitsubishi Corporation Food Tech.
Sorbitol: "Sorbit" (particle size: 152 μm) manufactured by Mitsubishi Corporation Food Tech.
Hydrochloric acid: Made by Wako Junyaku, "special grade reagent".
Malic acid: "DL malic acid" manufactured by Wako Pure Chemical Industries.

<Thermal stability evaluation method>
The semi-solid preparation for internal use of each example was placed in a tray, and the tray was wrapped in an aluminum gusset. This was stored in a constant temperature bath at 50 ° C. for 4 days. The mass of the internal semi-solid preparation before and after storage was measured, and the ratio (residual ratio (mass%)) of the mass of the internal semi-solid preparation after storage to the mass of the internal semi-solid preparation 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: 80 or more and less than 90% by mass Solid content remains.
3 points: 70 or more and less than 80% by mass Solid content remains.
2 points: 50 or more and less than 70% by mass Solid content remains.
1 point: More than 50% by mass is dissolved.
In addition, it was passed with 3 points or more.

<Taste evaluation method>
The semi-solid preparation for internal use of each example was taken, and the taste was evaluated in the following five stages. The semi-solid preparation for internal use was not swallowed and was exhaled when the evaluation was completed. The subjects were 9 healthy men, and the first decimal place of the average score was rounded off.
(Evaluation criteria)
5 points: I do not feel any unpleasant taste.
4 points: Almost no unpleasant taste is felt.
3 points: I feel a little unpleasant taste.
2 points: I feel unpleasant, but I can take it.
1 point: I feel a strong unpleasant taste and take it.
In addition, it was passed with 2 points or more.

<Drug content evaluation method>
The semi-solid preparation for internal use of each example was placed in a tray, and the tray was wrapped in an aluminum gusset. This was stored in a constant temperature bath at 50 ° C. and 75% RH for 4 days. The drug content before and after storage was measured, and the ratio of the drug content after storage to the drug content before storage (relative to initial value content (mass%)) was calculated. The initial content of the drug 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 revised Japanese Pharmacopoeia.
(Evaluation criteria)
5 points: Content with respect to initial value 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 content relative to the initial value is 80 or more and less than 85% by mass.
2 points: Content relative to initial value is 75 or more and less than 80% by mass.
1 point: Content relative to initial value is less than 70% by mass.
-: No drug is contained.
In addition, 3 points or more were passed.

(Examples 1 to 4, Comparative Examples 1 to 2)
According to the blending amount in Table 1, gelatin as a component (A) is swollen with purified water as a 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 to this gelatin solution as a component (C) to obtain a raw material solution. This raw material liquid is poured into a cornstarch mold (hemispherical shape with a radius of 8 mm) so as to have the blending amount shown in Table 1, covered, and cooled in a refrigerator at 5 ° C. for 7 hours. A semi-solid preparation for internal use was obtained. The obtained semi-solid preparation for internal use was evaluated for thermal stability, taste, and initial value content of the drug (Table 1).
As a result, when the component (C) such as aspirin or ibuprofen, loxoprofen dihydrate, and acetaminophen was added, the thermal stability of the semi-solid preparation for internal use was improved.
On the other hand, as shown in Comparative Example 1, the semi-solid preparation for internal use to which the component (C) was not added was dissolved in an amount of 50% by mass or more at 50 ° C. for 4 days. Further, as shown in Comparative Example 2, even when ketoprofen, which is a pharmaceutical component other than the component (C), was added, the semi-solid preparation for internal use was dissolved in an amount of 50% by mass or more.

(Examples 5 to 8, Comparative Example 3)
The raw material solution was adjusted in the same manner as in Example 1 except that the blending amount of hydrochloric acid, which is a pH adjuster, was changed according to the blending amount in Table 2, to obtain an elliptical spherical semi-solid preparation for internal use having a different pH. Similar to Example 1, the thermal stability, taste, and drug-to-initial value content of the semi-solid preparation for internal use after storage were evaluated (Table 2).
As a result, the gelatin solution showed thermal stability when the pH was 1.4 to 3.3. Further, even when the pH of the gelatin solution was 3.3, there was no problem in taste and drug content.
On the other hand, as shown in Comparative Example 3, the semi-solid preparation for internal use having a gelatin solution having a pH of 4.5 had no problem in thermal stability, but a decrease in the aspirin content was observed.

