JP2022159187A - Oral solid preparation and manufacturing method thereof - Google Patents

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 The present invention relates to a solid preparation for internal use and a method for producing the same. More specifically, the present invention relates to a pharmaceutical composition that suppresses color change and unpleasant odor that occur when cloperastine or a pharmaceutically acceptable salt thereof and mequitazine are blended.

Most common cold syndromes are respiratory infections caused by viruses, and their main symptoms are cough, sore throat, nasal congestion, increased nasal secretion, sputum production, and other localized symptoms such as fever, chills, and muscle weakness. Systemic symptoms such as pain, arthralgia, and general malaise are diverse.
In order to eliminate these symptoms early, cold medicines include antipyretic analgesic ingredients that relieve pain and fever, antihistamine ingredients that relieve nasal symptoms such as stuffy nose and increased nasal secretion, and antihistamine ingredients that aim to improve cough symptoms. (Non-Patent Document 1). For example, JP-A-2018-076306 (Patent Document 1) describes a cold medicine containing naproxen. In Patent Document 1, cloperastine hydrochloride and mequitazine are exemplified as antitussive and antinasal active ingredients (claim 2).

Since cold remedies are obtained by blending multiple ingredients, interactions between the ingredients may cause various inconveniences that affect product value.

JP 2018-076306 A

Sepy IP Kaze Gold Tablet package insert (Zeria Pharmaceutical Co., Ltd.)

When cloperastine hydrochloride and mequitazine were added, color tone change and unpleasant odor occurred over time. In addition, Patent Document 1 does not describe an example of producing a preparation containing cloperastine hydrochloride and mequitazine, nor does it describe changes in color tone over time or generation of an unpleasant odor.

Therefore, the object of the present invention is to provide an oral solid preparation such as a cold medicine that suppresses color tone change over time and generation of unpleasant odor when cloperastine or its pharmaceutically acceptable salt and mequitazine are blended. and Another object of the present invention is to provide a method for producing a solid preparation for internal use that suppresses color tone change and generation of unpleasant odor over time.

Basically, the present invention is based on examples showing that hesperidin can solve the color change over time and generation of unpleasant odor caused by blending a phenothiazine derivative (for example, cloperastine hydrochloride) and a piperidine derivative (mequitazine). based on the findings of

A first invention relates to a solid preparation for internal use. This oral solid formulation 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.

A preferred example of the above-mentioned oral solid preparation is (1) 1 part by weight of cloperastine or its pharmaceutically acceptable salt, and (2) 0.04 to 0.04 to 0.04 of mequitazine or its pharmaceutically acceptable salt. 35 parts by weight, and (3) 0.16-5 parts by weight of hesperidin or a pharmaceutically acceptable salt thereof.

Preferred examples of the above component (1) are cloperastine hydrochloride and cloperastine fendizoate. In addition, the oral solid preparation may be cold medicine (cold medicine).

A preferable example of the solid preparation for internal use is a solid preparation for internal use further containing one or more of crystalline cellulose, light anhydrous silicic acid, and calcium silicate.

The second invention relates to a method for producing a solid preparation for internal use. This method
(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.

INDUSTRIAL APPLICABILITY The present invention can provide an oral solid preparation such as a cold medicine that suppresses color tone change over time and generation of unpleasant odor when cloperastine or a pharmaceutically acceptable salt thereof and mequitazine are blended. In addition, the present invention can provide a method for producing a solid preparation for internal use that suppresses changes in color tone and generation of unpleasant odors over time.

DETAILED DESCRIPTION OF THE INVENTION Embodiments for carrying out the present invention will be described below. The present invention is not limited to the embodiments described below, and includes appropriate modifications within the scope obvious to those skilled in the art from the following embodiments.

A first invention relates to a solid preparation for internal use. Oral solid formulations are solid formulations that are taken orally by a subject. Examples of oral solids are tablets, capsules, and powders (eg powders and granules). Among these, the present invention can be preferably used for powders. This oral solid preparation may be an antitussive agent, an antinasal agent, a therapeutic agent for allergic rhinitis, or a cold medicine (cold medicine).

This oral solid formulation contains an effective amount of the active ingredient. Specifically, this oral solid formulation 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.

