JP3382076B2 - Cold medicine capsule obtained by dissolving ibuprofen and method for producing the same - Google Patents

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a cold medicine soft capsule obtained by dissolving ibuprofen, and a method for producing the same.

[0002]

2. Description of the Related Art Currently, in Japan, as a general cold medicine, cold medicine manufacturing (import)
There are used so-called non-standard prescription internal medicines, which are prescribed within the range of the active ingredient and the amount shown in the approval criteria (hereinafter, approval criteria) and the ingredients other than the approval criteria. Conventionally, tablets, granules, capsules, powders and the like have been widely used as the drug. In addition, liquids and syrups are widely used from the viewpoint of ease of drinking and convenience, but they are limited to children by the approval standard. The properties required as a remedy for cold syndrome include rapid onset of the effect of taking the drug, easy carrying, and easy administration when needed. On the other hand, although tablets and capsules are excellent in portability and ease of administration, it is hard to say that they are superior to liquids and syrups in terms of rapid onset of effects (MILO GIBALDI Written by Keiji Sekiguchi and others "Biopharmaceutical Overview" 71-81). On the other hand, although the liquid preparation and the syrup are excellent dosage forms in that they exhibit a rapid effect, they have a difficulty in portability and have a problem that they have to be weighed when they are taken. Therefore, it is desired to develop a dosage form which is easy to take, does not have to be complicated to measure, has excellent portability, can be taken as needed, and has a fast-acting property, as a drug preparation preferable as a cold medicine.

Ibuprofen is a phenylpropionic acid antiphlogistic / analgesic and antipyretic agent, and is effective in treating rheumatoid arthritis and arthritis, neuralgia, and postoperative antiphlogistic analgesia. Hitherto, ibuprofen has been used as a medicinal drug for these diseases, but due to its effectiveness and safety, it has recently come to be used as an over-the-counter drug for "antipyretic analgesics" and "cold drugs". There are sugar-coated tablets, film tablets, granules, hard capsules, etc. in the form of cold medicines containing ibuprofen. As antipyretic analgesics, plain tablets, sugar-coated tablets, and soft capsules containing dispersed and dissolved ibuprofen are on the market. The soft capsules are all formulations containing ibuprofen alone. When ibuprofen is mixed with a cold medicine, it falls under the non-standard ingredients of Section A of the above approval criteria, and for example, it is possible to apply for approval as a cold medicine for a soft capsule in which ibuprofen is dissolved, but in that case The obtained effect is "alleviation of various symptoms of cold (throat sore, chills, fever, headache, joint pain, muscle pain)", and "snot, stuffy nose, sneezing, coughing" often seen in cold syndrome. A dissolved soft capsule cold drug having the effect of "sputum" has not been put on the market yet. The following have been published as patent applications for soft capsules of ibuprofen. For example, in JP-A-1-502185, a part of ibuprofen is made into a potassium salt with potassium hydroxide or the like as a solubility-increasing agent for an ionizable drug to enhance the solubility and to contain a hydroxide ion. In the state, a method of dissolving in polyethylene glycol as a base is disclosed. However, this method has a drawback that ibuprofen forms an ester with polyethylene glycol as shown in Table 1 below, which increases with time.

[0004]

[Table 1] Table 1 ────────────────────────────── Weight per 6 capsules Ibuprofen 450 mg Polyethylene glycol 400 2, 500 mg potassium hydroxide 51 mg purified water 210 mg initial ibuprofen 99.2% PEG ester body 0% at 40 ° C. 1M ^* ibuprofen 94.8% PEG ester body 4.4% change 40 ° C. 3M ibuprofen 92.2% PEG ester Body 7.8% 40 ° C. 6M ibuprofen 88.8% PEG ester body 11.2% M ^* = represents a month as a period (hereinafter the same).

