WO2000041702A1 - Preparation steroide externe - Google Patents

Preparation steroide externe Download PDF

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Publication number
WO2000041702A1
WO2000041702A1 PCT/JP2000/000130 JP0000130W WO0041702A1 WO 2000041702 A1 WO2000041702 A1 WO 2000041702A1 JP 0000130 W JP0000130 W JP 0000130W WO 0041702 A1 WO0041702 A1 WO 0041702A1
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WO
WIPO (PCT)
Prior art keywords
ointment
steroid
castor oil
mass
propylene carbonate
Prior art date
Application number
PCT/JP2000/000130
Other languages
English (en)
Japanese (ja)
Inventor
Toru Nakamura
Yukiko Fujimaru
Shigeo Tanaka
Original Assignee
Taisho Pharmaceutical Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Taisho Pharmaceutical Co., Ltd. filed Critical Taisho Pharmaceutical Co., Ltd.
Priority to AU20036/00A priority Critical patent/AU2003600A/en
Publication of WO2000041702A1 publication Critical patent/WO2000041702A1/fr

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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
    • A61K31/56—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

Definitions

  • the present invention relates to a steroid external preparation containing a 21-alkoxy sulfide compound having a specific structure as an active ingredient, and more specifically, a 21-alkoxy compound having excellent dispersibility in a base and emulsion stability. It relates to topical steroid preparations. Further, the present invention relates to a steroid ointment. Background art
  • corticosteroids have been used as corticosteroids for the purpose of preventing, treating, and treating inflammatory skin diseases, asthma allergic diseases, and rheumatic diseases.
  • Such steroids have been variously developed according to the target disease.
  • Japanese Patent Application Laid-Open No. 3-68039 discloses a steroid having a strong anti-inflammatory effect upon topical administration.
  • 21-alkoxy sulfide compounds which are sulfide compounds.
  • methods for topical administration of steroid compounds include ointments, aqueous gels, mouthwashes, creams, powders, sprays, and tapes.
  • a steroid external preparation using an oily base is frequently used when the skin is wet or dry, and has the advantage of less irritation to the skin because white vaseline or the like is used as the base.
  • a cream using an emulsion base is often used when the lesion is moist on the skin, and has the advantage of having a beautiful appearance and being washable.
  • the choice of these topical steroid preparations depends not only on the above-mentioned safety and properties of the diseased site, but also on the view that the active ingredient exhibits its pharmacological action most effectively and is stable for a long period of time. Needed from the point.
  • 21 monoalkoxy steroid compounds are used for various clinical skin diseases such as acute eczema, chronic eczema, seborrheic eczema, atopic dermatitis, pediatric eczema, contact dermatitis, psoriasis vulgaris, etc. Can be used for treatment.
  • the present inventor found that propylene carbonate was blended with polyoxyethylene hydrogenated castor oil as a surfactant.
  • the present inventors have found that an ointment having extremely excellent solubility and drug release properties can be obtained, and have completed the present invention.
  • the present invention provides the following (1) to (8).
  • a 21-alkoxy sulfide compound represented by the formula (I) An external preparation for steroid containing propylene carbonate and polyoxyethylene hydrogenated castor oil.
  • R 1 represents an alkyl group having 1 to 4 carbon atoms or a methylthiomethyl group
  • R 2 represents an alkanol group having 2 to 7 carbon atoms
  • wavy lines represent Is shown.
  • a 21-alkoxy sulfide compound represented by the following formula (I) is dissolved in a liquid base containing propylene carbonate at a temperature of 40 to 100 ° C, and then cured with polyoxyethylene.
  • Solid base dissolved with castor oil Ointment obtained by mixing with an ointment base containing
  • the content of the 21-alkoxy sulfide compound is 0.01 to 1% by mass in the ointment
  • the propylene carbonate is 1 to 5% by mass in the ointment
  • the steroid ointment according to the above (6), wherein the ethylene-hardened castor oil is 0.01 to 3% by mass in the ointment.
  • a hardly soluble 21-alkoxy sulfide compound is used as a soluble form.
  • it is a steroid ointment that can provide excellent local anti-inflammatory activity even with a small amount.
  • propylene carbonate can be an extremely excellent dissolving agent, and that various surfactants can be used from the viewpoint of emulsion stability in an ointment base.
  • surfactants can be used from the viewpoint of emulsion stability in an ointment base.
  • the combination of the two not only provides excellent emulsion stability, but also provides rapid drug efficacy and sustained drug efficacy.
  • Such an effect is an excellent effect that cannot be obtained by simply blending an ointment base.
  • the amount of the compound added to the ointment base is small, a sufficient local anti-inflammatory effect can be obtained, so that the amount of the compound can be reduced.
  • the 21-alkoxy steroid compound of the present invention is a compound represented by the above formula (I).
  • examples of the alkyl group for R 1 include a methyl group, an ethyl group, and a propyl group.
  • examples of the alkanoyl group for R 2 include an alkanoyl group having a linear or branched alkyl group, such as an acetyl group, a propionyl group, a butyryl group, an isoptyryl group, a valeryl group, and an isovaleryl group.
  • R 2 is particularly preferably an alkanoyl group having 2 to 4 carbon atoms.
  • a compound in which R 2 is an acetyl group, a propionyl group or a butyryl group is preferable. This is because it has a particularly excellent local anti-inflammatory effect as compared with related steroid compounds such as mesasone 21-methoxide and beta-methasone 17-valerate.
