Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
  • A61K31/05—Phenols
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/16—Amides, e.g. hydroxamic acids
  • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
  • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/4164—1,3-Diazoles
  • A61K31/4166—1,3-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. phenytoin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
  • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
  • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
  • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
  • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
  • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• the present invention relates to a pharmaceutical composition containing betamethasone valerate. More specifically, the present invention relates to a pharmaceutical preparation containing betamethasone valerate as an anti-inflammatory agent. The present invention also relates to a new use of betamethasone valerate, which is an anti-inflammatory agent.
• corticosteroids are effective in improving symptoms such as itching, redness, and swelling of the skin with inflammation, and eczema (including eczema due to atopic dermatitis; the same applies hereinafter) and itching (sweat, buds). It includes pruritus caused by measles, rashes, insect bites, etc. The same shall apply hereinafter), and is widely used for the treatment of dermatitis, psoriasis, and the like.
• An object of the present invention is to provide a betamethasone valerate-containing pharmaceutical composition having good pharmaceutical stability. Another object of the present invention is to provide a new use of betamethasone valerate in terms of improving pharmaceutical stability.
• the present inventors have conducted extensive studies in designing an external preparation, and as a result, allantoin, glycyrrhetinic acid, isopropylmethylphenol, and lidocaine, which are generally used as active ingredients, have significantly changed in color tone after long-term storage. , It was found that coloring occurs.
• corticosteroids esteerified steroids
• betamethasone valerate has been confirmed to have low color change even when stored in a solid state for a long period of time. It has been found that by combining at least one of the acid and isopropylmethylphenol with betamethasone valerate, the color change of allantin and the like is significantly suppressed.
• lidocaine does not suppress the color change when used in combination with betamethasone valerate, but the color change is significantly suppressed when used in combination with betamethasone valerate and the above-mentioned allantoin. ..
• the present invention has been completed by repeating further improvements based on these findings, and includes the following embodiments.
• compositions (I-1) (A) Betamethasone valerate and (B) A pharmaceutical composition containing allantoin, glycyrrhetinic acid and a salt thereof, and at least one selected from the group consisting of isopropylmethylphenol.
• II-2) The pharmaceutical composition according to (I-1), which further contains (C) lidocaine or a salt thereof.
• III The pharmaceutical composition according to (I-1) or (I-2), which further contains (D) an external base.
• I-4) The pharmaceutical composition according to any one of (I-1) to (I-3), which is an external preparation for skin.
• betamethasone valerate-containing pharmaceutical composition having good pharmaceutical stability. More specifically, according to the present invention, it is possible to provide a color change-resistant betamethasone valerate-containing pharmaceutical composition characterized in that the color tone change that occurs over time is significantly suppressed.
• betamethasone valerate in a pharmaceutical composition. More specifically, according to the present invention, the color change of allantoin, glycyrrhetinic acid or a salt thereof, isopropylmethylphenol, or lidocaine that occurs over time can be significantly suppressed by the combined use of betamethasone valerate. It will be possible.
• the pharmaceutical composition of the present invention contains the following components (A) and (B).
• the present pharmaceutical composition may contain the following component (C) in addition to the above components (A) and (B).
• present pharmaceutical composition may contain the following component (D) in addition to the above-mentioned components (A) and (B) or the above-mentioned components (A) to (C).
• component (D) External base.
• the component betamethasone valerate is an esterified steroid in which the hydroxyl group at the 17-position is valeryrylized and the hydroxyl group at the 21-position is acetylated.
• the compound is a strong steroid with anti-inflammatory activity and is known to have the following indications: Eczema / dermatitis group (including progressive finger palmar keratoderma, female facial lichen planus, Vidal lichen, radiation dermatitis, sunlight dermatitis), dermatitis, pruritus group (lichen-like lichen, strophulus) , Including fixed urticaria), insect bites, psoriasis, palmoplantar pustulosis, lichen planus, glossy lichen planus, pore red erythema, gibelbara erythema, erythema (polymorphic exudative erythema, nodule) Erythema, Darier efferent ring erythema), erythema (including erythema due to malignant lymphoma), chronic discoid erythematosus, drug eczema / toxic eczema, circular
• the amount of the component (A) contained in the pharmaceutical composition may be an amount that exerts a desired medicinal effect without interfering with the effects of the present invention, and can be appropriately set and adjusted within that range.
• the present pharmaceutical composition is prepared as an external preparation (pharmaceutical preparation) for improving skin diseases (eg, eczema, prurigo, dermatitis, psoriasis, etc.) having symptoms such as itching, redness or swelling of the skin with inflammation.
