Solid Dosage Forms

Abstract

To provide a solid preparation containing ibuprofen, tranexamic acid and guaifenesin, where the preparation has reduced failures in appearance.SOLUTION: A solid preparation contains an uncoated tablet containing ibuprofen, tranexamic acid and guaifenesin, and a coating layer covering the uncoated tablet and containing a polyvinyl alcohol.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to a solid preparation containing ibuprofen, tranexamic acid and guaifenesin.

Background Art

[0002] In pharmaceutical preparations, especially over-the-counter pharmaceutical preparations, there are many active ingredients and additives, so they are likely to interact and cause physicochemical changes (such as appearance changes, melting point depression, swelling, discoloration, etc.). In particular, in preparations containing sublimable substances, low melting point substances, etc., due to the interaction between drugs and additives, physicochemical changes occur during storage, and the phenomenon of tablets swelling can be seen. Due to this phenomenon, in the case of uncoated tablets, cracks may appear on the surface or side of the uncoated tablets, and in the case of coated tablets, appearance defects such as cracks and peeling of the coating may occur.

[0003] Ibuprofen and guaifenesin are widely used as an antipyretic analgesic and an expectorant, respectively, and may be used in a general cold medicine in combination with tranexamic acid, which is widely used as an anti-inflammatory agent. Since ibuprofen and guaifenesin are sublimable substances, in coated tablets containing ibuprofen, tranexamic acid and guaifenesin, there has been a problem of appearance defects such as cracks and peeling of the coating due to swelling.

[0004] In order to eliminate appearance defects in pharmaceutical preparations containing ibuprofen and tranexamic acid, various techniques have been developed. For example, in Patent Document 1, by enclosing a desiccant in the packaging process in a pharmaceutical preparation containing ibuprofen and tranexamic acid, suppression of tablet swelling and stabilization of appearance are achieved. Further, Patent Document 2 discloses a film-coated tablet in which a pharmaceutical preparation containing ibuprofen and tranexamic acid is coated with a film coating layer containing polyvinyl alcohol and hypromellose in a specific ratio, and the film coating layer does not crack. Furthermore, Patent Document 3 describes how adding an inorganic salt containing magnesium to a solid preparation containing ibuprofen and tranexamic acid suppresses changes in the appearance of the preparation that occur during high-temperature storage. Furthermore, Patent Document 4 describes how a film-coated tablet, comprising a plain tablet containing ibuprofen, tranexamic acid, and a fluidizing agent such as sodium aluminometasilicate, and a film coating layer containing polyvinyl alcohol covering the plain tablet, achieves suppression of swelling and stabilization of the appearance of the formulation. However, none of the above-mentioned literature mentions any issues with the appearance of pharmaceutical preparations containing guaifenesin in addition to ibuprofen and tranexamic acid. [Prior art documents] [Patent Documents]

[0005] [Patent Document 1] Japanese Patent Publication No. 2007-145758 [Patent Document 2] Japanese Patent Publication No. 2015-137238 [Patent Document 3] Japanese Patent Publication No. 2017-002038 [Patent Document 4] Japanese Patent Publication No. 2019-019128 [Overview of the Initiative] [Problems that the invention aims to solve]

[0006] The present invention aims to provide a solid formulation containing ibuprofen, tranexamic acid, and guaifenesin, in which appearance defects such as cracking and peeling of the coating due to tablet expansion are improved. [Means for solving the problem]

[0007] As a result of diligent research, the present inventors have discovered that by incorporating polyvinyl alcohol into the coating layer covering the uncoated tablet containing ibuprofen, tranexamic acid, and guaifenesin in a solid dosage form, appearance defects such as cracking and peeling of the coating due to tablet expansion (especially expansion under high humidity) can be significantly improved, leading to the completion of the present invention. In other words, the present invention includes the following embodiments. [1] A solid preparation comprising an uncoated tablet containing ibuprofen, tranexamic acid, and guaifenesin, and a coating layer containing polyvinyl alcohol covering the uncoated tablet. [2] The solid preparation according to [1] above, wherein the coating layer further contains hypromellose. [3] The solid preparation according to [1] or [2] above, wherein the coating layer contains polyvinyl alcohol and hypromellose in a weight ratio of 1:7 to 7:1. [4] A solid preparation according to any of [1] to [3] above, wherein polyvinyl alcohol is a partially saponified product. [5] A solid dosage form described in any of [1] to [4] above, which is a film-coated tablet. [Effects of the Invention]