Examples of pharmaceutically acceptable salts are salts with mineral acids such as sulfuric acid, hydrochloric acid, phosphoric acid, acetic acid, oxalic acid, lactic acid, tartaric acid, fumaric acid, maleic acid, methanesulfonic acid, benzenesulfonic acid, phendizoate salts with organic acids such as trimethylamine, salts with amines such as methylamine, or salts with metal ions such as sodium ions, potassium ions and calcium ions. In addition, when each active ingredient has a solvate such as a hydrate, or when the active ingredient becomes a solvate due to change over time, it is included in each active ingredient or a pharmaceutically acceptable salt thereof.

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

An example of the second component mequitazine or a pharmaceutically acceptable salt thereof is mequitazine. Mequitazine has an anti-rhinitis effect and is effective in treating bronchial asthma, allergic rhinitis, hives, and itching associated with skin diseases (eczema/dermatitis, pruritus cutaneous). The content of the second component in the internal solid preparation is preferably 0.04-0.35 parts by weight, more preferably 0.08-0.17 parts by weight, per 1 part by weight of the first component.

An example of the third component, hesperidin, or a pharmaceutically acceptable salt thereof, is hesperidin. Hesperidin is a vitamin-like substance, also called vitamin P, and a kind of polyphenol.
As demonstrated by the examples, hesperidin can suppress color change over time and generation of unpleasant odor caused by blending a phenothiazine derivative (for example, cloperastine hydrochloride) and a piperidine derivative (mequitazine). The amount of the third component in the internal solid preparation is preferably 0.16-5 parts by weight, more preferably 0.37-3.75 parts by weight, per 1 part by weight of the first component.

The second invention relates to a method for producing a solid preparation for internal use. The method includes mixing a first component, a second component and a third component. The first component, second component and third component may be mixed simultaneously or in any order.

The oral solid preparation of the present invention can be made into a drug or pharmaceutical composition by combining the first component, second component and third component with one or more pharmaceutically acceptable carriers. Examples of carriers include excipients such as microcrystalline cellulose, light anhydrous silicic acid, calcium silicate, lactose, starch, maltose, mannitol, xylitol, erythritol, magnesium aluminometasilicate, anhydrous calcium hydrogen phosphate, hydroxypropylcellulose, Hydroxypropyl methylcellulose, gelatin, binders such as polyvinylpyrrolidone, disintegrants such as croscarmellose sodium, carmellose, carmellose calcium, carmellose sodium, low-substituted hydroxypropyl cellulose, magnesium stearate, hydrogenated castor oil, talc, macro There are lubricating agents such as goals, glidants such as light silicic anhydride, and, if necessary, disintegration aids, buffering agents, preservatives, fragrances, pigments, flavoring agents, and the like can be used. In particular, by using crystalline cellulose as an excipient, it is possible to further suppress generation of an unpleasant odor when cloperastine or a pharmaceutically acceptable salt thereof and mequitazine are blended. In addition, by using light anhydrous silicic acid and/or calcium silicate as excipients, it is possible to further suppress color change over time when cloperastine or its pharmaceutically acceptable salt and mequitazine are blended. can be done.

In addition to the first component, second component and third component, other antipyretic analgesics, other antihistamines, other anti-inflammatory drugs, anticholinergics, antitussives, bronchodilators, One or more selected from expectorants, anti-drowsiness drugs (central nerve stimulants), vitamins, herbal medicines, herbal medicines, and antacids can be blended.
Specifically, as antipyretic analgesics, aspirin or its salts, acetaminophen, ibuprofen, ethenzamide, isopropylantipyrine, ketoprofen, naproxen, loxoprofen or its salts, pranoprofen, diclofenac or its salts, other antihistamines , chlorpheniramine maleate (including d- and dl-isomers), carbinoxamine maleate, diphenhydramine or its salts, promethazine or its salts, homochlorcyclidine or its salts, other anti-inflammatory/anti-inflammatory enzyme drugs such as lysozyme chloride , semi-alkaline proteinase, tranexamic acid, serrapeptase, bromelain and its analogs, etc. Anticholinergic components: belladonna total alkaloids, isopropamide iodide, Rohto extract, etc. Antitussives: dihydrocodeine or its salts, codeine or its salts, dextrome Turphan or its salts, noscapine or its salts, dimemorphan or its salts, eprazinone or its salts, methoxyphenamine or its salts, etc., as bronchodilators, methylephedrine hydrochloride (including d-isomer, dl-isomer), ephedrine hydrochloride, hydrochloric acid Methoxyphenamine, trimetoquinol hydrochloride, theophylline, aminophylline, etc. Expectorants such as cresol potassium sulfonate, guaiacol sulfonate potassium, L-methylcysteine hydrochloride, L-ethylcysteine hydrochloride, anti-drowsiness drugs (central nervous system stimulants) Vitamins such as caffeine, vitamins such as vitamin B1 or its derivatives or their salts, vitamin B2 or its derivatives or their salts, vitamin C or vitamin E, herbal medicines, herbal medicines, antacids, etc. These can be used singly or in combination of two or more. Here, salts include hydrochloride, nitrate, sulfate, phosphate, oxalate, maleate, fumarate, hydrobromide, potassium salt, sodium salt, calcium salt, magnesium salt, and the like. be done.