• the content of the component (A) in the present pharmaceutical composition can be exemplified in the range of 0.0002 to 10% by mass. It is preferably 0.002 to 2% by mass, and more preferably 0.01 to 0.3% by mass.
• the ingredient (B) is at least one selected from the group consisting of allantoin, glycyrrhetinic acid and salts thereof, and isopropylmethylphenol.
• each of these components (B) is a component that is widely used as a medicinal component of an external preparation. These may be used alone or in combination with the component (A), or may be used in combination with the component (A) in any combination of two or more.
• a preferred combination is an embodiment in which all three types of the component (B) (allantoin, glycyrrhetinic acid or a salt thereof, and isopropylmethylphenol) are combined and used in combination with the component (A).
• the allantoin targeted by the present invention includes diureide of glyoxylic acid (also known as 5-ureidohydantoin, glyoxydiureide) and derivatives thereof, allantoinacetyl-DL-methionine, allantoindihydroxyaluminum, or allantoin polygalacturonic acid. Is included. Glyoxylic acid diureide is preferable.
• Known actions of allantoin include a keratinocyte proliferation promoting action, an antistimulant action, an anti-inflammatory sedative action, and an antiallergic action. In addition, allantoin exerts a wound healing action and a tissue repair activating action based on the keratinocyte proliferation promoting action.
• the amount of allantoin contained in the pharmaceutical composition may be an amount that exerts a desired medicinal effect without interfering with the effects of the present invention, and can be appropriately set and adjusted within that range.
• the present pharmaceutical composition is prepared as an external preparation (pharmaceutical preparation) for improving skin diseases (eg, eczema, prurigo, dermatitis, psoriasis, etc.) having symptoms such as itching, redness or swelling of the skin with inflammation.
• the content of psoriasis in the pharmaceutical composition can be exemplified in the range of 0.01 to 20% by mass. It is preferably 0.1 to 10% by mass, and more preferably 0.15 to 5% by mass.
• Glycyrrhetinic acid is known to have anti-inflammatory action, antipruritic action, mast cell degranulation inhibitory action, and phospholipase A2 inhibitory action, and is used for the treatment of eczema, pruritus dermatitis, and neurodermatitis.
• glycyrrhetinic acid ⁇ -glycyrrhetinic acid can be preferably mentioned.
• the salt of glycyrrhetinic acid is a pharmaceutically acceptable salt, and examples thereof include alkali metal salts such as potassium and sodium, and ammonium salts.
• the amount of glycyrrhetinic acid or a salt thereof contained in the pharmaceutical composition may be an amount that exerts a desired medicinal effect without interfering with the effects of the present invention, and can be appropriately set and adjusted within that range.
• the present pharmaceutical composition is prepared as an external preparation (pharmaceutical preparation) for improving skin diseases (eg, eczema, prurigo, dermatitis, psoriasis, etc.) having symptoms such as itching, redness or swelling of the skin with inflammation.
• the content of glycyrrhetinic acid or a salt thereof in the present pharmaceutical composition can be exemplified in the range of 0.01 to 20% by mass. It is preferably 0.02 to 10% by mass, and more preferably 0.05 to 5% by mass.
• Isopropylmethylphenol (hereinafter, simply referred to as "IPMP") is an isomer of thymol and is a compound having an acicular crystal form with a chemical name of 3-methyl-4-isopropylphenol. It has a wide range of antibacterial and antifungal spectrum (O-157, MRSA, Seratia, tinea bacillus, etc.), exerts a bactericidal effect against various bacteria, yeasts, and molds, and has low odor, low taste, and low taste. Due to its irritating and non-sensitizing properties, it is widely used as a bactericidal, antibacterial or preservative in pharmaceuticals and non-pharmaceutical products, as well as in cosmetics and daily necessities.
• the amount of IPMP contained in the pharmaceutical composition may be an amount that exerts a desired medicinal effect without interfering with the effects of the present invention, and can be appropriately set and adjusted within that range.
• the present pharmaceutical composition is prepared as an external preparation (pharmaceutical preparation) for improving skin diseases (eg, eczema, prurigo, dermatitis, psoriasis, etc.) having symptoms such as itching, redness or swelling of the skin with inflammation.
• the content of IPMP in the present pharmaceutical composition can be exemplified in the range of 0.01 to 20% by mass. It is preferably 0.02 to 10% by mass, and more preferably 0.05 to 5% by mass.
• these components (B) have a characteristic that the color tone changes with time and the storage stability is low.
• This characteristic color tone change, colorability
• the compounding ratio (mass ratio) of the component (A) and the component (B) in the pharmaceutical composition is not limited as long as the effects of the present invention (color resistance, color tone change resistance, color resistance) can be obtained.