Further, Japanese Patent Laid-Open No. 5-310566 discloses
The dissolution mechanism is the same as in the above example, except that the solvent is changed from polyethylene glycol to polysorbate 80. Further, when the hydroxide ion is 0.1 mol or less, ibuprofen is precipitated. Also in this method, since water-insoluble ibuprofen is dissolved as water-soluble K salt and Na salt, diphenhydramine hydrochloride necessary for obtaining the effects of cough, sputum, runny nose and stuffy nose when applied as a cold medicine. ,
When a water-soluble salt such as dihydrocodeine phosphate, noscapine hydrochloride, dl-methylephedrine hydrochloride dextromethorphan hydrobromide is blended, the solubility of the water-soluble drug increases, resulting in poor solubility and crystal precipitation.
Japanese Patent Publication No. 6-67829 discloses that a base composition is a non-aqueous system and ibuprofen is dissolved in a mixture of polyoxyethylene-polyoxypropylene polymer or polyalkylene glycol and a surfactant at 45 to 65 ° C. POE sorbitan fatty acid ester of the present invention, POE
A base composition consisting of water and a surfactant selected from the group consisting of hydrogenated castor oil and polyglycerin fatty acid ester is fundamentally different, and as described above, 1,2-
Propylene glycol, polyethylene glycol 40
0, polyalkylene glycols such as polyethylene glycol 600 have a drawback of forming an ester form of ibuprofen. Japanese Patent Application Laid-Open No. 6-9381 discloses a method in which ibuprofen is dissolved in medium-chain fatty acid triglyceride and / or vegetable oil at 55 to 65 ° C. and then cooled to room temperature, and the resulting fine crystals are encapsulated in a soft capsule. It is completely different from the method of clearly dissolving ibuprofen and encapsulating it in a soft capsule. Furthermore, these patent applications are all ibuprofen plain and do not mention at all the incorporation and dissolution of other medicinal ingredients.

Japanese Patent Application Laid-Open No. 3-5418 discloses that only an antitussive and expectorant component is blended, and if ibuprofen is blended instead of a cold medicine, formation of an ester body by polyethylene glycol is expected. According to these conventional methods, when a soft capsule containing a cold-effect drug component as a main component formulated according to the above-mentioned approval criteria and non-criteria is manufactured, it is difficult to fill in a clear state due to a change in appearance such as crystal precipitation, resulting in suspension. It is encapsulated in the liquid state. However, a soft capsule containing a suspension as a filling liquid has a problem in that the absorption is slower than that of a soft filling of the filling liquid in a solution state, and the rapid-acting property is high.

[0007]

Means for Solving the Problems As a result of intensive studies on a soft capsule having the above-mentioned basic properties, the present inventors have succeeded in making a cold clearing drug component a stable clear solution,
The present invention has been completed by confirming that a formulation in which this is filled in a soft capsule has excellent fast-acting properties. That is, the present invention is different from the conventional method in that the POE sorber
We succeeded in dissolving about 1000 mg of drug in 6 capsules daily by simply combining fatty acid ester with water. That is, the present invention is: Ibuprofen and one or more second agents selected from the group consisting of antihistamines, antitussives, expectorants, sympathomimetics and central stimulants, POE sorbitan fatty acid
Contains ester and water, polyhydric alcohol medium chain fatty acid
1. A cold medicine soft capsule characterized by being dissolved in a base material which does not contain stealth and hydroxide ions, and 1. Ibuprofen and one or more second agents selected from the group consisting of antihistamines, antitussives, expectorants, sympathomimetics and central stimulants, POE sorbitan fatty acid
Contains ester and water, polyhydric alcohol medium chain fatty acid
The present invention relates to a method for producing a cold medicine soft capsule, which comprises dissolving stells and hydroxide ions without being present.

