JP6410895B2 - Pharmaceutical composition - Google Patents

Description

  The present invention relates to a pharmaceutical composition containing fexofenadine.

  Fexofenadine [4- [1-hydroxy-4- (4-hydroxy-diphenylmethyl) -1-piperidinyl] butyl] -α, α-dimethyl-benzeneacetic acid] may have a histamine H1 receptor antagonistic action. In addition, it has various chemical mediator release inhibitory effects, inflammatory cytokine release inhibitory effects, and eosinophil migration inhibitory action, so it has allergic rhinitis, urticaria, eczema / dermatitis, skin sores As a therapeutic agent for various allergic diseases such as pruritus associated with skin diseases such as pruritus and atopic dermatitis, a preparation containing the hydrochloride has already been put into practical use. However, fexofenadine hydrochloride is known to be a photolabile substance, and due to concerns that it can be decomposed by light at the stage of its production and distribution, it is a stable substance containing fexofenadine hydrochloride. In order to obtain a composition for taking, various ingenuity of formulation and ingenuity of packaging are required.

  Conventionally, a technique for shielding the unpleasant taste and odor of the main agent and improving the stability against light and moisture by coating a solid dispersion with a plasticizer typified by polyethylene glycol (Patent Document 1) Has been proposed. On the other hand, polyethylene glycol is known to have an adverse effect on the heat and light stability of fexofenadine. In order to ensure the stabilization of the general formulation of fexofenadine hydrochloride, A method for improving storage stability such as light stability (Patent Document 2) and the like by applying a coating using methylcellulose or the like as a film coating composition without containing benzene has been proposed.

However, it is considered that the ingenuity with the above-mentioned additives alone is still insufficient for the photostability, and the actually marketed fexofenadine solid formulation is a film in order to further improve the photostability. Actually, not only coating but also PTP (press through package) packaging is used to complement its light stability. Manufacturing costs and manufacturing time required for coating and packaging process equipment for light shielding There was also a problem. For this reason, the conventional technology for improving the stabilization alone is not always sufficient, and the development of a stabilization technology that can further reduce the manufacturing time and further useful low cost is desired.
On the other hand, it is not known at all what effect the sugar alcohol or saccharide and the terpenoid compound have on the light stabilization of fexofenadine hydrochloride.

JP 2008-81512 A JP 2011-162531 A

  An object of the present invention is to provide a preparation containing fexofenadine hydrochloride whose light stability is improved by a simple method for fexofenadine hydrochloride, which is concerned about light stability.

  The present inventor has intensively studied to solve the above-mentioned problems. As a result, the photostability of fexofenadine hydrochloride is greatly increased by combining fexofenadine hydrochloride with a sugar alcohol or a saccharide and a terpenoid compound in combination. As a result, the present invention has been completed. In particular, in the present invention, in the case of a solid preparation containing sugar alcohol or saccharide alone or terpenoid compound alone in fexofenadine hydrochloride, as shown in the following examples, fexofenadine hydrochloride Despite the tendency to reduce photostability, we found that the photostability of fexofenadine hydrochloride was greatly improved unexpectedly by combining the two into fexofenadine hydrochloride. It is an invention based on that.

Specifically, the present invention provides the following pharmaceutical compositions and the like.
[Item 1] A pharmaceutical composition comprising (A) fexofenadine or a pharmaceutically acceptable salt thereof, (B) a sugar alcohol and / or a saccharide, and (C) a terpenoid compound.

  [Item 2] The pharmaceutical composition according to Item 1, wherein (B) the sugar alcohol is at least one selected from the group consisting of mannitol, sorbitol and xylitol.

  [Item 3] The pharmaceutical composition according to Item 1 or 2, wherein the saccharide (B) is a disaccharide.

  [Item 4] The pharmaceutical composition according to item 3, wherein the (B) disaccharide is lactose.

  [Item 5] The pharmaceutical composition according to any one of Items 1 to 4, wherein the (C) terpenoid compound is at least one selected from the group consisting of dl-menthol, 1-menthol, dl-camphor and d-camphor. object.

  CLAIM | ITEM 6 (A) Pharmaceutical composition in any one of claim | item 1 -5 whose fexofenadine or its pharmaceutically acceptable salt is fexofenadine hydrochloride.