  • R 1 is a methyl group
  • R 2 is an acetyl group
  • Compounds hereinafter, this compound is referred to as “amelomezone”) are preferred. The reason is that the vasoconstriction is mild and can be maintained for a long period of time, and excellent vasoconstriction is exhibited even when a diluted ointment is prepared.
  • the method for producing the above 21-alkoxy sulfide compound is not particularly limited, and for example, it can be produced by the method described in Japanese Patent Publication No. 3-68039.
  • a liquid base component and a solid base component can be used: (a) Liquid base component
  • the liquid base component refers to a base liquid at room temperature.
  • a liquid base component can be used as an ointment base component, and examples thereof include propylene carbonate.
  • the present invention is particularly characterized in that propylene carbonate is used. According to propylene carbonate, the hardly soluble 21-alkoxysulfide compound can be easily dissolved. In addition, it is excellent as an ointment base even at the L 'point, which has little irritation to the skin.
  • propylene carbonate when used as an ointment base for a 21-alkoxysteroid compound, it is excellent in releasing 21-alkoxycysteloid compounds from the base and extremely excellent as an ointment base for topical anti-inflammatory agents. It is.
  • propylene carbonate be blended as an ointment base component, but one or more other liquid bases may be blended as long as the properties of the ointment are not lost. Good.
  • a combination of propylene glycol and propylene carbonate is preferable, and a mixture of liquid paraffin is also preferable.
  • Pro pyrengli This is because coal has excellent affinity with propylene carbonate and has a moisturizing effect.
  • the solid base component refers to a base that is solid at normal temperature.
  • the solid base that can be used in the present invention is not particularly limited as long as it is solid at normal temperature.
  • solid triglyceride, solid fatty acid ester, solid hydrocarbon, and the like can be used.
  • Triglycerides as solid bases include cocoa butter, palm fat, palm kernel oil, mokurou, coconut oil, beef tallow, lard, hydrogenated oil, hydrogenated castor oil, lanolin fatty acid triglyceride, etc.
  • No. Fatty acid esters as solid bases include beeswax, carnauba wax, whale wax, lanolin, hydrogenated lanolin, hard lanolin, candelilla wax, ceresin and the like.
  • hydrocarbon as a solid base examples include white petrolatum, yellow petrolatum, paraffin, solid paraffin, ozokerite, ceresin, microcrystalline wax, polyethylene powder, and the like. There is no problem if it is used for cosmetics. In the present invention, these solid bases are blended together with the liquid base. In the present invention, it is preferable to use white petrolatum, solid paraffin, and ceresin as the solid base.
  • the steroid ointment of the present invention is characterized by containing polyoxyethylene hydrogenated castor oil as a surfactant. This is because it is particularly excellent in affinity with propylene carbonate. Therefore, even when a propylene carbonate solution in which a sparingly soluble 21-alkoxy sulfide compound is dissolved is mixed with a solid base, the polyoxyethylene-hardened castor oil exhibits an extremely excellent emulsifying action, This is because a steroid ointment having excellent emulsion stability can be obtained.
  • polyoxyethylene cured castor Among these oils, those which repeat oxyethylene units by 10 to 60 are preferable, and those which repeat oxyethylene units by 20 to 50, especially 20 are particularly preferable.
  • one or more other surfactants can be used in combination as the surfactant.
  • the nonionic surfactant include polyoxyethylene alkyl ether, polyoxyethylene alkylphenyl ether, and polyoxyethylene fatty acid ester.
  • the anionic surfactant include a linear or branched alkylbenzene sulfonate, a linear or branched alkyl or alkenyl ether sulfate, an alkyl or alkenyl sulfate having an alkyl group or a alkenyl group, and an alkyl.
  • amphoteric surfactant there is a phosphoric acid monomer- or diester-type surfactant containing a group or an alkenyl group.
  • amphoteric surfactant include imidazoline-based amphoteric surfactants having an alkyl group, an alkenyl group, or an acyl group, a carbobenzoin-based surfactant, an amide-based surfactant, and a sulfobetaine-based surfactant.
  • amphoteric surfactants such as hydroxysulfobetaine and amidesulfobetaine.
  • the topical steroid formulation of the present invention is characterized by containing a 21-alkoxy sulfide compound represented by the above formula (I), propylene carbonate and polyoxyethylene hydrogenated castor oil.
  • Dosage forms obtained using steroid external preparations include ointments, aqueous gel ointments, lotions, There are creams, powders, sprays, tapes and the like. In the present invention, among these, ointments, lotions and creams are preferred, and ointments are particularly preferred.
  • propylene carbonate and hardened castor oil of polyoxyethylene make the hardly soluble 21-alkoxysteride compounds soluble. This makes it possible to provide a steroid external preparation which rapidly exerts the pharmacological action of the 21-alkoxysteride compound and has excellent stability.
  • Steroid ointment represented by the above formula (I), propylene carbonate and polyoxyethylene hydrogenated castor oil.
  • an ointment can be prepared using the above-mentioned steroid external preparation.
  • the steroid ointment of the present invention is characterized in that propylene carbonate and polyoxyethylene hydrogenated castor oil are contained in a solid base, and the propylene carbonate is contained in the ointment in an amount of 1 to 5% by mass. It is preferable that the content is 1.5 to 3.5% by mass.
  • the ointment preferably contains 0.01% to 3% by mass of polyoxyethylene hydrogenated castor oil, and more preferably 0.05% to 2% by mass. If both are present in this range, excellent emulsification stability of the 21-alkoxysulfide compound in the base can be ensured.