• the ratio of the component (B) to 100 parts by mass of the component (A) is 10 to 10000 parts by mass, preferably 30 to 5000 parts by mass, and more preferably 50 to 3000 parts by mass;
• the ratio of the component (B) to 100 parts by mass of the component (A) is 10 to 10000 parts by mass, preferably 30 to 5000 parts by mass, and more preferably 50 to 3000 parts by mass.
• the ratio of the component (B) to 100 parts by mass of the component (A) is 1 to 10000 parts by mass, preferably 10 to 5000 parts by mass, and more preferably 20 to 2000 parts by mass of the component (B).
• Mass part; Etc. can be exemplified.
• the component lidocaine (2-dimethylamino-N- (2,6-dimethylphenyl) acetamide) (C) is a compound widely used as a highly safe local anesthetic.
• the lidocaine salt are pharmaceutically acceptable salts, and examples thereof include hydrochlorides, carbonates, and sulfates.
• lidocaine hydrochloride can be preferably mentioned.
• the amount of the component (C) contained in the pharmaceutical composition may be an amount that exerts a desired medicinal effect without interfering with the effects of the present invention, and can be appropriately set and adjusted within that range.
• the present pharmaceutical composition is prepared as an external preparation (pharmaceutical preparation) for improving skin diseases (eg, eczema, prurigo, dermatitis, psoriasis, etc.) having symptoms such as itching, redness or swelling of the skin with inflammation.
• the content of the component (C) in the present pharmaceutical composition can be exemplified in the range of 0.005 to 30% by mass. It is preferably 0.05 to 10% by mass, and more preferably 0.1 to 5% by mass.
• the component (C) has a characteristic that the color tone changes with time and the storage stability is low. This characteristic (color tone change, colorability) is improved by mixing the above-mentioned components (A) and (B) and keeping the component (C) in a coexisting state of the component (A) and the component (B). be able to.
• the component (B) to be used is not limited, and any of the above-mentioned three types can be used.
• the component (B) one kind alone, two or more kinds, or all three kinds can be used in combination. It is preferably allantoin, and even when two or more kinds are combined, it is preferable to include allantoin in at least one kind.
• the compounding ratio (mass ratio) of the component (A), the component (B), and the component (C) in the pharmaceutical composition is limited to the effect of the present invention (color resistance, color change resistance, color resistance). , Not limited.
• the ratio of the component (C) to 100 parts by mass of the component (A) 10 to 10000 parts by mass, preferably 30 to 8000 parts by mass, and more preferably 50 to 5000 parts by mass can be mentioned.
• the compounding ratio (mass ratio) of the component (A) and the component (B) when the component (C) is combined the above-mentioned ratio can be adopted.
• the pharmaceutical composition can be prepared as an external preparation by mixing the above-mentioned ingredients (A) and (B) or ingredients (A) to (C) together with (D) an external base. .. More preferably, it is an external preparation for skin.
• the dosage form of the external preparation is not limited, and may be either a liquid form or a solid form.
• the solid state targeted by the present invention means that it is not liquid, and includes those in a semi-solid state.
• Examples of external preparations include, but are not limited to, liquid preparations (including lotions, emulsions, and aerosols), sticks, creams, ointments, plasters, gels, poultices, and powders. .. It is preferably a solid pharmaceutical composition such as a cream, ointment, or gel.
• a conventional external base can be used depending on the shape (dosage form) of the present pharmaceutical composition. It is not limited as long as it is normally used in the manufacture of pharmaceuticals or quasi-drugs.
• oils such as white vaseline, cetanol, beeswax, lanolin, paraffin, and liquid paraffin; natural rubber, isoprene rubber, polyisobutylene, and styrene-isoprene.
• -Sterene block copolymer styrene-butadiene-styrene block copolymer, styrene-ethylene / butylene-styrene block copolymer, (meth) acrylic acid alkyl ester (co) polymer, poly (meth) acrylic acid ester, Rubbers such as (meth) acrylic acid ester, polyisobutylene, polybutene, liquid polyisoprene; water-soluble polymers such as carboxyvinyl polymer, starch acrylate, sodium polyacrylate, sodium carmellose; glycerin; macrogol; An acid or the like can be exemplified.
• excipients for example, sugars such as sucrose; starch derivatives such as dextrin; cellulose derivatives such as carmellose sodium; water-soluble polymers such as xanthan gum
• excipients for example, sugars such as sucrose; starch derivatives such as dextrin; cellulose derivatives such as carmellose sodium; water-soluble polymers such as xanthan gum
• the content of the component (D) in the pharmaceutical composition can be exemplified in the range of 0 to 99.999% by mass. It is preferably 5 to 99.9% by mass, and more preferably 10 to 99.9% by mass.