  [Item 7] The pharmaceutical according to any one of Items 1 to 6, wherein the component (B) and the component (C) are 0.3 to 1000 parts by weight of the component (B) with respect to 1 part by weight of the component (C). Composition.

  [Item 8] The pharmaceutical composition according to Items 1 to 7, wherein the component (A) and the component (C) are 0.01 to 1.4 parts by weight of the component (C) with respect to 1 part by weight of the component (A). object.

  CLAIM | ITEM 9 (B) Pharmaceutical composition in any one of claim | item 1, 2, 5-8 whose sugar alcohol and / or saccharide | sugar are sugar alcohols.

  [Item 10] The pharmaceutical composition according to any one of Items 1, 3 to 8, wherein (B) the sugar alcohol and / or the saccharide is a saccharide.

  [Item 11] The pharmaceutical composition according to any one of Items 1 to 10, wherein the pharmaceutical composition is a solid preparation.

  [Item 12] The dosage form is tablet, hard capsule, soft capsule, granule, powder, powder, fine granule, pill, oral tablet, film, dry syrup, jelly, semi-solid oral Item 11. The pharmaceutical composition according to any one of Items 1 to 10, wherein the composition is an internal preparation of any of confectionery, liquid, and liquid.

  [Item 13] An agent for improving the stability of fexofenadine or a pharmaceutically acceptable salt thereof, comprising (B) a sugar alcohol and / or a saccharide, and (C) a terpenoid compound.

[Section 14]
A combination of (A) fexofenadine or a pharmaceutically acceptable salt thereof, (B) a sugar alcohol and / or saccharide, and (C) a terpenoid compound, and fexofenadine or a pharmaceutically acceptable salt thereof Acceptable salt stabilization methods.

The pharmaceutical composition of the present invention contains (A) fexofenadine hydrochloride, (B) a sugar alcohol and / or saccharide, and (C) a terpenoid compound, and is unstable to light. Even a composition containing a salt has excellent stability. As a result, it is expected to reduce the size and the like of a preparation that may not require a coating such as a sugar coating or a film coating as in the conventional solid preparation for fexofenadine. Furthermore, if the coating process is not necessary, the equipment for that purpose is also unnecessary, and the manufacturing cost and the manufacturing time can be significantly reduced. Moreover, light shielding by PTP packaging etc. becomes unnecessary, and the possibility of the preservation | save with a highly transparent container is also suggested.
In addition, the formulation of sugar alcohol and / or saccharide and a terpenoid that can be expected to have a refreshing effect can contribute to the provision of a preparation that is easy to swallow without the possibility of impairing the dose.

The result of Test Example 1 is shown.

The “fexofenadine” used in the present invention is a chemical name: 4- [1-hydroxy-4- (4-hydroxy-diphenylmethyl) -1-piperidinyl] butyl] -α, α-dimethyl-benzeneacetic acid. A preparation containing the hydrochloride salt thereof is already marketed as a tablet or an orally disintegrating tablet (OD tablet) as a therapeutic agent for allergic diseases.
Pharmaceutically acceptable salts of fexofenadine include inorganic acid salts such as hydrochloride, hydrobromide and phosphate; acetate, oxalate, malonate, succinate and fumaric acid Examples thereof include salts of organic acids such as salts, maleates, lactates, malates, citrates, tartrates, carbonates, picrates and glutamates, with hydrochlorides being preferred.

  The “sugar alcohol” used in the present invention means a pharmaceutically acceptable sugar alcohol, and examples thereof include mannitol, sorbitol, xylitol, maltitol, lactitol, glycerin, sucrose, and preferably mannitol, sorbitol. And xylitol, and mannitol is particularly preferable. In the present invention, two or more kinds of the above sugar alcohols may be contained. Since these sugar alcohols may have stereoisomers, these isomers are also included in the “sugar alcohol” herein, and also include a mixture thereof. Further, even when stereoisomers exist in the above-described acid forming a salt with fexofenadine and each component added to fexofenadine described below, each isomer and a mixture thereof are also included in the present invention.

  The “saccharide” used in the present invention means a pharmaceutically acceptable saccharide, and examples thereof include monosaccharides such as glucose, fructose, mannose and galactose, disaccharides such as lactose and trehalose, and the like. Disaccharides, more preferably lactose. In the present invention, two or more kinds of the above saccharides may be contained.