[0008]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention will be described in more detail below. P used as the base of the soft capsule of the present invention
OE sorbitan fatty acid ester usually has an HLB of 10
-20, preferably 13-18, particularly preferably 15-
POE sorbitan fatty acid ester in the range of 17
If so, there is no particular limitation . As the POE sorbitan fatty acid ester, a POE sorbitan fatty acid ester having 5 to 40, preferably 10 to 30, and more preferably 15 to 25, moles of ethylene oxide (OE) added in the molecule can be preferably used. Incidentally, as long as ethylene oxide (OE) is contained in a predetermined amount, propylene oxide may be contained in the molecule together with ethylene oxide. When the added mole number of ethylene oxide is within 5 to 40 moles, HLB becomes 10 to 20, which is preferable. The fatty acid constituting the POE sorbitan fatty acid ester usually has 12 to 18 carbon atoms, preferably 16 carbon atoms.
-18 fatty acids, for example, oleic acid, and fatty acids such as stearic acid, isostearic acid, palmitic acid, and lauric acid. Particularly preferred POE sorbitan fatty acid esters include, for example, POE (2
0) sorbitan monooleate, POE (20) sorbitan monostearate, POE (20) sorbitan monoisostearate, POE (20) sorbitan monopalmitate, POE (20) sorbitan monolaurate, etc. can be mentioned. . Specific examples of preferable POE (20) sorbitan monooleate include Nikkor TO-10M (Nikko Chemicals) and Leodol TW-0120 (Kao) as trade names.

The base of the soft capsule of the present invention is a polyvalent alcohol.
Addition of other surface-active agent than rucol medium chain fatty acid ester
And may include POE hydrogenated castor oil, for example.
It As a preferable POE hydrogenated castor oil, ethylene oxide of 40 to 100, preferably 50 to 70, particularly preferably 55 to 65 mono-added can be suitably used. As long as the number of moles of added ethylene oxide is within a predetermined range, propylene oxide may be contained in the molecule together with ethylene oxide. When the addition mole number of ethylene oxide is 40 to 100 moles, HLB becomes 10 to 20, which is preferable. Examples of preferable POE hydrogenated castor oil include POE (5
0) hydrogenated castor oil and POE (60) hydrogenated castor oil, PO
E (80) hydrogenated castor oil and the like can be mentioned. Particularly preferred POE hydrogenated castor oils include Nikkor HCO-60 (Nikko Chemicals) and UNIOX HC-60 (NOF Corporation) as trade names.

POE sorbitan fatty acid ester alone
May be used as a base in polyhydric alcohol medium chain fatty acids
It may also be used as a mixture with other surfactants, which does not contain tellurium . The surfactant is preferably used in an amount of usually 70 to 95% by weight, preferably 80 to 90% by weight, more preferably 85 to 90% by weight, based on the total weight of the surfactant and water. When the amount of the surfactant is 70 to 95% by weight, the solubility is increased, which is preferable. Purified water is preferably used as the water for the base of the soft capsule of the present invention. The amount of water used in the base is usually 5 to 15 based on the total weight of the surfactant and water base.
% By weight, preferably 9 to 11% by weight, particularly preferably 1
It is 0 to 11% by weight. When the amount of water is 5 to 15% by weight, the solubility is increased, which is preferable. Drugs dissolved in the base are ibuprofen, antihistamines, antitussives,
A second drug selected from the group consisting of an expectorant, a sympathomimetic and a central stimulant. As the antihistamine agent used as the second drug, various antihistamine agents can be used. Preferred antihistamines include, for example, isothipendyl hydrochloride, diphenylpyraline hydrochloride,
Diphenhydramine hydrochloride, difeterol hydrochloride, triprolidine hydrochloride, triperenamine hydrochloride, tonzylamine hydrochloride, phenetadine hydrochloride, metzirazine hydrochloride, diphenhydramine salicylate, carbinoxamine diphenyldisulfonate, diphenylhydraline tannic acid, dioctyl methanopyrrolamine, diphenylpyrroline methacryloline, napadicillate naphthalicilate Examples include various antihistamines such as disalicylate, carbinoxamine maleate, dl-chlorpheniramine maleate, d-chlorpheniramine maleate, and difeterol phosphate.

