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WO1993012783A1 - Pommade oleagineuse - Google Patents

Pommade oleagineuse Download PDF

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Publication number
WO1993012783A1
WO1993012783A1 PCT/JP1992/001716 JP9201716W WO9312783A1 WO 1993012783 A1 WO1993012783 A1 WO 1993012783A1 JP 9201716 W JP9201716 W JP 9201716W WO 9312783 A1 WO9312783 A1 WO 9312783A1
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WO
WIPO (PCT)
Prior art keywords
fatty acid
oily
oil
higher fatty
ointment
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/JP1992/001716
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English (en)
Japanese (ja)
Inventor
Tadahiko Chiba
Saichi Ono
Fumihiko Kimura
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Kureha Corp
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Kureha Corp
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Filing date
Publication date
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Publication of WO1993012783A1 publication Critical patent/WO1993012783A1/fr
Anticipated expiration legal-status Critical
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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions

Definitions

  • the present invention relates to 7- [3- (4-acetyl-3-methoxy-2-propylphenoxy) propho. [Xi]] The present invention relates to an oily ointment having 1,3,4-dihydro-18-propyl-12H-11-benzopyran-12-potency rubonic acid, a salt or ester thereof as a pharmacologically active ingredient. Background art
  • the compound used as the pharmacologically active ingredient in the present invention is a compound represented by the following formula (I) [hereinafter sometimes abbreviated as compound (I)], which is disclosed in Japanese Patent Publication No. 64-38045 (US Pat. No. 4,889,871).
  • a selective antagonist of the compound (I) is leukotriene 8 4 (LTB 4), for example, inflammatory bowel disease, rheumatoid arthritis, anti-inflammatory agents useful in the treatment of gout, and psoriasis Is described.
  • LTB 4 leukotriene 8 4
  • psoriasis is a skin if disease of unknown etiology.
  • treatment by topical administration of an ointment containing coal tar, corticosteroid, vitamin A or vitamin D as an active ingredient has been conventionally performed.
  • the topical administration of ointments in dermatological diseases requires that the drug reach the target affected area directly through transdermal absorption. It is generally effective in gaining.
  • conventional psoriatic ointments not only had side effects, but also had insufficient effects. There is no description of useful transdermal preparations in JP-A 64-38045.
  • a softening agent is defined as an external preparation applied to the skin, which is manufactured in a semi-solid form of appropriate consistency and full quality and is applied to the skin. It is classified into oily ointments, emulsion ointments and water-soluble ointments.
  • the use of soft threat agents depends on the condition.
  • the pathological condition of psoriasis is redness, papules, and irritated keratinization of the skin.
  • an external preparation use an emulsion ointment or water-soluble ointment that is irritating to the skin. It is desirable to use an oily / soft threat that has excellent coatability and poor skin irritation.
  • Oily ointments are distinct from emulsion ointments in that they lack an aqueous phase, and are distinct from water-soluble ointments in that they are insoluble in water.
  • the oily soft made by mixing the compound (I) as it is with the oily soft blue base such as petrolatum conventionally used in a conventional manner and producing II has poor transdermal absorbability.
  • an object of the present invention is to provide an oily ointment having excellent transdermal absorbability, which contains compound (I), a salt or an ester thereof as a pharmacologically active ingredient.
  • the present inventors have conducted intensive studies to achieve this object, and as a result, by using a higher fatty acid ester which is liquid at 35'C, a surfactant, or a combination thereof as a transdermal absorption enhancer, It has been found that transdermal absorbability of a compound (I) -containing oily ointment is remarkably improved.
  • the present invention relates to (a) a pharmacologically active ingredient, 7-C3- (4-acetinole-3-methoxy-12-propylphenoxy) propoxy] -13,4-dihydro-8-propyl-12H — 1—Benzopyran-1-2-Rubonic acid
  • the present invention relates to an oil-based ointment comprising [compound (I)], a salt or ester thereof, (b) an oil-based ointment base, and (c) a transdermal absorption enhancer.