  The “terpenoid compound” used in the present invention means a pharmaceutically acceptable terpenoid compound, such as dl-menthol, 1-menthol, dl-camphor, d-camphor, d-borneol, geraniol, cineol, Citronellol, carvone, anethole, eugenol, limonene, linalool, linalyl acetate and the like can be mentioned, preferably dl-menthol, l-menthol, dl-camphor, d-camphor, more preferably dl-menthol, l-menthol. is there. In the present invention, two or more of the above terpenoid compounds may be contained.

  Moreover, you may use the essential oil and fragrance | flavor containing the said terpenoid compound as a terpenoid compound in this invention. Examples of such essential oils include eucalyptus oil, bergamot oil, peppermint oil, cool mint oil, spearmint oil, peppermint oil, fennel oil, cinnamon oil, rose oil, camphor oil and the like. These essential oils may be used alone or in any combination of two or more. You may use it in combination with the said terpenoid compound.

  All of fexofenadine or a pharmaceutically acceptable salt, sugar alcohol, saccharide, and terpenoid compound used in the present invention can be obtained commercially or can be produced according to a known method.

In the present invention, the weight ratio of the component (B) to the component (C) is not particularly limited, but is usually in the range of 0.3 to 1000 parts by weight, preferably 1 with respect to 1 part by weight of the component (C). It is -400 weight part, More preferably, it is 5-80 weight part, More preferably, it is 6-70 weight part.
Or although the said weight ratio is not restrict | limited, when the dosage form of the pharmaceutical composition of this invention is an internal use, (A) component is 1 weight part, (B) component is usually 0. 1 to 50 parts by weight, preferably 0.8 to 20 parts by weight, more preferably 2.5 to 5.5 parts by weight, and even more preferably 2.5 to 4.5 parts by weight. Usually, it is in the range of 0.01 to 1.4 parts by weight, preferably 0.02 to 1.2 parts by weight, more preferably 0.06 to 0.55 parts by weight, still more preferably 0.06 to 0. .45 parts by weight.

  As long as the effects of the present invention are sufficiently exerted, the pharmaceutical composition of the present invention can contain various other components (pharmacological activity) as necessary in addition to the components (A), (B), and (C). Components or bioactive ingredients) or can be used in combination with them. The type of such ingredients is not particularly limited, and for example, active ingredients in various pharmaceuticals described in the Pharmaceutical Manufacturing and Sales Guidelines separate volume General Occupational Drug Manufacturing and Sales Approval Standards 2012 (supervised by the Japan Society for Regulatory Science), for example, Histamine component, antiallergic component, parasympathetic blocking component, sympathomimetic component, anti-inflammatory enzyme, antiplasmin component, antipyretic analgesic component, antitussive component, expectorant, mucosal protective component, xanthine derivative, herbal medicine, vitamins, etc. It can be illustrated. Specific examples include the following components and possible pharmaceutically acceptable salts thereof, but are not limited to these components. In addition, the compounding quantity of these components is suitably selected according to the kind of formulation, the kind of active ingredient, etc.

  Antihistamine component or antiallergic component: istipendil, iproheptin, dipheterol, diphenylpyralin, diphenhydramine, triprolidine, tripelenamine, tondilamine, promethazine, methozirazine, carbinoxamine, alimemazine, chlorpheniramine, mequitazine, loratadine, chinadastine, chinadastine, chinadastin, Ketotifen, sodium cromoglycate, amlexanox, tranilast, pemirolast potassium, olopatadine, oxatomide, ebastine, cetirizine, levocetirizine, bepotastine and the like.

  Parasympathetic nerve blocking components: atropine, scopolamine, belladonna total alkaloid, belladonna extract, iodopropamide iodide, datsura extract, funnel extract, etc.

  Sympathomimetic components: methylephedrine, pseudoephedrine, phenylephrine, phenylpropanolamine, ephedrine, ethylephrine, methoxamine, middolin, methoxyphenamine and the like.

  Anti-inflammatory enzymes: lysozyme, serrapeptase, bromelain, pronase, etc.

  Antiplasmin component: tranexamic acid.

  Antipyretic analgesic ingredients: aspirin, acetaminophen, ethenamide, sazapyrine, salicylamide, salicylic acid, lactylphenetidine, ibuprofen, ketoprofen, thiaramide, aluminoprofen, loxoprofen, etc.

