Oral solid preparation and method for manufacturing the same

Abstract

To provide an oral solid preparations that suppress color change and generation of unpleasant odors, and to provide a manufacturing method thereof.SOLUTION: Provided are an oral solid preparation containing (1) Cloperastine or a pharmaceutically acceptable salt thereof, (2) Mequitazine or a pharmaceutically acceptable salt thereof, and (3) Hesperidin or a pharmaceutically acceptable salt thereof; and a manufacturing method of the oral solid preparation, comprising mixing (1) Cloperastine or a pharmaceutically acceptable salt thereof, (2) Mequitazine or a pharmaceutically acceptable salt thereof, and (3) Hesperidin or a pharmaceutically acceptable salt thereof.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to an oral solid preparation and a method for producing the same. More specifically, the present invention relates to a pharmaceutical composition in which color tone change and unpleasant odor generation that occur when cloperastine or a pharmaceutically acceptable salt thereof and mequitazine are blended are suppressed.

Background Art

[0002] Cold syndrome is mostly a respiratory infectious disease derived from viruses, and its main symptoms range from local symptoms such as cough, sore throat, nasal congestion, increased nasal secretion and sputum, to systemic symptoms such as fever, chills, myalgia, arthralgia and general malaise. In order to eliminate these symptoms at an early stage, various ingredients are blended in cold remedies, such as antipyretic analgesic ingredients that alleviate pain and fever, antihistamine ingredients that alleviate nasal symptoms such as nasal congestion and increased nasal secretion, and antitussive ingredients aimed at improving cough symptoms (Non-Patent Document 1). For example, Japanese Unexamined Patent Publication No. 2018-076306 (Patent Document 1) describes a cold remedy containing naproxen. In Patent Document 1, cloperastine hydrochloride and mequitazine are exemplified as an antitussive ingredient and an anti-rhinitis active ingredient (claim 2).

[0003] Since a cold remedy is obtained by blending a plurality of ingredients, various inconveniences that affect product value may occur due to the interaction between the blended ingredients.

Prior Art Documents

Patent Documents

[0004]

Patent Document 1

Non-Patent Documents

[0005]

Non-Patent Document 1

Summary of the Invention

[0006] When cloperastine hydrochloride and mequitazine were added, changes in color over time and an unpleasant odor occurred. It should be noted that Patent Document 1 does not describe any examples of manufacturing a formulation containing cloperastine hydrochloride and mequitazine, nor does it mention any changes in color over time or the occurrence of an unpleasant odor.

[0007] Therefore, the present invention aims to provide an oral solid preparation, such as a cold medicine, that suppresses changes in color over time and the generation of unpleasant odors when clotherastine or a pharmaceutically acceptable salt thereof is combined with mequitazine. The present invention also aims to provide a method for producing an oral solid preparation that suppresses changes in color over time and the generation of unpleasant odors. [Means for solving the problem]

[0008] This invention is fundamentally based on the findings from examples that hesperidin can solve the problems of color changes over time and the generation of unpleasant odors caused by combining phenothiazine derivatives (e.g., cloperastine hydrochloride) and piperidine derivatives (mequitazine).

[0009] The first invention relates to an oral solid preparation. This oral solid preparation is (1) Cloperastin, or a pharmaceutically acceptable salt thereof; (2) Mequitazine, or a pharmaceutically acceptable salt thereof; and (3) containing hesperidin or a pharmaceutically acceptable salt thereof.

[0010] Preferred examples of the above oral solid preparations are those containing (1) cloperastine or a pharmaceutically acceptable salt thereof in a ratio of 1 part by weight, (2) 0.04 to 0.35 parts by weight of mequitazine or a pharmaceutically acceptable salt thereof, and (3) 0.16 to 5 parts by weight of hesperidin or a pharmaceutically acceptable salt thereof.

[0011] Preferred examples of the component in (1) above are cloperastine hydrochloride and cloperastine fendizoate. The oral solid preparation may also be a cold medicine.

[0012] A preferred example of the above oral solid preparation is an oral solid preparation further containing one or more of crystalline cellulose, light anhydrous silicic acid, and calcium silicate.