The drug of the present invention is prepared as oral dosage forms such as tablets, capsules, and powders (eg, powders, fine granules and granules) by commonly used formulation techniques.

The dosage of each component may be appropriately adjusted according to the type of disease to be treated, age, body weight and symptoms of the patient. The first component is preferably 12 to 100 mg, more preferably 24 to 48 mg per day for adults in terms of cloperastine hydrochloride. The second component is preferably 1 to 10 mg, more preferably 2 to 6 mg per day for adults in terms of mequitazine. The third component is preferably 8-120 mg, particularly preferably 18-90 mg, in terms of hesperidin.

This specification also provides the use of the first component, the second component and the third component to make an oral solid dosage form.
Further, this specification also provides a method of treating a cold, cough, rhinitis, or allergic rhinitis comprising administering to a subject (human or non-human mammal) a first component, a second component and a third component. offer.

Color Tone Change Suppressing Effect Test A solid preparation for internal use was produced according to the blending amounts shown in Table 1 below. In the examples, 24 to 48 g of cloperastine hydrochloride and 8 to 90 g of hesperidin were added to 4 g of mequitazine. As comparative examples, 24-48 g of cloperastine hydrochloride, 90 g of glucosylhesperidin instead of hesperidin, 12 g of riboflavins, 500 g of ascorbic acids, or 20 g of calcium tocopherol succinate were blended with 4 g of mequitazine.
Specifically, each component shown in Table 1 was 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, and the color difference between the samples before and after storage. was calculated as ΔE (a value defined by the distance between coordinates in the L*a*b* color system). As for the color difference index ΔE, a smaller numerical value means a smaller degree of discoloration.

Aging conditions The aging conditions were as follows. 10 g of each sample was placed in a glass bottle (product name: PS-4K, Daiichi Glass Co., Ltd.), covered (sealed), placed in a paper box, and aged under the following conditions. As a 60° C. constant temperature bath, ELH-868-20 manufactured by ETAC was used.
Aging conditions Sealed 60°C for 1 week (1W)
Table 1 shows the results obtained.

Results after 1 week at 60° C. A color change was observed with 24-48 g of cloperastine hydrochloride for 4 g of mequitazine.
By adding 8 to 90 g of hesperidin to the above mixture, a color tone change suppressing effect was observed.
In the comparative examples, no effect of suppressing color change was observed, or only a weaker effect of suppressing color change than hesperidin was observed. From these results, it was found that hesperidin has the effect of improving color change over time that occurs in mixtures of phenothiazine derivatives and piperidine derivatives.

Odor Generation and Color Tone Change Suppressing Effect Test A solid preparation for internal use was produced according to the compounding amounts shown in Table 2 below. In an example, 10 g of cloperastine hydrochloride and 5 g of hesperidin were mixed with 1 g of mequitazine. The ingredients shown in Table 2 were uniformly mixed using a pestle and mortar.

Aging conditions Each sample was placed in a glass bottle, capped (sealed), placed in a paper box, and aged under the following conditions.
Aging conditions Sealed 60°C for 1 week (1W)
Table 2 shows the results obtained.