  Antitussive ingredients: achloramide, cloperastine, pentoxyberine (carbetapentane), tipepidine, dibutate, dextromethorphan, codeine, dihydrocodeine, noscapine, etc.

  Expectorants: potassium guaiacol sulfonate, guaifenesin, etc.

  Mucosal protective components: aminoacetic acid, dry aluminum hydroxide gel, aluminum-based mucosal protective agent such as dihydroxyaluminum aminoacetate, magnesium metasilicate, aluminum silicate, hydrotalcite, magnesium aluminate hydroxide, aluminum hydroxide gel , Aluminum hydroxide / sodium bicarbonate coprecipitation product, aluminum hydroxide / magnesium carbonate mixed dry gel, aluminum hydroxide / calcium carbonate / magnesium carbonate coprecipitation product, magnesium carbonate, magnesium oxide, magnesium hydroxide, silica Magnesium-based mucosal protective agents such as coprecipitation products of magnesium oxide, magnesium hydroxide and potassium aluminum sulfate.

  Xanthine derivatives: caffeine, theophylline, aminophylline, theobromine, diprofeline, proxyphylline, pentoxifylline and the like.

  Herbal medicine and herbal medicine-derived ingredients: shrimp, licorice, carrot, mao, keihi, kei-gai, saishin, shinii, nantenjitsu, hakuji, juniper, zenko, kyoto, shazenshi, goo, gadget, peafowl, gentian, gentian, fennel, onji, Awaku, Auren, Chikutsujinjin, Chimpi, Clove, Senega, Shazenso, Shajin, Glycyrrhizic acid, etc.

  Vitamins: B vitamins (eg, thiamine, thiamine disulfide, dicetiamine, octothiamine, chicotiamine, bisbutiamine, bisbentiamine, prosultiamine, benfotiamine, fursultiamine, riboflavin, flavin adenine dinucleotide, Vitamin Cs (for example, ascorbic acid, erythorbic acid, or derivatives thereof), other vitamins (for example, hesperidin) and the like.

  These components may be free forms or salts.

  Among them, for example, in the case of an internal medicine for rhinitis, at least one or more selected from belladonna total alkaloid, belladonna extract, iodopropamide, methylephedrine, pseudoephedrine, phenylephrine, lysozyme, glycyrrhizic acid, caffeine and salts thereof are preferable. It can be used suitably.

  For the pharmaceutical composition of the present invention, various dosage forms that can be applied to the efficacy of fexofenadine can be selected. For example, as internal preparations, tablets [including orally disintegrating tablets, chewable tablets (chewable tablets), effervescent tablets, dispersible tablets, dissolving tablets, film-coated tablets, uncoated tablets, dragees, etc.], capsules [hard capsules and Including soft capsules, etc.], granules [including effervescent granules], powders, powders, fine granules, pills, oral tablets [troches, sublingual tablets, buccal tablets, adhesive tablets, gums, etc. Solid agents such as film agents, dry syrup agents, jelly agents, semisolid oral preparations, confectionery agents [including candy (gummy), gummi agents, nougat agents, etc.], and other liquid agents [elixirs] Preparations, suspensions, emulsions and limonades, etc.], syrups [including syrup preparations], eye drops, eye ointments, etc. (including eye drops that can be applied while wearing contact lenses) Nasal drops [nasal powders and spots Liquid preparations, etc.], solid preparations for external use [including powders for external use], ointments, creams, gels, patches [including tapes and poultices], liquids for external use [liniments and lotions, etc.] And the like, and spray preparations [including aerosols for external use, pump sprays and the like] and the like.

In the pharmaceutical composition of the present invention, various preparation additives are contained in accordance with the preparation to be applied. For example, in internal use, excipients, disintegrants, disintegration aids, binders, lubricants, fluidizers, buffers, sustaining agents, stabilizing agents, antioxidants, reducing agents, cooling agents Agent, sweetener, flavoring agent, fragrance, colorant, surfactant, plasticizer, solubilizing agent, suspending agent, dispersing agent, emulsifier, solubilizing agent, brightening agent, coating agent, etc. Can be included.
In addition, content of these additives is not specifically limited, It can set arbitrarily.