[0008] According to the present invention, in solid formulations containing ibuprofen, tranexamic acid, and guaifenesin, appearance defects such as cracking and peeling of the coating due to tablet swelling (especially swelling under high humidity) can be significantly improved. [Modes for carrying out the invention]

[0009] The solid dosage form of the present invention comprises a tablet containing ibuprofen, tranexamic acid, and guaifenesin, and a coating layer containing polyvinyl alcohol covering the tablet.

[0010] The "ibuprofen" used in this invention is ibuprofen in accordance with the Japanese Pharmacopoeia, and can be manufactured by known methods or commercially available ibuprofen can be used. The ibuprofen content in the solid formulation of the present invention is not particularly limited, but is, for example, 1 to 60% by mass of the total solid formulation, preferably 5 to 50% by mass, and more preferably 10 to 30% by mass.

[0011] The "tranexamic acid" in this invention is tranexamic acid in accordance with the Japanese Pharmacopoeia, and can be manufactured by known methods or commercially available tranexamic acid can be used. The content of "tranexamic acid" in the solid formulation of the present invention is not particularly limited, but for example, it is 1 to 70% by mass of the total solid formulation, preferably 5 to 60% by mass, and more preferably 10 to 50% by mass.

[0012] The "guaifenesin" used in this invention is guaifenesin in accordance with the Japanese Pharmacopoeia, and can be manufactured by known methods or commercially available guaifenesin can be used. The content of "guaifenesin" contained in the solid formulation of the present invention is not particularly limited, but for example, it is 1 to 60% by mass of the total solid formulation, preferably 2 to 40% by mass, and more preferably 4 to 20% by mass.

[0013] The ratio of ibuprofen to tranexamic acid in the present invention is not particularly limited, but for example, 0.2 to 3 parts by mass, preferably 0.6 to 2 parts by mass, of tranexamic acid per 1 part by mass of ibuprofen. The ratio of ibuprofen to guaifenesin in the present invention is not particularly limited, but for example, ibuprofen is 0.4 to 6 parts by mass, preferably 0.9 to 4 parts by mass, per 1 part by mass of guaifenesin. The blending ratio of "tranexamic acid" and "guaifenesin" in the present invention is not particularly limited, but for example, 0.5 to 7 parts by mass, preferably 1.5 to 6 parts by mass, of tranexamic acid per 1 part by mass of guaifenesin.

[0014] The "uncoated tablet" in the present invention means a solid preparation coated with a coating layer. As long as it can be coated with a coating layer, its shape, size, form, etc. are not particularly limited, and examples include tableted solid preparations. The "uncoated tablet" in the present invention contains the above-mentioned "ibuprofen", "tranexamic acid" and "guaifenesin".

[0015] In the "uncoated tablet" of the present invention, drugs other than ibuprofen, tranexamic acid and guaifenesin may be formulated as long as they do not inhibit the effects of the present invention. Examples include analgesics and antipyretics other than ibuprofen, drugs for rhinitis, antihistamines, antitussives, noscapines, expectorants other than guaifenesin, bronchodilators, gastric mucosal protectants, caffeine, vitamins, hypnotics and sedatives, mucolytic agents, anti-inflammatory agents other than tranexamic acid, anticholinergics, crude drugs, traditional Chinese medicine prescriptions, etc.