  • transdermal absorption enhancer As a transdermal absorption enhancer,
  • A higher fatty acid ester
  • 35 C solid hydrophobic base as an oily soft threat base
  • the pharmacologically active ingredient used in the present invention is 7- [31- (4-acetyl-3-methoxy-12-propylphenoxy) propoxy] -13,4-dihydro-8-propyl-12 represented by the above formula (I).
  • H- 1-benzopyran one 2 Ichiriki carboxylic acid [compound (I); mp 6 5-6 8 crystal, 8 0 to 8 3 e C, etc.), a salt or ester thereof.
  • any of racemates and stereoisomers such as optically enantiomers can be used.
  • Compound (I) exhibits polymorphism and has different melting points depending on the crystal structure.
  • the salt of compound (I) that can be used in the present invention is not particularly limited as long as it is a pharmaceutically acceptable salt.
  • a non-toxic salt with an inorganic salt group for example, Salts of alkali metals (sodium, potassium, lithium, rubidium, cesium, etc.), salts of alkaline earth metals (calcium, magnesium, etc.), and light metals belonging to Group III of the Periodic Table (alminium, etc.) Salts or ammonium salts; furthermore, non-toxic salts with organic bases, such as organic amines, ie, primary, secondary or tertiary amines ('mono-, di- or trialkyl or cycloalkylamines).
  • ester of the compound (I) is not particularly limited as long as it is a pharmaceutically acceptable ester.
  • examples thereof include alkyl esters having 1 to 6 carbon atoms, preferably methyl ester or ethyl ester. Can be mentioned.
  • the compound (I), a salt or an ester thereof is used in an amount of 0.01 to 30% by weight, preferably 0.3 to 10% by weight, and more preferably 0.1 to 30% by weight, based on the total weight of the oily and delicate composition of the present invention. It can be used in an amount of 1 to 5% by weight.
  • the content of the salt or ester thereof is less than 0.01% by weight, the medicinal effect is insufficient, and when it exceeds 30% by weight, the shape as an ointment cannot be maintained. It becomes unsatisfactory as a dosage form of oily ointment.
  • Compounds that can be used as an oily ointment base in the present invention include hydrocarbons, silicones, lanolins, sterols, higher alcohols, higher fatty acids, higher alcohol esters of higher fatty acids, fatty acid triglycerides, and waxes.
  • a vegetable oil or an animal oil, and these compounds can be used as one kind or as a mixture of two or more kinds.
  • “higher” is used to mean 6 or more carbon atoms. Preferably it has 10 or more carbon atoms.
  • These oily ointment bases are available in solid, semi-solid or liquid form at 35.
  • hydrocarbon base examples include paraffin (paraffin, solid paraffin, paraffin solid, paraffin wax, etc.), liquid paraffin (liquid paraffin, mineral oil, etc.), light liquid paraffin (light fluid paraffin, light mineral oil) Etc.), petrolatums (vaseline, yellow petrolatum, yellow soft paraffin, white petrolatum, white soft paraffin, cellulose jelly, etc.), microcrystalline wax, polyethylene, squalane, squalene, plastibase and the like.
  • Alastibase is a hydrocarbon gel soft threat based on polyethylene and liquid paraffin. Silicones include, for example, dimethylpolysiloxane Or polymethylsiloxane.
  • the lanolins are, for example, lanolin, liquid lanolin, purified lanolin, lanolin alcohol, lanolin wax, anhydrous lanolin, wool fat or isopropyl lanolin.
  • Sterols are, for example, cholesterol, sitosterol or ergosterol ⁇
  • Higher alcohols include, for example, aliphatic alcohols, in particular, cetanol, isocetanol, cetostearyl alcohol, stearyl alcohol, oleyl alcohol, myristyl alcohol, lauryl alcohol, and ethanol. Noremicyl alcohol, laxeryl alcohol or citronellol can be used. Higher fatty acids include, for example, lauric acid, myristic acid, and phenol. Lumitic acid, stearic acid or oleic acid can be mentioned.