  In the present invention, “stability” and “stabilization” mainly mean light stability and stabilization, for example, light stability and stabilization against light such as white fluorescent lamps and sunlight. .

  If the pharmaceutical composition of this invention contains (A) component, (B) component, and (C) component, there will be no limitation in particular in the mixing | blending order, a preparation method, etc. according to a method well-known to those skilled in the art. Can be prepared.

  Specifically, when the pharmaceutical composition of the present invention is a solid preparation, for example, the above ingredients, and optionally, other pharmacologically active ingredients, physiologically active ingredients, and raw materials containing additives are granulated (for example, dry granulation). , Extrusion granulation, fluidized bed granulation, kneading granulation, spray drying granulation, etc.) to produce granules. The granule may be a single granule containing the component (A), the component (B) and the component (C), or a combination of two or more types of granules having different compositions, and a granule containing the component (A) (B) You may combine with the granule containing a component to make a granule. Moreover, a hard capsule or a tablet can be produced by using this granule by an ordinary method. In addition, for example, after each component is suspended in an appropriate amount of a base material, a soft capsule can be produced by an ordinary method. Here, it is preferable to employ a method in which the respective components are sufficiently mixed.

  In addition, when the pharmaceutical composition of the present invention is a solution or a jelly agent, for example, (A) component, (B) component, (C) component, and other pharmacologically active components, physiologically active components, and additives as necessary. After the raw material to be dissolved is dissolved with an appropriate amount of purified water, the pH is usually adjusted to 2.5 to 9.0, and then the remaining purified water is added to adjust the volume, whereby a liquid agent can be produced. Further, if necessary, it can be filtered and sterilized, and filled into a container. Here, it is preferable to employ a method in which the components are sufficiently mixed. In addition, there is no limitation in particular in the capacity | capacitance and viscosity of this liquid agent, According to a well-known method, processes, such as dilution and concentration, may be performed. Moreover, it is good also as an on-use preparation type liquid agent which melt | dissolves the raw material mixture of the said liquid agent at the time of use, and makes it liquid state.

The container for filling the pharmaceutical composition of the present invention may be any one that uses a material that can be used for a general container in the field, such as a resin material, a glass material, and a metal material. It can be appropriately selected and used depending on the purpose and application.
Since the pharmaceutical composition of the present invention has high photostability, a highly transparent container can be selected.

The pharmaceutical composition of the present invention is useful not only as a single-use type packaging form, but also as a multi-dose pharmaceutical composition that is packaged in a form to be administered multiple times and used continuously by the user.
The pharmaceutical composition of the present invention has high photostability, and even if the light-shielding property of the product is reduced by opening the package, it can suppress a decrease in the content of fexofenadine. It is.

  The pharmaceutical composition of the present invention is, for example, a pharmaceutical, a quasi-drug, a food, or a raw material thereof [for example, a pharmaceutical preparation, a quasi-drug formulation, a food for specified health use, a nutritional functional food, a food for the elderly, a special use Food, functional food, health supplement (supplement), food preparation (eg, confectionery tablet)].

  The pharmaceutical composition of the present invention can be used without particular limitation depending on its form. For example, in the case of a composition for internal use, any disease for which (A) fexofenadine hydrochloride, (B) a sugar alcohol and / or saccharide, and (C) a terpenoid compound, or a combination thereof is desired In particular, it is useful as an internal medicine for rhinitis and as an antiallergic agent. Specifically, acute rhinitis, allergic rhinitis or sinusitis, as well as relief of the following symptoms by pollen and house dust (indoor dust) (sneezing, nasal drip [excessive nasal discharge], nasal congestion, sneezing, Can be used suitably for applications such as pruritus, rhinitis, bronchodilation associated with any pain, headache [heavy head]), hives, skin disease (eczema / dermatitis, cutaneous pruritus, atopic dermatitis) .

The dosage of the pharmaceutical composition of the present invention is appropriately set according to the form, administration method, purpose of administration and the age, weight and symptom of the subject of administration of the composition, and is not constant, for example, as an internal medicine for rhinitis When taken orally, the daily dose for adults is usually about 60 to 180 mg of component (A), about 25 to 3000 mg of component (B), and about 3 to 80 mg of component (C).
The pharmaceutical composition of the present invention can be administered in the same manner as a normal pharmaceutical composition, and may be performed once or divided into several times within a desired dose range, It may be administered before meals, between meals, after meals, or simultaneously with meals. In addition, the term “administration” in the present specification is intended to encompass “take”, and the term “internal use” in the present specification may be used interchangeably with “oral administration”.