As the antitussive, various antitussives can be used. Preferred antitussives include, for example, alloclamide hydrochloride, cloperastine hydrochloride, carbetapentane citrate, tipepidine citrate, sodium dibnate, dextromethorphan hydrobromide, dextromethorphan phenolphthaline salt, tipepidine hibenzate, fendizoic acid. Examples include cloperastine, codeine phosphate, dihydrocodeine phosphate, noscapine hydrochloride, noscapine. As the expectorant, various expectorants can be used. Examples of preferred expectorants include potassium guaiacol sulfonate, guaifenesin and the like. Various sympathomimetic agents can be used as the sympathomimetic agent. Examples of preferred sympathomimetic agents include dl-methylephedrine hydrochloride, dl-methylephedrine saccharin salt, phenylpropanolamine hydrochloride, and the like. As the central stimulant, various central stimulants can be used. Examples of preferred central stimulants include anhydrous caffeine, caffeine, sodium caffeine benzoate, and the like.

These drug components can be used alone or as a mixture of two or more kinds with respect to ibuprofen. In the present invention, the amount of the second drug used together with ibuprofen is based on the total amount of ibuprofen and the second drug,
Usually 5 to 70% by weight, preferably 10 to 60% by weight,
It is particularly preferably 40 to 55% by weight. As the drug used in the capsule of the present invention, various other drugs and compounds can be used in combination with ibuprofen and the second drug, if necessary. Examples of such other drugs and compounds include vitamins, crude drugs, parasympathetic nerve blockers, and the like. Examples of the vitamin agent include vitamin B1, derivatives thereof and salts thereof, vitamin B2 (riboflavin), derivatives thereof and salts thereof, and vitamin C (ascorbic acid), derivatives thereof and salts thereof, hesperidin, derivatives thereof and salts thereof and the like. be able to. These vitamin agents may be added alone or as a mixture of two or more kinds. Examples of the crude drug as an optional component include, e.g., ephedra extract, nantenjitsu extract, spruce extract, syrup extract, licorice extract, kyoto extract, chazenshi extract, chazensou extract, garlic extract, senega extract,
Bimo extract, fennel extract, laurel extract, zedoary extract, chamomile extract, cinnamon tree extract, gentian extract, sycamore extract, animal gall extract, shajin extract, ginger extract, clove extract, chinpi extract, juniper extract, earth dragon extract, ginseng extract. , Carrot extract and the like. These crude drugs may be used alone or as a mixture of two or more kinds.

Further, as the parasympathetic nerve blocking agent as an optional component, for example, datura extract, belladonna alkaloid and the like can be used alone or as a mixture of two or more kinds. The film of the soft capsule of the present invention,
Any film conventionally used as a film for soft capsules can be used without particular limitation. As a film of such a soft capsule, a gelatin film can usually be preferably mentioned. The film of the soft capsule may contain various additives such as glycerin, sorbit, antiseptic, colorant, and titanium oxide, if necessary. The compounding amounts of ibuprofen and the second drug are
In the case of approval criteria, it can be selected within the range of the maximum daily dose and the maximum daily dose shown or out of the standard depending on the usage and dose. Usually, it is preferable to mix the maximum daily dose in 6 to 9 capsules. Usually, the daily dose of ibuprofen is usually 200-600 mg, preferably 300-
600 mg, particularly preferably 400-600 mg. The second drug selected from the group consisting of antihistamines, antitussives, expectorants, sympathomimetics and central stimulants varies depending on the type.