[0016] Examples of analgesics and antipyretics other than ibuprofen include aspirin (acetylsalicylic acid), aluminum aspirin, acetaminophen, salicylamide, sodium salicylate, ethenzamide, salsalate, lactylphenetidine, ketoprofen, isopropylantipyrine, sodium loxoprofen, etc. Examples of drugs for rhinitis include pseudoephedrine hydrochloride, chlorpheniramine dl - maleate, d - chlorpheniramine maleate, belladonna total alkaloids, isopropamide iodide, dipotassium glycyrrhizinate, etc. Examples of antihistamines include diphenhydramine hydrochloride, diphenhydramine salicylate, diphenhydramine tannate, alimazine tartrate, isotipendyl hydrochloride, promethazine methylene disalicylate, diphenylpyraline hydrochloride, diphenylpyraline theoclate, isotipendyl hydrochloride, difeterol hydrochloride, difeterol phosphate, triprolidine hydrochloride hydrate, triperenamine hydrochloride, tondiamine hydrochloride, phenetazine hydrochloride, methodilazine hydrochloride, diphenyldisulfonic acid carbinoxamine, mebhydroline napadisylate, carbinoxamine maleate, iproheptine hydrochloride, promethazine hydrochloride, alimazine tartrate, phenetazine tannate, clemastine fumarate, and mequitazine. Examples of cough suppressants include codeine phosphate hydrate, dihydrocodeine phosphate, dextromethorphan hydrobromide hydrate, dextromethorphan phenolphthalein salt, alloclamide hydrochloride, cloperastine hydrochloride, cloperastine fendizoate, pentoxyverin citrate (carbetapentane citrate), tipepidine hibenzate, dibnate sodium, tipepidine citrate, and dimemorphan phosphate. Examples of noscapines include noscapine and noscapine hydrochloride hydrate. Examples of expectorants other than guaifenesin include potassium guaiacolsulfonate, bromhexine hydrochloride, tipepidine citrate, L-carbocysteine, ammonium chloride, l-menthol, ammonia / fennel extract, and potassium cresolsulfonate. Examples of bronchodilators include dl-methyl ephedrine hydrochloride, dl-methyl ephedrine saccharin salt, trimethoquinol hydrochloride, phenylpropanolamine hydrochloride, methoxyphenamine hydrochloride, l-methyl ephedrine hydrochloride, pseudoephedrine hydrochloride, aminophylline, diprophylline, theophylline, and proxyphylline. Examples of gastric mucosal protectants include glycine, aminoacetic acid, magnesium silicate, synthetic aluminum silicate, synthetic hydrotalcite, magnesium oxide, dihydroxyaluminum glycinate, aluminum hydroxide gel, dried aluminum hydroxide gel, mixed dried gel of aluminum hydroxide and magnesium carbonate, coprecipitated product of aluminum hydroxide and sodium hydrogen carbonate, coprecipitated product of aluminum hydroxide, calcium carbonate and magnesium carbonate, coprecipitated product of magnesium hydroxide and potassium aluminum sulfate, magnesium carbonate, etc. Examples of caffeine compounds include sodium caffeine benzoate, caffeine hydrate, anhydrous caffeine, etc. Examples of vitamins include vitamin B1 or its derivatives or salts thereof, vitamin B2 or its derivatives or salts thereof, vitamin C or its derivatives or salts thereof, vitamin P (hesperidin) or its derivatives or salts thereof, etc. Examples of hypnotics and sedatives include allylisopropylacetylurea, bromvalerylurea, etc. Examples of expectorants include lysozyme chloride, L-ethylcysteine hydrochloride, methylcysteine hydrochloride, etc. Examples of anti-inflammatory agents other than tranexamic acid include glycyrrhizic acid and its salts, etc. Examples of anticholinergics include belladonna total alkaloids, isopropamide iodide, etc. Examples of crude drugs include Ephedrae Herba, Nantenjitsu, Cinnamomi Ramulus, Onji, Glycyrrhizae Radix, Platycodonis Radix, Schizandrae Fructus, Schizandrae Herba, Sesshankakkonto, Senega Root, Baimo, Wikyo, Aukyak, Ouren, Gadutsu, Chamomillae Flos, Cinnamomi Cortex, Gentianae Radix, Gooku, Fel Ursi (including Yuutan), Shajin, Zyozyo, Soushutsu, Caryophylli Flos, Chinpi, Byakujutsuninjin, Carotae Radix, etc. Examples of Kampo prescriptions include Keishito, Keishito plus Kikyo, Keihi-to, Kososhosan, Saiko-keihi-to, Sho-saikoto, Shoseiryu-to, Baikamotsuto, Hange-shashin-to, Maekito, etc.