  Further, the present invention stabilizes fexofenadine or a pharmaceutically acceptable salt thereof by containing a sugar alcohol and / or a saccharide and a terpenoid compound. Provided is a stability improving agent for fexofenadine hydrochloride characterized by containing a sugar alcohol and / or a saccharide and a terpenoid compound because the action is more effectively exhibited.

  The stability improver of the present invention is not particularly limited as long as it contains a sugar alcohol and / or a saccharide and a terpenoid compound, and the content, types of ingredients added and blended, preparation methods, forms, etc. This is the same as the pharmaceutical composition of the present invention.

  Furthermore, by adding (B) a sugar alcohol and / or saccharide and (C) a terpenoid compound to a pharmaceutical composition containing (A) fexofenadine or a pharmaceutically acceptable salt thereof, Since the stability of phenazine hydrochloride is improved, the present invention stabilizes a pharmaceutical composition containing fexofenadine hydrochloride, characterized in that it contains a sugar alcohol and / or a saccharide, and a terpenoid compound. Provide a method.

  As a method for stabilizing a pharmaceutical composition, specifically, (A) fexofenadine hydrochloride is contained in the pharmaceutical composition together with (B) a sugar alcohol and / or saccharide, and (C) a terpenoid compound. As long as the component (B) and the component (C) are present around the component (A), there is no particular limitation.

  In the method for stabilizing a pharmaceutical composition, the components (A), (B), and (C) may be blended simultaneously or separately, and the order thereof is not particularly limited. Considering the decomposition of the component (A), it is preferable that there is no difference in the blending time of the component (A), the component (B), and the component (C). In addition, in these methods, the types of (A) component, (B) component, and (C) component to be used, their contents, and their content ratios, the types of components added and blended, and the preparation method The use, formulation form, administration target and the like are the same as those of the pharmaceutical composition of the present invention.

Light stability tests were performed on various test samples of fexofenadine hydrochloride. Specifically, various test samples are set under severe conditions, that is, a light resistance test apparatus (SUNTESTER XF-180CPS manufactured by Shimadzu Corporation), and white light of 765 W / m ² (sunlight on a midsummer day at 12:00 to 14:00) The residual ratio of fexofenadine hydrochloride was evaluated when irradiated for 24 hours (corresponding to the intensity) (accumulated dose: 60,000 kJ / m ² ).

分析条件
検出器：紫外線吸光光度法（波長２２０ｎｍ）
カラム：Inertsil Ph ５μｍ（GL Sciences INC.）
内径４．６ｍｍ、長さ１５０ｍｍ、粒子径５μｍ
カラム温度：２５℃付近の一定温度
移動相：リン酸二水素ナトリウム二水和物７．５１ｇ及び過塩素酸ナトリウム０．８４ｇを水１０００ｍＬに溶かし、リン酸を加えてｐＨ２．０に調整した液６５０ｍＬにアセトニトリル３５０ｍＬ及びトリエチルアミン３ｍＬを加えた液 Test example 1
(1) Test method Each component described in Table 1 below was mixed according to the prescription, prepared as a powder in a transparent plastic petri dish (35 mm × 10 mm dish), and the edge of the petri dish was covered with parafilm to prepare a test sample. This test sample was set in a light resistance test apparatus (SUNTESTER XF-180CPS manufactured by Shimadzu Corporation) and irradiated for 24 hours with white light of 765 W / m ² (equivalent to sunlight intensity at noon from 12 to 14 o'clock on a summer day). The irradiation rate was 60,000 kJ / m ² ), the residual ratio of fexofenadine hydrochloride was determined, and the stability was evaluated.
The residual rate of fexofenadine hydrochloride was calculated by the following formula after obtaining the content of fexofenadine hydrochloride by liquid chromatography.