The soft capsule of the present invention can be manufactured, for example, as follows. That is, POE sorbie
After heating the tan fatty acid ester to 40 to 80 ° C., preferably 40 to 70 ° C., and particularly preferably 50 to 60 ° C., it is composed of ibuprofen and an antihistamine, antitussive, expectorant, sympathomimetic and central stimulant. A second drug selected from the group is mixed, and for example, it is uniformly mixed with a homogenizer or the like and dissolved. Then, the solution is cooled to 10 to 40 ° C., preferably 15 to 30 ° C., particularly preferably 20 to 30 ° C., and then water such as purified water is added to the solution to further dissolve ibuprofen and the second drug. To do. Finally, the obtained drug solution is encapsulated as a transparent liquid by a conventional method using a capsule film such as gelatin. In this case, POE sorbitan fatty acid
Dissolving ibuprofen and the second drug in the ester gives a pale yellow transparent solution. When a crude drug, which is an optional component, is further added, a clear brown solution is obtained.
If desired, the resulting drug solution may be degassed before encapsulation.

[0015]

EXAMPLES The present invention will be described in more detail below with reference to Examples and Comparative Examples, but the scope of the present invention is not limited by these Examples and Comparative Examples. Example 1 Weight per 6 Capsules Ibuprofen 450 mg Diphenhydramine Hydrochloride 75 mg Dihydrocodeine Phosphate 24 mg Noscapine Hydrochloride 48 mg dl-Methylephedrine Hydrochloride 60 mg Guaifenesin 250 mg Anhydrous Caffeine 30 mg Nichol TO-10M 2061 mg Purified Water 212 M 103 TO 10 mg Nicol 32-10 mg After heating to about 60 ° C., 225 g of ibuprofen, 37.5 g of diphenhydramine hydrochloride, 12 dihydrocodeine phosphate were added.
g, 24 mg of noscapine hydrochloride, 30 g of dl-methylephedrine hydrochloride, 125 g of guaifenesin and 15 g of anhydrous caffeine were added and dissolved by vigorously stirring with a homogenizer, then cooled to about 40 ° C. and 106 g of purified water was added, followed by stirring to completeness. After confirming that it was dissolved in water, it was degassed under reduced pressure and then filtered through 100 mesh to obtain a pale yellow transparent solution. Using a gelatin film in which 30 g of glycerin was mixed with 100 g of gelatin, 535 mg per capsule was filled with the above transparent solution by a conventional method to prepare 3000 soft capsules.

Example 2 Weight per 6 capsules Ibuprofen 450 mg Diphenylpyraline hydrochloride 4 mg Dihydrocodeine phosphate 24 mg dl-Methylephedrine hydrochloride 60 mg Guaifenesin 250 mg Anhydrous caffeine 30 mg Nikkor TO-10M 2061 mg Purified water 212 mg Total 3091 mg As in Example 1. According to the above prescription, 515 mg per capsule was filled to prepare 3000 soft capsules.

Example 3 Weight per 6 capsules Ibuprofen 450 mg Diphenhydramine hydrochloride 37.5 mg Dextromethorphan hydrobromide 24 mg Noscapine hydrochloride 24 mg Anhydrous caffeine 30 mg Nikkor TO-10M 2061 mg Purified water 212.4 mg Total 2838 mg 0.9 mg In the same manner as in Example 1, according to the above formulation, 473.2 mg was filled per capsule, and the soft capsule 300 was prepared.
0 pieces were produced.

Example 4 Weight per 6 capsules ibuprofen 450 mg diphenhydramine hydrochloride 75 mg dl-methylephedrine hydrochloride 60 mg dihydrocodeine phosphate 24 mg noscapine hydrochloride 48 mg anhydrous caffeine 30 mg Nikkor TO-10M 2061 mg purified water 213 mg total 2961 mg In the same manner as in Example 1, according to the above formulation, 493.5 mg was filled per capsule, and the soft capsule 300
0 pieces were produced.

Example 5 Weight per 6 capsules Ibuprofen 450 mg Dihydrocodeine phosphate 24 mg Guaifenesin 250 mg Anhydrous caffeine 30 mg Phenylpropanolamine hydrochloride 75 mg Diphenylpyraline hydrochloride 4 mg Reodol TW-0120 2061 mg Purified water 212.4 mg Total 3106.4 mg According to the above prescription, in the same manner as in Example 1, 517.7 mg per capsule was filled to give 300 soft capsules.
0 pieces were produced.