• any pharmacologically active ingredient in addition to the above-mentioned ingredients (A) and (B), or ingredients (A) to (C), the pharmaceutical composition may contain, as long as it does not interfere with the effects of the present invention. , And other pharmacologically active ingredients may be contained.
• Non-steroidal anti-inflammatory drugs, local anesthetics, antipruritic agents, blood circulation promoters, fungicides, skin protectants, antibiotics, moisturizers, and / or refreshing agents can be exemplified, but not limited.
• compositions of the present invention may be used for skin diseases (eg, eczema) having symptoms such as itching, redness or swelling of the skin with inflammation. , Itching, dermatitis, psoriasis, etc.)
• skin diseases eg, eczema
• the ingredient can be blended in the external preparation.
• the present pharmaceutical composition at least the component (A) and the component (B) among the above-mentioned components are mixed with the component (D) as necessary, and an external preparation, preferably a cream preparation, is prepared according to a conventional manufacturing method. Alternatively, it can be produced in the form of a solid external preparation such as an ointment.
• an external preparation preferably a cream preparation
• the present pharmaceutical composition is a composition further containing the component (C)
• the components (A) to (C) are mixed with the component (D) as necessary and applied externally according to a conventional manufacturing method.
• Manufactured in the form of agents preferably solid external preparations such as creams or ointments.
• the pharmaceutical composition thus prepared in the form of an external preparation improves skin diseases having symptoms such as itching, redness or swelling of the skin with inflammation (for example, eczema, prurigo, dermatitis or psoriasis). It can be suitably used as an external preparation (pharmaceutical preparation).
• the application is not limited and can be widely used on the skin in general, such as hands, feet, fingers, face, head, and body. It can also be applied to areas with thin skin such as the anus and the area around the genital area.
• the amount and usage of these substances on the skin are not particularly limited, and they should be used by applying an appropriate amount to the outer skin such as the skin once to several times a day depending on the symptoms of the affected area and the content of the active ingredient. Can be done.
• the present invention is a method for improving the stability of a pharmaceutical composition containing the above-mentioned component (B) or a pharmaceutical composition containing the above-mentioned component (C).
• I will provide a.
• both the components (B) and (C) described above have low color tone stability, and a pharmaceutical composition containing one or more of them tends to change color (color tone change) with time. Is recognized.
• the change in color tone of the pharmaceutical composition containing the component (B) can be improved by coexisting the above-mentioned component (A) in the pharmaceutical composition.
• the pharmaceutical composition may contain the component (C). Further, the color tone change of the pharmaceutical composition containing the component (C) can be improved by coexisting the above-mentioned component (A) and component (B) in the pharmaceutical composition in combination.
• the "improvement of stability of a pharmaceutical composition” which is the subject of the present invention, preferably includes suppressing the color change caused by the component (B) and / and the component (C) of the pharmaceutical composition. ..
• the pharmaceutical composition containing the component (B) and the component (A) has less change in color tone over time as compared with the pharmaceutical composition containing the component (B) not containing the component (A)
• the former pharmaceutical composition is used. It can be judged that the color tone change caused by the component (B) is suppressed by the blending of the component (A) and the stability is improved.
• the pharmaceutical composition containing the component (C), the component (A) and the component (B) is compared with the pharmaceutical composition containing the component (C) which does not contain the component (A) and the component (B).
• the former pharmaceutical composition suppresses the color tone change caused by the component (C) by blending the component (A) and the component (B), and the stability is improved. It can be judged that there is.
• the pharmaceutical composition to be measured was stored in a dark place at 40 ° C. and 75% constant temperature and humidity for 4 weeks, and the color difference before and after storage was measured with a chromaticity meter, and the degree of the color difference was measured. Can be evaluated by comparing. For details, the description of the experimental example described later can be referred to.
• the component (B) may include at least one selected from the group consisting of the above-mentioned allantoin, glycyrrhetinic acid and salts thereof, and IPMP. These may be individually blended in the pharmaceutical composition, or two or more thereof may be arbitrarily combined and blended in the pharmaceutical composition. Preferably, it is a pharmaceutical composition in which all three types are blended.
• the method for coexisting the component (A) with this is not limited as long as it is a method for obtaining the effect of the present invention.
• a method of mixing the component (B) and the component (A) may be used, or the component (B) and the component (A) may be mixed together with at least the above-mentioned component (D) to form (B).
• a method of forming a coexistence state of the component (A) and the component (A) may be used.