  • esters of higher fatty acids examples include esters of the higher alcohols and higher fatty acids, such as myristyl myristate, no, cetyl lumitate, no, isocetyl lumitate, no, palmityl lumitate, no, and lumitin.
  • Myristyl acid, no ,. Lacteryl lumitate and the like can be mentioned.
  • fatty acid triglyceride any of a single triglyceride comprising the same kind of fatty acid group and a mixed triglyceride containing two or three kinds of fatty acid groups can be used.
  • hydrogenated fatty acid triglyceride, hydrogenated oil, hydrogenated tallow fatty acid triglyceride, hydrogenated castor oil, synthetic fatty acid triglyceride, hard fat, medium chain fatty acid triglyceride and the like can be mentioned.
  • the waxes are, for example, carnauba wax, beeswax, salami beeswax, or beeswax.
  • Vegetable oils are, for example, peanut oil, armon oil, corn oil, cottonseed oil, olive oil, soybean oil, orange oil, cocoa butter, eucalyptus oil, wheat germ oil, coconut oil, camellia oil, rapeseed oil or sesame oil.
  • Animal oils include, for example, beef tallow and lard.
  • hydrocarbons particularly, white petrolatum, liquid paraffin, paraffins.
  • silicones especially purified lanolin or lanolin alcohol
  • sterols higher alcohols, higher fatty acids, fatty acids Triglycerides, higher alcohol esters of higher fatty acids having at least 12 carbon atoms (particularly myristyl myristate or isocetyl palmitate), waxes, vegetable oils (particularly sesame oil, corn oil, olive oil, Soybean oil, peanut oil or rapeseed oil) and animal oil (especially beef tallow), which can be used alone or as a mixture of two or more.
  • the above-mentioned oleaginous soft base can be used in an amount of 20 to 8% by weight, preferably 30 to 95% by weight, based on the total amount of the oleaginous ointment of the present invention.
  • the oily soft blue base can be used in an amount of 20 to 95.99% by weight.
  • the oily ointment base is used in an amount of 20 to 95.889% by weight. be able to.
  • oil-based ointment base By using an oil-based ointment base within this range, the dosage form of the oil-based ointment can be maintained. When the concentration of the oil-based ointment base is less than 20% by weight, the ointment base can be maintained. It becomes difficult.
  • These oil-based ointment bases are not only low in volatility and good in skin coverage, but also have low irritation to the skin itself, making them preferable as bases for external preparations for psoriasis treatment. .
  • the percutaneous absorption enhancer preferred in the present invention is (A) a higher fatty acid ester liquid at 35 or (B) a surfactant, or one or two of these compounds (A) and / or compound (B).
  • the higher fatty acid ester (A) lower alcohol esters of higher fatty acids may be used alone or in combination of two or more.
  • higher fatty acids are fatty acids having 6 or more carbon atoms
  • lower alcohols of lower alcohol esters are alcohols having 1 to 4 carbon atoms.
  • a lower alcohol Any of ester, diester and triester can be used, but at least one of them is preferably a lower alcohol monoester of higher fatty acid.
  • the higher fatty acid ester (A) can be used alone or in combination of two or more. When used in combination, a mixture of two or more lower alcohol monoesters of higher fatty acids or a mixture of lower alcohol monoesters of higher fatty acids and lower alcohol diesters of higher fatty acids is preferred.
  • lower alcohol monoester of a higher fatty acid a monoester of a higher fatty acid having 20 to 20 carbon atoms and a lower alcohol having 1 to 4 carbon atoms is preferable.
  • Preferred examples of lower alcohol monoesters of higher fatty acids are methyl, methyl, n-propyl, isopropyl, butyl, isobutyl or t-butyl ester of either myristic acid, palmitic acid or stearic acid. Further preferred examples are isopropyl myristate or isopropyl palmitate. Isopropyl myristate is particularly preferred.