[0013] The second invention relates to a method for producing oral solid preparations. This method is (1) Cloperastin, or a pharmaceutically acceptable salt thereof; (2) Mequitazine, or a pharmaceutically acceptable salt thereof; and (3) A step of mixing hesperidin or a pharmaceutically acceptable salt thereof. [Effects of the Invention]

[0014] The present invention can provide an oral solid preparation, such as a cold medicine, that suppresses the time-dependent color change and the generation of unpleasant odors when clotherastine or a pharmaceutically acceptable salt thereof is combined with mequitazine. Furthermore, the present invention can provide a method for producing an oral solid preparation that suppresses the time-dependent color change and the generation of unpleasant odors. [Modes for carrying out the invention]

[0015] The following describes embodiments for carrying out the present invention. The present invention is not limited to the embodiments described below, but also includes modifications made to the embodiments described below to the extent that is obvious to those skilled in the art.

[0016] The first invention relates to an oral solid preparation. An oral solid preparation is a solid drug taken orally by the subject. Examples of oral solid preparations include tablets, capsules, and powders (e.g., powders and granules). Among these, the present invention is preferably applicable to powders. This oral solid preparation may be a cough suppressant, an antirhyntic agent, or a treatment for allergic rhinitis, or it may be a cold medicine.

[0017] This internal solid preparation contains an effective amount of an active ingredient. Specifically, this internal solid preparation is (1) cloperastine, or a pharmaceutically acceptable salt thereof; (2) mequitazine, or a pharmaceutically acceptable salt thereof; and (3) hesperidin, or a pharmaceutically acceptable salt thereof.

[0018] Examples of pharmaceutically acceptable salts include salts with mineral acids such as sulfuric acid, hydrochloric acid, and phosphoric acid, salts with organic acids such as acetic acid, oxalic acid, lactic acid, tartaric acid, fumaric acid, maleic acid, methanesulfonic acid, benzenesulfonic acid, and fendizoic acid, salts with amines such as trimethylamine and methylamine, or salts with metal ions such as sodium ions, potassium ions, and calcium ions. When each active ingredient exists as a solvate such as a hydrate, or when the active ingredient becomes a solvate due to aging, such forms are also included in each active ingredient or a pharmaceutically acceptable salt thereof.

[0019] Examples of cloperastine or a pharmaceutically acceptable salt thereof as the first component include cloperastine hydrochloride and cloperastine fendizoate. Cloperastine is a phenothiazine derivative and is known as a non-narcotic antitussive.

[0020] An example of mequitazine or a pharmaceutically acceptable salt thereof as the second component is mequitazine. Mequitazine has anti-rhinitis effects and is effective for treating bronchial asthma, allergic rhinitis, urticaria, and pruritus associated with skin diseases (eczema / dermatitis, cutaneous pruritus). In the internal solid preparation, the blending amount of the second component is preferably 0.04 to 0.35 parts by weight, more preferably 0.08 to 0.17 parts by weight, relative to 1 part by weight of the first component.

[0021] An example of hesperidin or a pharmaceutically acceptable salt thereof as the third component is hesperidin. Hesperidin is a vitamin-like substance also called vitamin P, and is a type of polyphenol. As demonstrated by the examples, hesperidin can suppress the time-dependent changes in color and the generation of unpleasant odors caused by the combination of phenothiazine derivatives (e.g., cloperastine hydrochloride) and piperidine derivatives (mequitazine). The amount of the third component in the oral solid preparation is preferably 0.16 to 5 parts by weight, and more preferably 0.37 to 3.75 parts by weight, per 1 part by weight of the first component.

[0022] The second invention relates to a method for producing an oral solid preparation. This method includes the step of mixing a first component, a second component, and a third component. The first component, the second component, and the third component may be mixed simultaneously or in any order.