• the component (C) can be blended as another component. After mixing each of these components to form a coexistence state of at least the component (B) and the component (A), if necessary, a cream, an ointment, a gel, a plaster, etc. It can also be prepared in the form of a conventional solid preparation of.
• the ratio of the component (B) to the component (A), the compounding ratio, and the like in the pharmaceutical composition are as described in (I) above, and the description can be incorporated herein by reference.
• the component (C) is the above-mentioned lidocaine or a salt thereof.
• the method for coexisting the component (A) and the component (B) is not limited as long as the method can obtain the effect of the present invention.
• the component (B) any one of the above may be used, or two or more of them may be used in any combination.
• the component (B) is preferably allantoin, and even when two or more kinds are arbitrarily combined, it is preferable to use at least one kind of allantoin.
• the method for coexisting the component (A) and the component (B) in the component (C) is not limited, but the method for mixing the components (A) to (C) and at least the above-mentioned component (D) are combined with the method.
• a method may be used in which the components (A) to (C) are mixed to form a coexistence state of the component (C), the component (A) and the component (B).
• the ratios of the components (C), (A) and (B) in the pharmaceutical composition, the blending ratios thereof, etc. are as described in (I) above, and the description may be incorporated herein by reference. can.
• Betamethasone valerate Sicor Glycyrrhetinic acid: Alps Pharmaceutical Industry Co., Ltd. Allantoin: Hokudai Trading Co., Ltd. Isopropylmethylphenol: Osaka Kasei Co., Ltd. Lidocaine: Nippon Bulk Pharmaceutical Co., Ltd. White petrolatum: CALMET Liquid paraffin: SONNEBORN
• Method for measuring color tone of pharmaceutical composition 3 g of the pharmaceutical composition (test composition) to be measured is spread thinly over the entire petri dish with a diameter of 10 cm, set, and at 40 ° C. without a lid. , 75% RH for a predetermined period (4 weeks).
• the test compositions before and after storage are placed in a measurement cell ( ⁇ 30 mm cell) of a spectrocolorimeter, and the brightness (L) and color difference (a, b) are measured under the following conditions. The change in color tone was calculated as the color difference.
• NBS criteria color tone change inhibitory property, discoloration resistance
• Example 1 Preparation of pharmaceutical composition and evaluation of its stability
• (1) Experimental Method A solid pharmaceutical composition (Samples 1-1 to 1-7) was prepared according to the composition shown in Table 2. Specifically, in Samples 1-3, 1-5 and 1-7, the two components (A) and (B) are mixed in advance in a mortar, and the component (D) is mixed and mixed. Prepared in solid form (cream form). Samples 1-1, 1-2, 1-4 and 1-6 were prepared by mixing the component (A) or the component (B) with the component (D) to prepare a solid (creamy) pharmaceutical composition. ..
• Examples 1-1 to 1-7 A pharmaceutical composition (a pharmaceutical composition comprising (A) and / or (B)) before blending the components was carried out. Specifically, the color tone of each of the prepared pharmaceutical compositions (samples 1-i to 1-vii) was measured by the method described above, and then stored under the storage conditions described above for 4 weeks. After storage, the color tone was measured again to determine the difference (color difference) from the color tone before storage, and the stability (color resistance) of the pharmaceutical composition was evaluated according to the above criteria.
• the color tone measurement was performed for each of the above-mentioned pharmaceutical compositions (Samples 2-1 to 2-5).
• D) The pharmaceutical composition before blending the ingredients was carried out. Specifically, after measuring the color tone of each of the prepared pharmaceutical compositions (samples 2-i to 2-v), this was stored under the above-mentioned storage conditions for 4 weeks. After storage, the color tone was measured again to determine the difference (color difference) from the color tone before storage, and the stability (color resistance) of the pharmaceutical composition was evaluated according to the above criteria.
• Example 2-ii As shown in Table 3, it was confirmed that the component (C) had low stability (color resistance) and the color tone changed over time (Sample 2-ii). Moreover, even if the component (A) was combined with the component (C), the stability was not improved (Sample 2-iv). However, the stability (color resistance) of the component (C) was improved by further adding the component (B) to the component (C) in addition to the component (A) (Sample 2-v). .. Further, by further blending the component (B) in addition to the component (A) to the component (C), the stability (color resistance) of the component (B) is low at the same time (see Sample 2-iii). ), And it was confirmed that a pharmaceutical composition having good stability (color resistance) can be obtained.
• Table 4 shows an example of the formulation of a creamy pharmaceutical composition having good stability in which the change in color tone of the component (B) is suppressed.

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