  • dimethyl, getyl, dipropyl or diisopropyl esters of adipic acid, suberic acid or sebacic acid can be used.
  • Disopropyl adipate or getyl sebacate are preferred.
  • Triesters such as triethyl citrate can be used.
  • Compound (I) or a salt or ester thereof as a pharmacologically active ingredient is mixed with the oily and delicate base as it is by a conventional method to prepare an oily ointment, and then the transdermal absorption of the pharmacologically active ingredient is achieved. Is scarce. However, it has been surprisingly found that the percutaneous absorbability is remarkably improved by adding such a higher fatty acid ester (A) which is liquid at 35 ° C. to such a conventional oil-based ointment. Was.
  • oily ointment of the present invention when a higher fatty acid ester (A) which is liquid at 35 ° C. is used as a transdermal absorption enhancer, 35 as an oily ointment base.
  • a hydrophobic base solid at 35 ° C in addition to a semisolid or liquid base at C, the effect of promoting the percutaneous absorption of the higher fatty acid ester (A) is still surprising. It is even more significantly enhanced.
  • the hydrophobic base that is solid at 35 C can be selected from the above-mentioned oleaginous ointment bases, and among the oleaginous soft threat bases, those that are solid at 35 ° C are used.
  • Particularly preferred hydrophobic base materials from the viewpoint of enhancing the transdermal absorption effect are solid hydrocarbons such as paraffins (paraffin, solid no. Raffin, no. Raffin solid, no. Raffin wax) and microcrystalline wax. Waxes, higher alcohol esters of higher fatty acids, hydrogenated fatty acid triglycerides, hydrogenated oils, hydrogenated tallow fatty acid triglycerides, hydrogenated castor oil, synthetic fatty acid triglycerides or hard fats.
  • one or more compounds selected from these groups are contained in the oily and delicate base.
  • the hydrophobic base solid at 35 C is preferably used in an amount of 3 to 50% by weight based on the total amount of the oily ointment. More preferably, it is used in an amount of 5 to 40% by weight.
  • isopropyl myristate or isopropyl palmitate also has the advantage of improving the elongation of soft blue and giving the hand a soft touch when rubbing it.
  • isopropyl myristate and isopropyl palmitate are colorless, transparent, and odorless liquids, and have the advantage of reducing the unique odor often found in other softwood bases.
  • an anionic, cationic, amphoteric or nonionic surfactant can be used, but a nonionic surfactant is used. Is preferred.
  • Non-ionic When a surfactant is used, the skin irritation of the oil-based ointment is reduced as compared with the case where an anionic, cationic, or Z- or amphoteric surfactant is used, and further, there is an effect of improving a therapeutic effect.
  • anionic surfactant for example, sodium lauryl sulfate, sodium alkylbenzenesulfonate or sodium polyoxyethylene lauryl ether phosphate can be used.
  • cationic surfactant include benzalkonium chloride and benzethonium chloride.
  • amphoteric surfactant egg yolk lecithin or soybean lecithin can be used.
  • Nonionic surfactants include, for example, polyethylene glycol monostearate, polyethylene glycol distearate, polyethylene glycol monolaurate, polyethylene glycol fatty acid esters such as lauromacrogol, propylene glycol fatty acid esters, polyglycerin fatty acid Esters, sucrose fatty acid ester, polyoxyl stearate, glyceryl monooleate, polyoxyethylene hydrogenated castor oil, polyoxyethylene phytosterols, polyoxyethylene stearate, polyoxyethylene stearate amide, boroxylene ethylene citrate, Polyoxyethylene alkyl phenyl ethers, polyoxyethylene polyoxypropylene glycol, polyoxyethylene Polyoxypropylene alkyl ethers, Poriokishechire down alkyl ethers, polyoxyethylene sorbitan fatty acid esters, sorbitan fatty acid esters, glyceryl monostearate, polyethylene O alkoxy ethylene lanolins or polyoxyethylene lan
  • polyoxyethylene alkylphenyl ethers examples include polyoxyethylene nonylphenyl ether.