As shown in Table 2, a mixture of 1 g of mequitazine and 10 g of cloperastine hydrochloride produced an unpleasant odor. By adding 5 g of hesperidin to this mixture, generation of an unpleasant odor was suppressed. Furthermore, it was shown that the generation of unpleasant odors can be further suppressed by adding crystalline cellulose. Furthermore, it was shown that the addition of light anhydrous silicic acid and/or calcium silicate improved color tone change over time. In addition, when the suppression of unpleasant odor generation and color change were integrated, and an overall evaluation was performed as an evaluation of changes in the overall physical properties of the formulation, the overall evaluation was favorable with the addition of hesperidin. It was shown that the addition of calcium silicate improved the overall evaluation.

In other words, the present specification also provides a color tone change inhibitor and an unpleasant odor inhibitor of a mixture of a phenothiazine derivative and a piperidine derivative containing hesperidin as an active ingredient. The present specification also provides a method for suppressing color change of a mixture of a phenothiazine derivative and a piperidine derivative, and a method for suppressing generation of an unpleasant odor, including the step of mixing the phenothiazine derivative, piperidine derivative and hesperidin. .

Formulation example
Tablets, granules, or powders were manufactured according to the formulations shown in Tables 3 and 4 according to the Japanese Pharmacopoeia General Rules for Preparations, “Tablets,” “Granules,” and “Powders.” This solid preparation for internal use does not change color over time, does not emit an unpleasant odor, and can be used as a product without any problems. The formulation example is also a cold medicine from the compounded active ingredients.

A solid formulation for internal use was prepared by uniformly mixing the components with a pestle and mortar according to the formulation amounts shown in Table 5 of the color tone suppression effect test so that the total amount was 3,060 g. In addition to the formulations shown in Table 5, acetaminophen, anhydrous caffeine, L-carbocysteine and excipients were mixed. Ingredients such as excipients were carmellose calcium, calcium silicate, microcrystalline cellulose, magnesium stearate, hydroxypropyl cellulose, mannitol, and light anhydrous silicic acid.

Aging conditions
Put 10 g of each sample in a glass bottle (Daiichi Glass Co., Ltd., product name: PS-4K), cover the sample under sealed conditions, and leave the sample under open conditions without a lid, and place it in a paper box under the following conditions. Time course was performed at .
Sealed: 60°C for 1 week (1W)
Open: 40°C/75%RH 3 months and 6 months (3M and 6M)
Open: 30°C/75% RH 3 months and 6 months (3M and 6M)
As a 60° C. constant temperature bath, ELH-868-20 manufactured by ETAC was used.
SRH-25VEVJ4 manufactured by Nagano Science Co., Ltd. was used as a constant temperature and humidity chamber at 40° C./75% RH.
SRH-10VEVJ2 manufactured by Nagano Science Co., Ltd. was used as a constant temperature and humidity chamber at 30°C/75% RH.
A color tester (CC-i, Suga Test Instruments Co., Ltd.) was used as a color tone measuring instrument. Table 6 shows the results obtained.

As shown in Table 6, when the three components of cloperastine or a pharmaceutically acceptable salt thereof; mequitazine or a pharmaceutically acceptable salt thereof; and hesperidin or a pharmaceutically acceptable salt thereof are mixed, It was shown that it is possible to effectively suppress a significant color tone change. In particular, it was shown that the color tone change over time can be significantly suppressed by mixing the three components in a storage state at a high temperature.

INDUSTRIAL APPLICABILITY The present invention can be used in the pharmaceutical industry.

Claims (5)

(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,
Oral solid formulation. 2. The solid preparation for internal use according to claim 1, wherein the amount of (1) to (3) is (1) per 1 part by weight of cloperastine or a pharmaceutically acceptable salt thereof, (2 ) 0.04-0.35 parts by weight of mequitazine or a pharmaceutically acceptable salt thereof, and (3) 0.16-5 parts by weight of hesperidin or a pharmaceutically acceptable salt thereof. 2. The oral solid preparation according to claim 1, wherein said cloperastine or a pharmaceutically acceptable salt thereof is cloperastine hydrochloride or cloperastine fendizoate. The oral solid preparation according to any one of claims 1 to 3,
A solid preparation for internal use, further comprising any one or more of crystalline cellulose, light anhydrous silicic acid and calcium silicate. (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,
A method for producing a solid formulation for internal use.