Analysis conditions Detector: UV absorption photometry (wavelength 220 nm)
Column: Inertsil Ph 5 μm (GL Sciences INC.)
Inner diameter 4.6 mm, length 150 mm, particle diameter 5 μm
Column temperature: A constant temperature around 25 ° C. Mobile phase: A solution prepared by dissolving 7.51 g of sodium dihydrogen phosphate dihydrate and 0.84 g of sodium perchlorate in 1000 mL of water and adjusting the pH to 2.0 by adding phosphoric acid. A solution obtained by adding 350 mL of acetonitrile and 3 mL of triethylamine to 650 mL

(2) Test results The results are shown in Table 1 and summarized in FIG.
When irradiated with white light of 765 W / m ² for 24 hours (accumulated dose of 60,000 kJ / m ² ), the residual rate in the powder (comparative example 1) consisting only of fexofenadine hydrochloride was 92.4%. The decrease in the content of fexofenadine hydrochloride by light was observed by 7% or more. On the other hand, in the powders (Comparative Examples 2 and 5) in which D-mannitol or lactose was blended with fexofenadine hydrochloride, the residual ratios of fexofenadine hydrochloride were 89.7% and 90.9%, which were those of Comparative Example 1. As a result, the stability was further lowered, and it was suggested that sugar alcohols typified by D-mannitol and saccharides typified by lactose destabilize fexofenadine. Further, the residual ratio of fexofenadine hydrochloride in the powder (Comparative Examples 3 and 4) in which l-menthol was blended with fexofenadine hydrochloride was 89.5 to 91.6%, and the stability thereof was that of Comparative Example 1. The result decreased to the same level as or below.
On the other hand, in the powder which mix | blended D-mannitol or lactose and 1-menthol in combination with fexofenadine hydrochloride (Examples 1-4), when each additive is mix | blended separately (Comparative Examples 2-5) Unlike the case of Comparative Example 1, it was observed that the remaining ratio of fexofenadine hydrochloride was improved. That is, surprisingly, it was confirmed that the photostability of fexofenadine was improved only by combining them. In addition, even if it changed the compounding ratio of (B) component and (C) component with respect to (A) component, the effect was recognized similarly (Example 5).

Test example 2
In order to confirm whether sugar alcohols other than D-mannitol can achieve the same effects as in Test Example 1, the following tests were performed using xylitol as the sugar alcohol.
(1) Test Method Each component described in Table 2 below was mixed according to the formulation, and the same test as in Test Example 1 was performed. The preparation of each test sample and the photostability test were performed separately from Test Example 1 on different days.

(2) Test results The results are summarized in Table 2.
In the powder (comparative example 6) which mix | blended xylitol with fexofenadine hydrochloride, compared with the residual rate of the powder (control) which consists only of fexofenadine hydrochloride, it is not as much as the case of D-mannitol of test example 1. However, a decrease in stability was also confirmed.
On the other hand, in the powder containing xylitol and l-menthol in combination with fexofenadine hydrochloride (Example 6), it was compared with the powder containing xylitol in fexofenadine hydrochloride (Comparative Example 6). The residual ratio of phenazine hydrochloride was improved by 3.1%.

As described above, from the results of Test Examples 1 and 2, fexofenadine is mixed with sugar alcohols such as D-mannitol and xylitol, sugars including lactose, and terpenoid compounds (1-menthol). As a result, a remarkable effect of suppressing the decrease in the residual rate of fexofenadine was observed, that is, it was confirmed that the composition was stable.
Although D-mannitol, lactose, and the like are components necessary for imparting the shape of solid preparations such as tablets, it has been suggested that they are more unstable to light when combined with fexofenadine hydrochloride. It was revealed that stability can be improved by blending with terpenoid compounds such as l-menthol.

Examples of formulation preparation are given below.
Formulation Examples 1-13
About the formulation example of Table 3, a tablet is manufactured using a well-known technique.

Formulation Examples 14-65
About the formulation example of Table 3, a powder (formulation example 14-26) or a granule (formulation example 27-39) is manufactured using a well-known technique.
The obtained powder or granule is filled into a hard capsule using a known technique to produce a hard capsule (Formulation Examples 40 to 65).

Claims (1)

A pharmaceutical composition comprising (A) fexofenadine or a pharmaceutically acceptable salt thereof, (B) a sugar alcohol and / or saccharide, and (C) dl-menthol and / or l-menthol , A pharmaceutical composition wherein the component (A) and the component (C) are 0.01 to 0.55 parts by weight of the component (C) with respect to 1 part by weight of the component (A) .

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