  • polyoxyethylene sorbitan fatty acid esters include polysorbate 40, polysorbate 60, polysorbate 65, and polysorbate 80.
  • sorbitan fatty acid esters include sorbitan monolaurate, sorbitan monooleate, and sesquioleic acid Sorbitan, sorbitan trioleate and the like.
  • nonionic surfactants from the viewpoint of transdermal absorption are sorbitan monooleate, sorbitan monolaurate, sorbitan sesquioleate, etc., sorbitan fatty acid esters, polysorbate 40, polysorbate 60, polysorbate 65, polysorbate 80, etc.
  • Polyethylene glycol fatty acid esters such as polyoxyethylene sorbitan fatty acid esters and lauromacrogol.
  • Particularly preferred are sorbitan fatty acid esters such as sorbitan monooleate, sorbitan monolaurate and sorbitan sesquioleate.
  • the surfactant (B) can be used singly or as a mixture of two or more.
  • the HLB (Hydrophile-Lipophile Balance) value of the nonionic surfactant or the HLB value of the mixed system is used. It is preferably 2 to 20.
  • the HLB value of the nonionic surfactant is given by the following equation (1).
  • Mw is the molecular weight of the hydrophilic group of the surfactant
  • Mo is the molecular weight of the water-storage group (lipophilic group) of the surfactant. Represents molecular weight.
  • HLBab [(HLBaXWa) + (HLBbXWb)] / (Wa-f-Wb) (2) where HLBa and HLBb are surfactant a and surfactant, respectively.
  • HLB value of b, HLBab is the HLB value of the mixed system, and Wa and Wb are the weights (g) of surfactant a and surfactant b, respectively.
  • the HLB value of a mixed system of three or more nonionic surfactants is also obtained as a weighted average in the same manner as in the above formula (2).
  • the surfactant (B) is used in an amount of 0.1 to 40% by weight, preferably 0.5 to 30% by weight, more preferably 1 to 20% by weight, based on the total amount of the oily ointment.
  • the amount is less than 0.1% by weight, the transdermal absorption of the pharmacologically active ingredient becomes insufficient, and when it exceeds 40% by weight, the skin irritation is not preferred.
  • the oil-based ointment contains 4 to 20% by weight of a nonionic surfactant, an HLB value of about 2 to 9 facilitates percutaneous absorption, and when it contains 1 to 3% by weight. It is particularly preferable to use such a content and an HLB value since a dermal absorption of 1 to 8 is about 10 to 20 and the percutaneous absorption is often promoted.
  • the surfactant (B) When the surfactant (B) is used as a transdermal absorption enhancer, the surfactant (B) achieves a uniform dispersion of the pharmacologically active ingredient in the oleaginous base, thereby increasing the stability as a formulation.
  • the grease-like sticky feeling of conventional serine ointment is reduced, the feel is improved, it can be washed off with water after use, and the dirt removal becomes good, so-called feeling of use is improved. There are advantages too.
  • the percutaneous absorption enhancer of the present invention is improved by using one or more higher fatty acid esters (A) and one or more surfactants (B) in combination.
  • the weight of the higher fatty acid ester (A) is preferably used in a proportion of 0.01 to 60 times the weight of the surfactant (B), and in a proportion of 1 to 58 times. Is more preferred.