[0023] The oral solid preparation of the present invention can be combined with the first, second, and third components and one or more pharmaceutically acceptable carriers to form a drug or pharmaceutical composition. Examples of carriers include excipients such as crystalline cellulose, light anhydrous silicic acid, calcium silicate, lactose, starch, maltose, mannitol, xylitol, erythritol, magnesium aluminometasilicate, and anhydrous calcium hydrogen phosphate; binders such as hydroxypropyl cellulose, hydroxypropyl methylcellulose, gelatin, and polyvinylpyrrolidone; disintegrants such as croscarmellose sodium, carmellose, carmellose calcium, carmellose sodium, and low-substituted hydroxypropyl cellulose; lubricants such as magnesium stearate, hydrogenated castor oil, talc, and macrogol; and flow promoters such as light anhydrous silicic acid. In addition, disintegration aids, buffers, preservatives, fragrances, pigments, and flavoring agents may be used as needed. In particular, using crystalline cellulose as an excipient can further suppress the generation of unpleasant odors when cloperastin, or its pharmaceutically acceptable salts, and mequitazine are incorporated. Furthermore, using light anhydrous silicic acid and / or calcium silicate as an excipient can further suppress changes in color over time when cloperastin, or its pharmaceutically acceptable salts, and mequitazine are incorporated.

[0024] In addition to the first, second, and third components, one or more other antipyretic analgesics, other antihistamines, other anti-inflammatory drugs, anticholinergics, antitussives, bronchodilators, expectorants, anti-drowsiness agents (central nervous system stimulants), vitamins, herbal medicines, Chinese herbal medicines, and antacids may be added as needed. Specifically, as antipyretic and analgesic drugs, aspirin or its salts, acetaminophen, ibuprofen, ethenzamide, isopropylantipyrine, ketoprofen, naproxen, loxoprofen or its salts, pranoprofen, diclofenac or its salts; as other antihistamines, chlorpheniramine maleate (including d- and dl-isomers), carbinoxamine maleate, diphenhydramine or its salts, promethazine or its salts, homochlorcyclidine or its salts; as other anti-inflammatory enzyme drugs, lysozyme chloride, semi-alkaline proteinase, tranexamic acid, serrapeptase, bromelain and its related substances, etc.; as anticholinergic components, total belladonna alkaloids, isopropamide iodide, belladonna extract, etc.; as antitussives, dihydrocodeine or its salts, codeine or its salts, dextrose This formula can contain stromethorphan or its salts, noscapine or its salts, dimemorphan or its salts, eprazinon or its salts, methoxyphenamine or its salts, etc. as bronchodilators such as methyl ephedrine hydrochloride (including d- and dl-isomers), ephedrine hydrochloride, methoxyphenamine hydrochloride, trimethoquinol hydrochloride, theophylline, aminophylline, etc. as expectorants such as potassium cresolsulfonate, potassium guaiacolsulfonate, L-methylcysteine ​​hydrochloride, L-ethylcysteine ​​hydrochloride, etc. as anti-drowsiness agents (central nervous system stimulants) such as caffeine, etc. as vitamins such as vitamin B1 or its derivatives or their salts, vitamin B2 or its derivatives or their salts, vitamin C, or vitamin E, etc. as well as herbal medicines, Chinese herbal medicines, antacids, etc., and these can be used alone or in combination of two or more. Here, "salt" refers to hydrochloride salts, nitrates, sulfates, phosphates, oxalates, maleates, fumarates, hydrobroms, potassium salts, sodium salts, calcium salts, magnesium salts, etc.

[0025] The drug of the present invention is prepared by commonly used formulation techniques as an orally administered preparation such as tablets, capsules, and powders (e.g., powders, granules, and fine granules).

[0026] The dosage of each component may be adjusted as appropriate depending on the type of disease being treated, the patient's age, weight, and symptoms. For the first component, the dosage is preferably 12 to 100 mg per day for adults, in terms of cloperastine hydrochloride, and particularly preferably 24 to 48 mg. For the second component, the dosage is preferably 1 to 10 mg per day for adults, in terms of mequitazine, and particularly preferably 2 to 6 mg. For the third component, the dosage is preferably 8 to 120 mg per day, in terms of hesperidin, and particularly preferably 18 to 90 mg.