(Examples 9 to 16)
The raw material liquid was prepared in the same manner as in Example 1 except that the aspirin blending amount of the component (C) and the purified water of the component (B) were changed according to the blending amounts in Table 3. The obtained elliptical spherical semi-solid preparation for internal use was evaluated for thermal stability after storage, taste, and initial value content of the drug in the same manner as in the above-mentioned Examples (Table 3).
As a result, the thermal stability was shown when the component (C) was added in an amount of 14% by mass or more with respect to 100% by mass of the semi-solid preparation for internal use. In particular, good thermal stability was exhibited when the component (C) was added in an amount of 26% by mass or more with respect to 100% by mass of the semi-solid preparation for internal use. The taste and drug content were within the 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 semi-solid preparation for internal use. Further, good thermal stability is obtained when the mass ratio represented by ([mass of component (A)] / [mass of component (A) + mass of component (B)]) × 100 is 9.0% by mass or more. Showed sex.

(Examples 17 to 21)
According to the blending amount in Table 4, 50% of the purified water described as the component (B) in which any one of the white sugar, the powdered malt reducing sugar starch syrup, xylitol, and sorbitol of the component (D) was dissolved in the gelatin solution. Diverted and dissolved.) The pH of this solution was adjusted to 2.5 with hydrochloric acid. Further, aspirin was added as a component (C) to obtain a raw material liquid. This raw material solution was adjusted in the same manner as in Example 1 to obtain an elliptical spherical semi-solid preparation for internal use. Thermal stability, taste, and drug content to initial value were evaluated in the same manner as in the above-mentioned Examples (Table 4).
As a result, when any one of the component (D), sucrose, powdered malt-reducing sugar starch syrup, xylitol, and sorbitol, was added, the decrease in the drug content of the semi-solid preparation for internal use was better suppressed. In particular, when powdered malt-reducing sugar starch syrup was added, a high effect was obtained in suppressing the decrease in drug content.
On the other hand, when cornstarch was added as an optional ingredient, the effect of suppressing the decrease in drug content was not confirmed. Even when the water content in the same formulation as in Example 1 was used, the effect of suppressing the decrease in the content of the drug was confirmed by adding the component (D) in the same manner.

(Examples 22 to 27)
According to the blending amount in Table 5, any one of dry aluminum hydroxide gel, magnesium oxide, synthetic hydrotalcite, and magnesium carbonate was mixed with the gelatin solution as the component (E). The pH of this solution was adjusted to 2.5 with hydrochloric acid. Further, aspirin was added as a component (C) to obtain a raw material liquid. This raw material solution was adjusted in the same manner as in Example 1 to obtain an elliptical spherical semi-solid preparation for internal use. Similar to the above-mentioned examples, the thermal stability after storage, the taste, and the initial value content of the drug were evaluated (Table 5).
As a result, when any of the components (E) was added, there was an effect of improving the taste of the semi-solid preparation for internal use. In particular, when a dry aluminum hydroxide gel was added, a high effect was obtained.
On the other hand, when cornstarch was added as an optional ingredient, 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 dried aluminum hydroxide gel was used as the component (E), the best results were obtained in all of the thermal stability, the taste, and the initial value content of the drug.

(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. Further, aspirin was added as a component (C) to obtain a raw material liquid. This raw material solution was adjusted in the same manner as in Example 1 to obtain an elliptical spherical semi-solid preparation for internal use.
As a result of evaluating the thermal stability after storage, the taste, and the initial value content of the drug in the same manner as in the above-mentioned examples, good thermal stability was shown even when the pH adjuster was changed to malic acid (Table 6). .. The taste and the initial value content of the drug were also good.

Claims (5)

It contains gelatin (A), water (B), and at least one drug (C) selected from the group consisting of acetaminophen and a salt thereof, and the mass of the component (C) / the (A). A semi-solid preparation for internal use having a mass of ingredients of 2.3 to 9.0 and a pH of 1.0 to 3.5. The semi-solid preparation for internal use according to claim 1, wherein the component (A) has a weight average molecular weight of 30,000 to 270,000. The semi-solid preparation for internal use according to claim 1 or 2, further containing the saccharide (D). The method for producing a semi-solid preparation for internal use according to any one of claims 1 to 3.
Production of a semi-solid preparation for internal use, which comprises a step of dispersing the component (A) and the component (C) in the component (B) and gelling a raw material liquid having a pH of 1.0 to 3.5. Method. The method for producing a semi-solid preparation for internal use according to claim 4 , further comprising a step of dispersing the component (A) in the component (B) and then dispersing the component (C) to obtain the raw material solution. ..