  • Pharmacologically active ingredient Compound (I); Transdermal absorption enhancers: isopropyl myristate and Z or isopropyl palmitate;
  • Oil-based soft blue base white ⁇ serine, liquid paraffin and solid at 35 ° C ⁇ aqueous base [paraffins (paraffin, solid paraffin, paraffin solid, no. Raffin wax), microcrystalline wax, waxes, One or more compounds selected from the group consisting of higher alcohol esters of higher fatty acids, hydrogenated fatty acid triglycerides, hydrogenated oil, hydrogenated tallow fatty acid triglycerides, hydrogenated castor oil, synthetic fatty acid triglycerides, and hard fats;
  • Transdermal absorption enhancer Mixtures of isopropyl and myristate or Z or isopropyl propyl palmitate with disopropyl adipate and / or getyl sebacate;
  • Oil-based soft base white ⁇ -serine, and oil-based base solid at 35 [paraffins (paraffin, solid paraffin, paraffin solid, paraffin wax), microcrystalline wax, waxes, higher grades of higher fatty acids Alcohol esters, hydrogenated fatty acid triglycerides, hydrogenated oils, hydrogenated tallow fatty acid tridalicerides, hydrogenated castor oil, synthetic fatty acid triglycerides, or hard fats!
  • Transdermal absorption enhancer Surfactant based on sorbitan fatty acid esters
  • Oily and soft base One to three types of white cellulose, liquid paraffin and / or plastic base, dimethylpolysiloxane, purified lanolin, cholesterol, stearyl alcohol, cetanol, setosteryl alcohol, 'stearin Acid, myristic acid, beeswax, medium chain fatty acid tri Base containing 0-4 types of glyceride, soybean oil, sesame oil and / or tallow.
  • Pharmacologically active ingredient Compound (I);
  • Transdermal absorption enhancer One or more compounds selected from the group consisting of surfactants mainly composed of isopropyl myristate and Z or isopropyl palmitate and sorbitan fatty acid esters; oily soft blue base: White petrolatum, liquid paraffin, and a hydrophobic base that is solid at 35 [paraffins (paraffin, solid paraffin, no., Raffin solid, noraffin wax), microcrystalline wax, mouth water, higher alcohols of higher fatty acids Ester, hydrogenated fatty acid triglyceride, hydrogenated oil, hydrogenated tallow fatty acid triglyceride, hydrogenated castor oil, synthetic fatty acid triglyceride, or hard fat] or one or more compounds selected from the group consisting of:
  • the oil-based ointment according to the present invention may contain any usual additives, for example, coloring agents, flavors, preservatives, antioxidants, solubilizing agents, etc., within the range allowed by conventional oil-based ointments. May be.
  • solubilizing agent include polyethylene glycols such as Macrogol 300 or Macrogol 400.
  • the oily ointment of the present invention can be prepared, for example, as follows. That is, one or two or more oleaginous ointment bases are mixed and heated at about 60 to 80, and one or two kinds of transdermal absorption enhancers are added to the oleaginous ointment base under heating.
  • the desired oil-and-oil ointment can be obtained by mixing the above, mixing the obtained mixture with the pharmacologically active ingredient, and cooling the mixture to room temperature.
  • the oily ointment of the present invention can be obtained even if the order of mixing the above components is changed.
  • Oleaginous ointment of the present invention is the treatment of inflammatory skin disorders, for example, treatment of LTB 4 dependent skin diseases, especially psoriasis vulgaris, pustular psoriasis, guttate dry ⁇ the treatment of psoriasis, such as erythrodermic psoriasis It is suitable. For treatment of psoriasis, it is applied to the affected skin.
  • the amount applied is the concentration of the pharmacologically active ingredient in the oily ointment, the type of psoriasis Or, depending on the degree, usually 0.01 to 30% by weight of the pharmacologically active ingredient, preferably 0.03 to 10% by weight, and preferably 0.1 to 1% by weight of the oily oily soft jelly 1 to 1% Apply 50 mg Zcm 2 to the affected area of skin 1 to 4 times a day.
  • the use of topical preparations for the treatment of dermatitis allows the effective concentration of the drug to be maintained at the affected area without affecting the whole body. However, if dermal absorption is extremely high, systemic levels of the drug may exceed safe limits. In order to avoid this situation and achieve effective treatment, it is desirable that the transdermal absorption of the external preparation be within the appropriate range.