[0020]

[0021]

Example 6 Weight per 6 capsules ibuprofen 450 mg dl-chlorpheniramine maleate 3.75 mg dextromethorphan hydrobromide 24 mg dl-methylephedrine hydrochloride 30 mg guaifenesin 125 mg anhydrous caffeine 30 mg Nikkor TO -10M 2243.3 mg Purified water 220.5 mg Total 3126.6 mg In the same manner as in Example 1, according to the above formulation, 521.1 mg was filled per capsule, and the soft capsule 300 was prepared.
0 pieces were produced.

Example 7 Weight per 6 capsules Ibuprofen 450 mg Diphenhydramine hydrochloride 37.5 mg Dextromethorphan hydrobromide 24 mg Noscapine 30 mg Anhydrous caffeine 30 mg Reodol TW-0120 2322.5 mg Purified water 212.4 mg Total 3106.4 mg In the same manner as in Example 1, according to the above formulation, each capsule was filled with 517.7 mg, to give a soft capsule 300.
0 pieces were produced.

[0024]

Example 8 Weight per 6 Capsules Ibuprofen 450 mg Diphenhydramine Hydrochloride 37.5 mg Dextromethorphan Hydrobromide 24 mg Noscapine Hydrochloride 24 mg Anhydrous Caffeine 30 mg Belladonna Total Alkaloids 0.6 mg Nikkor TO-10M 2061 mg Purified water 212 mg Total 2839.1 mg According to the above formulation, gelatin 100 and sorbit 3
473.2 mg per capsule in the same manner as in Example 1 except that a gelatin film containing 0 was used.
Each of them was filled to obtain 3000 soft capsules.

Example 9 Weight per 6 capsules ibuprofen 450 mg guaifenesin 250 mg diphenhydramine hydrochloride 75 mg dl-methylephedrine hydrochloride 60 mg dihydrocodeine phosphate 24 mg noscapine hydrochloride 48 mg anhydrous caffeine 30 mg ascorbic acid 63 mg 20 leodol TW-01 1894 mg Purified water 212 mg Total 3106 mg In the same manner as in Example 8 , 517 mg per capsule was filled in accordance with the above formulation to prepare 3000 soft capsules.

Example 10 Weight per 6 capsules Ibuprofen 450 mg Dihydrocodeine phosphate 24 mg Guaifenesin 250 mg Anhydrous caffeine 30 mg Phenylpropanolamine hydrochloride 75 mg Riboflavin butyrate 2 mg Nikkol TO-10M 2059 mg Purified water 212 mg Total 3106 mg In the same manner as in Example 8 , according to the above formulation, each capsule was filled with 517.7 mg, to give 300 soft capsules.
0 pieces were produced.

Comparative Example 1 Weight per 6 Capsules Ibuprofen 450 mg Diphenhydramine Hydrochloride 75 mg Dihydrocodeine Phosphate 24 mg Noscapine Hydrochloride 48 mg dl-Methylephedrine Hydrochloride 60 mg Guaifenesin 250 mg Anhydrous Caffeine 30 mg Potassium Hydroxide 51 mg Nicol TO-10M 2061 mg Purified Water 212 A soft capsule preparation was produced in the same manner as in Example 1 except that potassium oxide was added.