[0017] In the present invention, the "plain tablet" may further contain, in addition to the above-mentioned components, conventionally pharmaceutically acceptable carriers or additives in the pharmaceutical technology field, as long as they do not inhibit the effects of the present invention. Examples of carriers or additives include excipients, disintegrants, binders, fluidizers, lubricants, colorants, pH adjusters, surfactants, stabilizers, acidulants, and fragrances. These are used individually or as additives in amounts conventionally used in the pharmaceutical technology field.

[0018] Examples of excipients include starches such as corn starch, potato starch, wheat starch, rice starch, partially pregelatinized starch, pregelatinized starch, and porous starch; sugars or sugar alcohols such as lactose monohydrate, sucrose, fructose, glucose, mannitol, sorbitol, erythritol, xylitol, trehalose, maltitol, powdered reduced maltose syrup, and lactitol; and anhydrous calcium hydrogen phosphate, crystalline cellulose, powdered cellulose, precipitated calcium carbonate, and calcium carbonate. Examples of disintegrants include carmellose, carmellose calcium, carboxymethyl starch sodium, carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellose sodium, crospovidone, low-substituted hydroxypropylcellulose (L-HPC), and hydroxypropyl starch, with croscarmellose sodium and L-HPC being preferred. Examples of binders include hydroxypropylcellulose, hypromellose (hydroxypropylmethylcellulose), polyvinylpyrrolidone, copolyvidone, acacia powder, methylcellulose, low-substituted hydroxypropylcellulose, carmellose sodium, dextrin, partially pregelatinized starch, pullulan, acacia gum, agar, gelatin, tragacanth, and sodium alginate. Examples of fluidizing agents include light anhydrous silicic acid, hydrated silicon dioxide, calcium silicate, magnesium silicate, magnesium aluminometasilicate, and talc. Examples of lubricants include stearic acid, magnesium stearate, calcium stearate, talc, sucrose fatty acid esters, and sodium stearyl fumarate. Examples of coloring agents include yellow iron(III) oxide, iron(III) oxide, food blue No. 1, food blue No. 2, food yellow No. 4, food yellow No. 5, food green No. 3, food red No. 2, food red No. 3, food red No. 102, food red No. 104, food red No. 105, food red No. 106, food lake pigment, riboflavin, and sodium riboflavin phosphate. Examples of pH adjusters include citrates, phosphates, carbonates, tartrates, fumarates, acetates, and amino acid salts. Examples of surfactants include sodium lauryl sulfate, polysorbate 80, and polyoxyethylene (160) polyoxypropylene (30) glycol. Examples of stabilizers include tocopherol, tetrasodium edetate, nicotinamide, and cyclodextrins. Examples of acidulants include ascorbic acid, citric acid, tartaric acid, and malic acid. Examples of fragrances include L-menthol, peppermint oil, lemon oil, and vanillin. The carriers or additives described above may be used in appropriate mixtures of two or more types.

[0019] The "coating layer" in this invention is a coating applied to the "plain tablet" and contains "polyvinyl alcohol." Polyvinyl alcohol is also known as PVA. The "polyvinyl alcohol" in this invention is not particularly limited, but "partially saponified polyvinyl alcohol" is preferred. The "partially saponified polyvinyl alcohol" used in this invention conforms to the "2013 Pharmaceutical Additives Standards" (Yakuji Nippo Co., Ltd.) and can be manufactured by known methods, or a commercially available product can be used. The "partially saponified polyvinyl alcohol" used in this invention is listed in the 2016 Dictionary of Pharmaceutical Additives, and examples include "PVA PE-05JPS" (Nippon Vinegar Vinegar Co., Ltd.). The content of "polyvinyl alcohol" contained in the solid formulation of the present invention is not particularly limited, but for example, it is 0.001 to 7% by mass of the total solid formulation, preferably 0.01 to 4.5% by mass, and particularly preferably 0.1 to 3% by mass.