  • One example of a method for evaluating the transdermal absorbability of the oily ointment of the present invention is an in vitro evaluation method using a Franz vertical cell.
  • the test method is as described in the pharmacological test example 2 below.
  • Transdermal absorbability is expressed as the concentration of pharmacologically active ingredient C (g / ml) in Franzell 24 hours later. Further, using this value, a pharmacologically active ingredient-converted absorption rate Q is / (cm 2 -g-h)] defined by the following equation is calculated.
  • W Weight of pharmacologically active ingredient in 100 g of oily ointment [g]
  • Pharmacologically active ingredient Conversion absorption of oleaginous ointment of the present invention are preferably 'a (g ⁇ h, more preferably 0. 3 ⁇ 4 g Z (cm 2 0. 3 ⁇ 20 g / cm 2)' g * h).
  • the oleaginous ointment of the present invention maintains the characteristics of the conventional oleaginous ointment base, which are inherently high in skin coverage and low skin irritation, while maintaining the transdermal absorbability of the pharmacologically active ingredient. It is an improved formulation.
  • An oily ointment was prepared according to the formulation shown in each example number in Tables 2 to 17 and according to the method described in Example 1.
  • a conventional oil-based ointment for control was prepared according to the method described in Example 1, using 99 g of white deserin and 1 g of compound (I).
  • An oily ointment of a comparative example was prepared according to the formulation shown in each comparative example number in Table 1 and according to the method described in Example 1.
  • Pharmacological test example 1 Acute toxicity
  • the acute toxicity of the oil-based ointment according to the present invention was examined using 10 male and female groups (20 in total) of Wistar rats weighing 15 to 200 g.
  • the oily ointment of the present invention (containing 1% by weight of the compound (I)) prepared according to the formulation of Example 5 was applied to the surface of the back skin, which had been depilated with an electric burr, in the maximum amount that could be applied. A certain amount of 500 mg / kg was applied, and the lethality was examined up to 14 days later. Was. No animals died, and no other abnormal findings were observed. Therefore, the safety of the oily ointment of the present invention was found to be high.
  • test method An in vitro evaluation method using a Franz vertical cell (manufactured by Crown Glass) was performed.
  • the test method and test conditions are as follows.
  • the cell used had a contact area of 3.14 cm 2 and an inner layer volume of 14 ml.
  • the biological membrane used was a back skin prisoner of a hairless mouse (Balb / c-hr, female, 8 to 10 weeks; L0 week old; or SKH-1, male, 8 to 10 weeks old).
  • Phosphate buffered saline (PH 7.4) was added to the inner layer of the cell, and the mixture was heated to 37.
  • the skin of a hairless mouse was mounted on this upper part, and an outer layer cell was placed on top of it and fixed with a flange.
  • Each lg of the oleaginous oily jelly of the present invention or the conventional oleaginous oily threat for control is uniformly placed on the outer surface of the hairless mouse skin, and the inner layer is a phosphate buffered saline. The liquid was stirred.
  • Tables 1 to 17 show the results obtained by using the oily and soft jelly (containing compound (I) as a pharmacologically active ingredient) prepared in Examples and Comparative Examples.
  • Tables 1 to 7 (excluding Comparative Example 4 in Table 1 and Example 54 in Table 7) show the results when Ba1bXc-hr (female, 8 to 10 weeks old) was used as a hairless mouse. Comparative Example 4 in Table 1 and Example 7 in Table 7 when 1 (male, 8 to 10 weeks old) was used 54 and Tables 8 to 17.
  • Data corresponding to ointments of the same composition are Example 15 and Example 54, and Example 5 and Example 55.
  • the oleaginous soft threat of Examples 30 and 97 contains 5% by weight of the compound (I) .For comparison, it was attempted to mix 5 g of the compound (I) with 95 g of white serine. It was difficult to mix uniformly, and it was not possible to prepare oleaginous soft jelly.