[0027] This specification also provides the use of the first, second, and third components for manufacturing oral solid dosage forms. Furthermore, this specification also provides a method for treating a cold, cough, rhinitis, or allergic rhinitis, comprising the step of administering the first, second, and third components to a subject (human or non-human mammal). [Examples]

[0028] Color change suppression effect test Oral solid preparations were manufactured according to the formulations shown in Table 1 below. In the example, 4 g of mequitazine was mixed with 24-48 g of cloperastine hydrochloride and 8-90 g of hesperidin. For the comparative example, 4 g of mequitazine was mixed with 24-48 g of cloperastine hydrochloride, 90 g of glucosyl hesperidin instead of hesperidin, 12 g of riboflavins, 500 g of ascorbic acid, or 20 g of tocopherol calcium succinate. Specifically, the components shown in Table 1 were uniformly mixed to obtain a mixture. Regarding the degree of color change, a color tester (CC-i, Suga Test Instruments Co., Ltd.) was used to measure the L*, a*, and b* values ​​of each sample. The color difference between the sample before and after storage was calculated as ΔE (a value defined by the distance between coordinates in the L*a*b* color system). A smaller ΔE value indicates a smaller degree of discoloration.

[0029] Time-dependent conditions The time course conditions were as follows: 10g of each sample was placed in a glass bottle (Daiichi Glass Co., Ltd., product name: PS-4K), sealed, and then placed in a cardboard box. The time course was then carried out under the following conditions. An ETAC ELH-868-20 constant temperature bath was used at 60°C. Time-dependent conditions Sealed, 60°C, 1 week (1W) The results obtained are shown in Table 1.

[0030] [Table 1-1]

[0031] [Table 1-2]

[0032] Results after 1 week at 60°C A change in color was observed when cloperastine hydrochloride was used in proportion to 4 g of mequitazine. Adding 8-90g of hesperidin to the above mixture showed an effect in suppressing color change. In the comparative example, no effect on suppressing color change was observed, or only a weaker effect than that of hesperidin was observed. From these results, it was found that hesperidin has the effect of improving the time-dependent color change that occurs in mixtures of phenothiazine derivatives and piperidine derivatives.

[0033] Test of effectiveness in suppressing the generation of unpleasant odors and changes in color tone. Oral solid preparations were prepared according to the formulations shown in Table 2 below. In the example, 1 g of mequitazine was mixed with 10 g of cloperastine hydrochloride and 5 g of hesperidin. The components shown in Table 2 were uniformly mixed using a mortar and pestle.

[0034] Time-dependent conditions Each sample was placed in a glass bottle, sealed, and then placed in a cardboard box. The following conditions were used to monitor the samples over time. Time-dependent conditions Sealed, 60°C, 1 week (1W) The results obtained are shown in Table 2.

[0035] [Table 2-1]

[0036] [Table 2-2]

[0037] As shown in Table 2, a mixture of 1 g of mequitazine and 10 g of cloperastine hydrochloride produced an unpleasant odor. Adding 5 g of hesperidin to this mixture suppressed the generation of the unpleasant odor. Furthermore, it was shown that adding crystalline cellulose further suppressed the generation of the unpleasant odor. In addition, it was shown that adding light anhydrous silicic acid and / or calcium silicate improved the change in color over time. Furthermore, when an overall evaluation was conducted by integrating the suppression of unpleasant odor generation and the change in color to assess the overall change in the physical properties of the formulation, it was shown that the overall evaluation was good with the addition of hesperidin, and that the overall evaluation was even better with the addition of crystalline cellulose, light anhydrous silicic acid, or calcium silicate.

[0038] In other words, this specification also provides a color change inhibitor and an odor inhibitor for a mixture of phenothiazine derivatives and piperidine derivatives, which contains hesperidin as an active ingredient. Furthermore, this specification also provides a method for inhibiting color change and the generation of an unpleasant odor for a mixture of phenothiazine derivatives and piperidine derivatives, which includes a step of mixing the phenothiazine derivative, the piperidine derivative, and hesperidin.

[0039] Examples of formulations Tablets, granules, or powders were manufactured according to the formulations listed in Tables 3 and 4, in accordance with the sections on "Tablets," "Granules," and "Powders" in the General Provisions of the Japanese Pharmacopoeia. This oral solid preparation shows no change in color over time, no unpleasant odor, and is otherwise a perfectly acceptable product. Based on the active ingredients, this particular formulation is a cold medicine. [Table 3]

[0040] [Table 4] [Examples]

[0041] Color tone suppression effect test An oral solid preparation was manufactured by uniformly mixing the ingredients using a mortar and pestle to a total volume of 3,060 g, according to the formulation amounts shown in the prescription table in Table 5. In addition to the formulations shown in Table 5, acetaminophen, anhydrous caffeine, L-carbocysteine, and excipients were mixed in. The components of the excipients were carmellose calcium, calcium silicate, crystalline cellulose, magnesium stearate, hydroxypropyl cellulose, mannitol, and light anhydrous silicic acid.