  • the 21-alkoxysteroid compound is preferably contained in the ointment in an amount of 0.01 to 1% by mass, more preferably 0.05 to 0.5% by mass.
  • the 21-alkoxy steroid compound used in the present invention has an excellent local anti-inflammatory action, and has an ointment in combination with propylene carbonate, polyoxyethylene hydrogenated castor oil and a solid ointment base. This is because release from the base is easy, and an extremely excellent local anti-inflammatory action can be obtained in the above range.
  • An example of such a liquid base is propylene glycol.
  • the amount of propylene glycol to be used is not particularly limited. However, when it is added, the amount of propylene is 0.1 to 20 parts by mass, more preferably 0.5 to 10 parts by mass, per 1 part by mass of propylene. It is preferred to mix in the range of parts. This is because the addition of propylene glycol can increase the content of the liquid base and easily adjust the softness of the ointment base.
  • a mixture of the obtained 21-alkoxy sulfide compound and a liquid base containing at least propylene carbonate is then heated and mixed with a dissolved solid base.
  • polyoxyethylene hydrogenated castor oil is added. This is because the polyoxyethylene hydrogenated castor oil acts as an emulsifier, and the soluble 21-alkoxysteroid compound can be easily and uniformly emulsified in the ointment base.
  • the hardly soluble 21-alkoxysteroid compound can be used as a soluble steroid ointment. Dissolved in a liquid base containing propylene carbonate at ⁇ 100 ° C, and then mixed with an ointment base containing a solid base dissolved with polyoxyethylene hydrogenated castor oil It can be said to be a method for solubilizing 2, 21-alkoxysteroid compounds.
  • the content of the 21-alkoxy systemide compound in the ointment is 0.01 to 1% by mass, and the content of the propylene carbonate in the ointment is 1 to 1%.
  • a stable local anti-inflammatory effect can be exerted over time when an appropriate amount is applied to the skin once or several times a day and used.
  • a 21-alkoxysteroid compound is preferably amelomethasone represented by the above formula (II).
  • the steroid ointment of the present invention may optionally contain an antioxidant, a preservative, a chelating agent, a fragrance, and the like, as necessary, in addition to the above components.
  • the steroid ointment of the present invention may be combined with one or more antibiotics, antihistamines, bactericides, and vitamins.
  • the steroid ointment of the present invention can be produced by mixing and mixing the above-mentioned base and surfactant according to a usual ointment production method.
  • the steroid ointment of the present invention is used by applying an appropriate amount to the skin once or several times a day. Since the steroid ointment of the present invention exhibits a local anti-inflammatory effect that is stable over time, it can be used regardless of the site where it is used.
  • the present invention will be described specifically with reference to examples.
  • An ointment was prepared by mixing amelomesone with propylene carbonate, polyoxyethylene hydrogenated castor oil and the like in the amounts shown in Table 1 below.
  • amelomesone was heated and dissolved in a mixture of propylene glycol and propylene carbonate at a temperature of 60 to 80 ° C in advance, and then dissolved in white petrolatum and liquid paraffin at about 80 ° C.
  • the blending amount of the polyoxyethylene (20) hydrogenated castor oil of Example 1 was 0 lg, and an ointment was obtained by the same production method. (Prescription 3)
  • polyoxyethylene (20) hydrogenated castor oil of Example 1 was changed to polyoxyethylene (60) hydrogenated castor oil, and an ointment was obtained by the same production method (process 4).
  • the polyoxyethylene (20) hydrogenated castor oil of Example 1 was An ointment was obtained in the same manner as above, except that the fatty acid ester was used (formulation 6).
  • the polyoxyethylene (20) hydrogenated castor oil of Example 1 was changed to polyethylene glycol fatty acid ester, and an ointment was obtained by the same production method (Formulation 7).
  • An emulsion was prepared by mixing amelomezone with propylene carbonate and polyoxyethylene hydrogenated castor oil in the amounts shown in Table 2 below. First, amelomethasone was converted to propylene glycol / propylene carbonate.
  • Test Solution 1 This was stirred for a certain period of time with a mixer to obtain a uniform emulsified emulsion, and then allowed to stand at room temperature. The degree of separation after 30 minutes and 60 minutes and 1 day was visually observed over time in a test tube. The sample volume in the test tube was 10 m 1. Table 3 shows the results.
  • the efficacy of the 21-alkoxy cystride compound in the ointments of Examples 1 to 5 and Comparative Examples 1 and 2 was evaluated by vasoconstriction.
  • the above ointment was applied to the inside of the forearm of about 20 healthy men for about 4 hours, and the vasoconstriction after removal of the sample was evaluated as a paleness phenomenon.
  • the emulsion stability differs depending on the type of polyoxyethylene hydrogenated castor oil.
  • the present invention is directed to dissolving a 21-alkoxy steroid compound which has not been able to exert its pharmacological action effectively because of its poor solubility.
  • a 21-alkoxy steroid compound which has not been able to exert its pharmacological action effectively because of its poor solubility.
  • polyoxyethylene hydrogenated castor oil as a surfactant, extremely excellent emulsion stability can be obtained. As a result, a quick and effective drug effect can be obtained. Therefore, even if the amount of the compound added to the ointment base is smaller than that of the conventional product, a sufficient local anti-inflammatory effect can be obtained, and the amount of the compound can be reduced.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract

Préparation stéroïde externe comprenant un composé 21-alcoxystéroïde de formule (I), du carbonate de propylène et un polyoxyéthylène/huile de ricin durcie. Dans la formule (I), R1 représente alkyle C¿1?-C4 ou méthylthiométhyle, R?2¿ représente alcanoyle C¿2?-C7 et le trait ondulé représente une liaison α ou β.
PCT/JP2000/000130 1999-01-13 2000-01-13 Preparation steroide externe WO2000041702A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU20036/00A AU2003600A (en) 1999-01-13 2000-01-13 External steroid preparation

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP11/6427 1999-01-13
JP642799 1999-01-13

Publications (1)

Publication Number Publication Date
WO2000041702A1 true WO2000041702A1 (fr) 2000-07-20

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PCT/JP2000/000130 WO2000041702A1 (fr) 1999-01-13 2000-01-13 Preparation steroide externe

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003086348A1 (fr) * 2002-04-08 2003-10-23 Dermcare-Vet Pty Ltd Formulation et methode de traitement de la dermatite allergique
EP1875905A2 (fr) 2003-04-28 2008-01-09 Bayer Schering Pharma Aktiengesellschaft Composition pharmaceutique sous la forme d'un hydrogel pour l'administration transdermique d'agents actifs

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5524131A (en) * 1978-08-09 1980-02-21 Nippon Redarii Kk Synthetic adrenal cortical hormone preparation ointment and its base
JPH05170643A (ja) * 1991-10-21 1993-07-09 Pola Chem Ind Inc 水性目薬及びその製造法

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5524131A (en) * 1978-08-09 1980-02-21 Nippon Redarii Kk Synthetic adrenal cortical hormone preparation ointment and its base
JPH05170643A (ja) * 1991-10-21 1993-07-09 Pola Chem Ind Inc 水性目薬及びその製造法

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003086348A1 (fr) * 2002-04-08 2003-10-23 Dermcare-Vet Pty Ltd Formulation et methode de traitement de la dermatite allergique
EP1875905A2 (fr) 2003-04-28 2008-01-09 Bayer Schering Pharma Aktiengesellschaft Composition pharmaceutique sous la forme d'un hydrogel pour l'administration transdermique d'agents actifs

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Publication number Publication date
AU2003600A (en) 2000-08-01

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