Comparative Example 2 Weight per 6 Capsules Ibuprofen 450 mg Diphenylpyraline Hydrochloride 4 mg Dihydrocodeine Phosphate 24 mg dl-Methylephedrine Hydrochloride 60 mg Guaifenesin 250 mg Anhydrous Caffeine 30 mg Potassium Hydroxide 51 mg Nichol TO-10M 2180 mg Purified Water 212 mg Total 3261 mg Potassium Hydroxide A soft capsule was produced in the same manner as in Example 2 except that was added. Comparative Example 3 Weight per 6 capsules Ibuprofen 450 mg Diphenhydramine hydrochloride 37.5 mg Dextromethorphan hydrobromide 24 mg Noscapine hydrochloride 24 mg Anhydrous caffeine 30 mg Potassium hydroxide 51 mg Nikkor TO-10M 2322 mg Purified water 212.4 mg A soft capsule was produced in the same manner as in Example 3 except that 3150.9 mg of potassium hydroxide was added in total.

Comparative Example 4 Weight per 6 Capsules Ibuprofen 450 mg Diphenhydramine Hydrochloride 75 mg dl-Methylephedrine Hydrochloride 60 mg Dihydrocodeine Phosphate 24 mg Noscapine Hydrochloride 48 mg Anhydrous Caffeine 30 mg Potassium Hydroxide 51 mg Nikkor TO-10M 2061 mg Purified water 213 mg total 3012 mg A soft capsule was produced in the same manner as in Example 4 except that potassium hydroxide was added.

Test Example 1 Change in Appearance (1) The turbidity of the liquid for internal use in the soft capsules of Examples 1 to 4 and Comparative Examples 1 to 4 was examined immediately after production and after storage at -5 ° C for 5 days. . The results are shown in Table 2 below.
The turbidity was measured using an integrating sphere turbidimeter. The smaller the value, the smaller the turbidity.

[0032]

[Table 2] From Table 2, as compared with Comparative Examples 1 to 4, the turbidity of the liquid for internal use of the soft capsules of Examples 1 to 4 is very small, and therefore the solubility of the liquid for internal use of Examples 1 to 4 is It can be seen that it is extremely superior to those of Comparative Examples 1 to 4. (2) The soft capsule preparation of Example 5 was stored in a constant temperature bath at -5 ° C and 40 ° C, and the properties were visually observed. The results are shown in Table 3 below.

[0033]

[Table 3]

Test Example 2 Stability The stability of the soft capsule of Example 2 when stored in a constant temperature bath at 40 ° C. was measured by liquid chromatography. The results are shown in Table 4 below.

[0035]

[Table 4] Table 4 Stability results of Example 2 (%) ────────────────────────────────── ──Initial 40 ℃ 1M 40 ℃ 3M 40 ℃ 6M Ibuprofen 99.8 100.1 98.8 98.6 Diphenylpyraline Hydrochloride 100.5 98.3 98.0 98.7 Dihydrocodeine Phosphate 98.4 98.2 98.2 0.0 98.6 dl-methylephedrine hydrochloride 100.4 101.1 98.5 98.8 guaifenesin 101.0 99.5 100.1 99.9 anhydrous caffeine 98.2 99.5 98.3 99.0

The results of Table 1 when using potassium hydroxide, etc. to improve the solubility of ibuprofen, the fourth
Comparison with the results in the table shows that in the liquid for internal use of the soft capsule of Example 2 , ibuprofen remained stable without being changed.

[0037] and soft capsule Test Example 3 Bioavailability Example 5 was orally administered to beagle dogs and control of hard capsules by each 2 capsule (ibuprofen 150 mg), administered immediately before and after administration 0.25 , 0.5,
Blood was collected after 0.75, 1, 1.5, 2, 3, 4, 6, 8, and 24 hours, and the amount of ibuprofen in the serum was quantified by liquid chromatography. One group consisted of 5 animals, a drug washout period of 2 weeks was provided, and crossover was performed. These results are shown in Table 5 below as average values. The components contained in the control hard capsule are present in the form of powder and have the following composition.