[0020] The "coating layer" in this invention may further contain "hypromellose" in addition to polyvinyl alcohol. Hypromellose is also known as hydroxypropyl methylcellulose or HPMC. The "hypromellose" used in this invention is hypromellose conforming to the Japanese Pharmacopoeia, and can be manufactured by known methods or commercially available hypromellose can be used. The "hypromellose" used in this invention is listed in the 2016 Dictionary of Pharmaceutical Additives, and examples include "TC-5" (Shin-Etsu Chemical Co., Ltd.). The content of "hypromellose" contained in the solid formulation of the present invention is not particularly limited, but for example, it is 0.001 to 7% by mass of the total solid formulation, preferably 0.01 to 4.5% by mass, and particularly preferably 0.1 to 3% by mass.

[0021] The "coating layer" in the present invention may contain other additives in addition to the polyvinyl alcohol and hypromellose mentioned above. As additives to be added to the "coating layer," it is preferable to use plasticizers and coating agents listed in the Pharmaceutical Additives Dictionary 2016 and the Pharmaceutical Additives Handbook 2007. For example, methacrylic acid copolymer L, Opadry OY-6950, macrogol 6000, polyethylene glycol, titanium dioxide, talc, etc., are preferred.

[0022] In the present invention, "solid dosage form" refers to a tablet in which an uncoated tablet is covered with a coating layer. Examples include coated tablets, film-coated tablets, sugar-coated tablets, thin-layer sugar-coated tablets, and sugarless thin-layer tablets, with film-coated tablets being preferred.

[0023] The solid dosage forms of the present invention can be manufactured using conventional methods, such as those described in publications like the Granulation Handbook (edited by the Japan Powder Technology Association, Ohmsha), Formulation Design for Orally Administered Formulations (edited by Professor Mitsuru Hashida, Graduate School of Pharmaceutical Sciences, Kyoto University, Yakugyo Jihosha), Compression Molding Technology of Powders (edited by the Powder Engineering, Formulation and Particle Design Subcommittee, Nikkan Kogyo Shimbun), and the Handbook of Pharmaceutical Machinery Technology (2nd edition, edited by the Pharmaceutical Machinery Technology Research Association 20th Anniversary Publication Editorial Committee, Pharmaceutical Machinery Technology Research Association). For example, ibuprofen, tranexamic acid, and guaifenesin may be granulated together, separately, or partially separately, along with additives commonly used in pharmaceuticals and other active ingredients as needed, to produce granules. These granules may then be further compressed with additives as needed to produce uncoated tablets. The method of granulation is not particularly limited, and any known method (extrusion granulation, rolling granulation, agitation granulation, fluid bed granulation, spray drying granulation, crushing granulation, melt granulation, etc.) may be used. Next, the obtained uncoated tablets can be manufactured by coating them with a coating layer containing polyvinyl alcohol, preferably hypromellose and other additives. The coating method is not particularly limited and can be carried out by known methods.