[0042] [Table 5]

[0043] Time-dependent conditions Teng of each sample was placed in a glass bottle (Daiichi Glass Co., Ltd., product name: PS-4K). Samples under sealed conditions were capped, while samples under open conditions were left uncapped. The bottles were then placed in a cardboard box, and the following time intervals were observed. Sealed: 60°C for 1 week (1W) Opening temperature: 40°C / 75%RH, 3 months and 6 months (3M and 6M) Opening temperature: 30°C / 75%RH, 3 months and 6 months (3M and 6M) A 60°C constant temperature bath, model ELH-868-20, manufactured by ETAC Corporation, was used. A Nagano Science SRH-25VEVJ4 was used as a constant temperature and humidity chamber at 40°C / 75%RH. A Nagano Science SRH-10VEVJ2 constant temperature and humidity chamber (30°C / 75%RH) was used. A color tester (CC-i, Suga Test Instruments Co., Ltd.) was used as the color measurement device. The results obtained are shown in Table 6.

[0044] [Table 6]

[0045] As shown in Table 6, it was demonstrated that mixing the three components—cloperastine or a pharmaceutically acceptable salt thereof; mequitazine or a pharmaceutically acceptable salt thereof; and hesperidin or a pharmaceutically acceptable salt thereof—effectively suppresses color changes over time. In particular, under high-temperature storage conditions, the mixing of the three components significantly suppresses color changes over time. [Industrial applicability]

[0046] This invention can be used in the pharmaceutical industry.

Claims

1. (1) Cloperastin, or a pharmaceutically acceptable salt thereof; (2) Mequitazine, or a pharmaceutically acceptable salt thereof; and (3) containing hesperidin or a pharmaceutically acceptable salt thereof An oral solid preparation wherein the amounts of (1) to (3) are as follows: (1) cloperastin or a pharmaceutically acceptable salt thereof, per 1 part by weight, (2) mequitazine or a pharmaceutically acceptable salt thereof, 0.04 to 0.35 parts by weight, and (3) hesperidin or a pharmaceutically acceptable salt thereof, 0.16 to 3.75 parts by weight. An oral solid preparation that suppresses the change in color over time and the generation of unpleasant odors caused by the combination of (1) cloperastine or a pharmaceutically acceptable salt thereof and (2) mequitazine or a pharmaceutically acceptable salt thereof.

2. An oral solid preparation according to claim 1, wherein the amounts of (1) to (3) are: (1) cloperastin or a pharmaceutically acceptable salt thereof, per 1 part by weight, (2) mequitazine or a pharmaceutically acceptable salt thereof, and (3) hesperidin or a pharmaceutically acceptable salt thereof, per 1 part by weight.

3. An oral solid preparation according to claim 1, wherein the cloperastine, or a pharmaceutically acceptable salt thereof, is cloperastine hydrochloride or cloperastine fendizoate.

4. An oral solid preparation according to any one of claims 1 to 3, An oral solid preparation further comprising one or more of crystalline cellulose, light anhydrous silicic acid, and calcium silicate.

5. (1) Cloperastin, or a pharmaceutically acceptable salt thereof; (2) Mequitazine, or a pharmaceutically acceptable salt thereof; and (3) A step of mixing hesperidin or a pharmaceutically acceptable salt thereof, A method for suppressing the time-dependent color change and the generation of an unpleasant odor in an oral solid preparation obtained by combining (1) cloperastin or a pharmaceutically acceptable salt thereof and (2) mequitazine or a pharmaceutically acceptable salt thereof, A method in which the proportions of (1) to (3) described above are: (1) cloperastin or a pharmaceutically acceptable salt thereof, per 1 part by weight, (2) mequitazine or a pharmaceutically acceptable salt thereof, 0.04 to 0.35 parts by weight, and (3) hesperidin or a pharmaceutically acceptable salt thereof, 0.16 to 3.75 parts by weight.

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