[0038]                                                       [In 6 capsules]               Japan Bureau Ibuprofen 450mg               Japan Bureau Guayacol Glycerin Ether 250mg               Foreign regulation diphenylpyraline hydrochloride 4 mg               Japanese Pharmacopoeia dihydrocodeine phosphate 24mg               JP Anhydrous Caffeine 30mg               Out-of-office regulation Phenylpropanolamine hydrochloride 75 mg     Excipients Japanese Pharmacopoeia anhydrous calcium hydrogen phosphate 800mg     Excipients Japanese corn starch 723mg     Binder JP H. P. CL (fine powder) 72 mg     Lubricant JP TALC-Manchurian 325 72mg     Lubricants Japan Magnesium Stearate 12mg

[0039]

[Table 5] From the results in Table 5, it can be seen that the formulation according to the present invention has a faster Tmax than that of the commercially available hard capsule, and thus the absorption of ibuprofen is faster.

[0040]

INDUSTRIAL APPLICABILITY The cold medicine soft capsule of the present invention is excellent in drug absorbability because a drug such as ibuprofen is dissolved in the liquid for internal use. In addition, since the internal solution does not contain hydroxide ions, ibuprofen in particular is stably present in the internal solution and improves the solubility with respect to other drugs. Furthermore, the cold medicine soft capsule of the present invention does not need to be weighed, has excellent portability, and effectively acts on various cold symptoms.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁷ Identification code FI A61K 47/14 A61K 47/14 47/34 47/34 A61P 11/10 A61P 11/10 11/14 11/14 25/02 25 / 02 25/04 25/04 25/20 25/20 25/26 25/26 29/00 29/00 43/00 113 43/00 113 (72) Inventor Shingo Maeda 6-8 Higashioi, Shinagawa-ku, Tokyo No. 5 within Sato Pharmaceutical Co., Ltd. (72) Inventor Yutaka Amabu 6-8-5 Higashiooi, Shinagawa-ku, Tokyo Within Sato Pharmaceutical Co., Ltd. (56) Reference JP-A-5-178763 (JP, A) ) JP-A-6-9381 (JP, A) Special Table Sho-59-501413 (JP, A) (58) Fields investigated (Int.Cl. ⁷ , DB name) A61K 31/19 A61K 9/48 A61K 45 / 00 A61K 47/14 A61K 47/34

Claims (7)

(57) [Claims] 1. POE sorbi containing ibuprofen and one or more second drugs selected from the group consisting of antihistamines, antitussives, expectorants, sympathomimetics and central stimulants.
Containing tan fatty acid ester and water, in polyhydric alcohol
A cold medicine soft capsule preparation characterized by being dissolved in a base material which does not contain a chain fatty acid ester and a hydroxide ion. 2. The cold medicine soft capsule according to claim 1, wherein the central nervous system stimulant is anhydrous caffeine, caffeine or sodium caffeine benzoate. 3. The cold medicine soft capsule according to claim 1, wherein the POE sorbitan fatty acid ester has an HLB of 13-18. 4. POE sorbi comprising ibuprofen and one or more second agents selected from the group consisting of antihistamines, antitussives, expectorants, sympathomimetics and central stimulants.
Containing tan fatty acid ester and water, in polyhydric alcohol
A method for producing a cold medicine soft capsule, which comprises dissolving it in a base containing no chain fatty acid ester and hydroxide ion. 5. The POE sorbitan fatty acid ester is added to the ibuprofen and the second drug in a polyhydric alcohol.
Solution in the absence of medium-chain fatty acid ester, and then dissolved at 50 to 60 ° C., cooled to 20 to 30 ° C., further added water and mixed by stirring to mix the ibuprofen and the second drug with the POE sorbitan. Dissolved in a base containing fatty acid ester and water in the absence of hydroxide ions, then
The method for producing a cold medicine soft capsule according to claim 4, wherein the obtained solution is encapsulated. 6. The method for producing a cold medicine soft capsule according to claim 4, wherein the central nervous system stimulant is anhydrous caffeine, caffeine or sodium caffeine benzoate. 7. The method for producing a cold medicine soft capsule according to claim 4, wherein the POE sorbitan fatty acid ester has an HLB of 13 to 18.