[0024] As described above, according to the present invention, a solid dosage form with improved appearance can be manufactured by incorporating polyvinyl alcohol into the coating layer covering a tablet containing ibuprofen, tranexamic acid, and guaifenesin. However, the technology of the present invention can also be applied to combinations of active ingredients other than ibuprofen, tranexamic acid, and guaifenesin. For example, in solid dosage forms containing "antipyretic analgesics (other than ibuprofen)," "anti-inflammatory agents (other than tranexamic acid)," and "expectorants (other than guaifenesin)" as active ingredients, which are prone to physicochemical changes due to interactions (e.g., expansion under high humidity), by incorporating polyvinyl alcohol into the coating layer covering the uncoated tablet containing the "antipyretic analgesic," "anti-inflammatory agent," and "expectorant," it is possible to manufacture solid dosage forms with improved appearance, such as film-coated tablets. "Antipyretic analgesic" refers to a drug that has antipyretic and analgesic effects, and is not particularly limited as long as it has antipyretic and analgesic effects, but examples include aspirin (acetylsalicylic acid), aluminum aspirin, acetaminophen, loxoprofen sodium, naproxen, ketoprofen, salicylic acid, salicylamide, sodium salicylate, ethenzamide, sazapyrin, lactylphenetidine, isopropylantipyrine, etc. Furthermore, in the solid dosage form of the present invention, there may be one or more antipyretic analgesics. "Anti-inflammatory agent" refers to a drug that has anti-inflammatory effects, and is not particularly limited as long as it has anti-inflammatory effects, but examples include epsilon-aminocaproic acid, aluminum chlorohydroxyallantoin, water-soluble azulene, and glycyrrhizic acid. Furthermore, in the solid dosage form of the present invention, there may be one or more anti-inflammatory agents. "Expectorant" refers to a drug that has expectorant properties, and is not particularly limited as long as it has expectorant properties, but examples include potassium guaiacolsulfonate, bromhexine hydrochloride, tipepidine citrate, L-carbocysteine, ammonia fennel extract, and potassium cresolsulfonate. In addition, in the solid dosage form of the present invention, the antipyretic analgesic may be one type or two or more types. [Examples]

[0025] The present invention will be described in more detail below with reference to examples, but the present invention is not limited to these examples.

[0026] (Examples 1-2 and Comparative Example 1) Each component was mixed according to the formulation and mixing ratio shown in Category A of Table 1 below, and compressed into tablets to obtain uncoated tablets. The obtained uncoated tablets were coated according to the formulation shown in Category B to obtain coated tablets. [Table 1]

[0027] (Example test) The coated tablets obtained as described above were stored under harsh test conditions (60°C or 50°C) or accelerated test conditions (40°C). The film cracking of the coated tablets after storage was evaluated. The results are shown in Table 2. [Table 2]

[0028] The inclusion of ibuprofen, tranexamic acid, and guaifenesin resulted in tablet swelling during harsh and accelerated testing, and as shown in Table 2, film cracking was observed in the HPMC film formulation (Comparative Example 1). On the other hand, for the PVA:HPMC = 1:1 and 1:2 film formulations (Examples 1 and 2), the sublimation of ibuprofen and guaifenesin was suppressed, and film cracking after storage under harsh or accelerated testing conditions was prevented.

[0029] (Manufacturing example) Each component was mixed according to the formulation and mixing ratio shown in Category A of Table 3 below, and compressed into tablets to obtain uncoated tablets. The obtained uncoated tablets were coated according to the formulation shown in Category B to obtain coated tablets. TIFF0007869650000003.tif123153 [Industrial applicability]

[0030] In a solid dosage form containing ibuprofen, tranexamic acid, and guaifenesin, incorporating polyvinyl alcohol into the coating layer covering the uncoated tablet containing ibuprofen, tranexamic acid, and guaifenesin significantly improves appearance defects such as cracking and peeling of the coating due to expansion (especially expansion under high humidity). This makes it possible to provide a solid dosage form that is free from appearance defects and ensures good quality.

Claims

1. A solid preparation comprising an uncoated tablet containing ibuprofen, tranexamic acid, and guaifenesin, and a coating layer containing polyvinyl alcohol covering the uncoated tablet, wherein the coating layer contains polyvinyl alcohol and hypromellose in a weight ratio of 1:7 to 7:

1.

2. The solid preparation according to claim 1, wherein the polyvinyl alcohol is a partially saponified product.

3. The solid dosage form according to claim 1 or 2, wherein the tablet is a film-coated tablet.

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