  • Pharmacological test example 3 Effect of oil-based ointment of the present invention on neutrophil migration in psoriatic model animals
  • LTB 4 is a inflammatory factor with potent neutrophil migration activating action, are important factors and considered et involved in psoriatic lesions. Therefore, the effect of the oil-based ointment of the present invention on neutrophil migration induced by injecting LTB 4 into guinea pig skin was examined.
  • T is the MP ⁇ activity in the skin of the oily ointment applied portion of the present invention
  • C is the MP 0 activity of the site to which only the oily ointment base containing no compound (I) was applied.
  • PJ mouth 1 100 100 100 100 100 100 100 100 Pharmaceutical active ingredient concentration in cell (g / ml) (Note 1) 1.00 1.29 1.56 1.04 7.51 Pharmaceutical active ingredient equivalent absorption rate [g / (cm ⁇ g_h)] 0.19 0.24 0.29 0.10 1.40
  • PJ1 100 100 100 100 100 100 100 100 100 100 100 100 Pharmaceutical active ingredient concentration in cell (g / ml) 2.10 2.17 3.60 5.71 7.79 3.62 5.31 7.14 6.65
  • Fluidized liquid 38.5 29 28.5 30 3 0 30 20 30 Waxes Beeswax 5
  • Pharmacologically active ingredient Compound (I) 1 1 1 1 1 1 1 1 1 1 1 + 100 100 100 100 100 100 100 100 Pharmacologically active ingredient concentration in cell (gZml) 5.50 3.86 4.72 5.51 2.50 4.30 4.40 4.15 3.35 Absorption rate
  • PJ o 1 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 Concentration of pharmacologically active ingredient in the cell (gZml) 4.51 6.24 6.13 4.93 5.93 6.72 4.96 9.32 6.47 Conversion rate of pharmacologically active ingredient
  • Oily ointment base
  • Oily ointment base
  • Pharmacologically active compound Compound (I) 1 1 2 0.5 0.25 0.125 2 2 Mouth +1 100 100 100 100 100 100 100 100 100 Cell pharmacologically active ingredient concentration (us Zml) 2.85 2.45 16.22 4.28 2.58 1.24 17.7 10.25 12.77 Component conversion rate
  • Oil-based ointment base hydrocarbons
  • Oily ointment base
  • an oily ointment in which the percutaneous absorbability of the compound (I), its salt or ester, which is a pharmacologically active ingredient, is improved.
  • the higher fatty acid esters (A> and Z) or the surfactant (B) which is liquid in 35 are used as a transdermal absorption enhancer, the transdermal absorbability of the pharmacologically active ingredient is remarkably improved.
  • a higher fatty acid ester (A) which is liquid at 35 C is used as a percutaneous absorption enhancer, percutaneous absorption is promoted by incorporating a solid hydrophobic base at 35 ° C into the oily ointment base.
  • oily ointment of the present invention can be used in the form of an ointment while maintaining the high skin coverage and low skin irritation inherently possessed by ordinary oily bases. It improves the transdermal absorbability of active compounds from stuffs and is suitable for the treatment of inflammatory skin diseases, especially for the treatment of psoriasis.

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  • Chemical & Material Sciences (AREA)
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  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
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  • Animal Behavior & Ethology (AREA)
  • General Chemical & Material Sciences (AREA)
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  • Dermatology (AREA)
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Abstract

L'invention se rapporte à une pommade oléagineuse, dont un composé pharmacologiquement actif présente une absorbabilité percutanée améliorée et qui contient: (a) de l'acide 7-[3-(4-acétyl-3-méthoxy-2-propylphénoxy)propoxy]-3,4-dihydro-8-propyl-2H-1-benzopyranne-2-carboxylique, représenté par la formule (I), ou un sel ou ester de cet acide comme constituant pharmacologiquement actif, (b) une base de pommade oléagineuse, et (c) un activateur d'absorption percutanée, tel que de préférence un ester d'acide gras supérieur et/ou un tensioactif qui sont/est à l'état liquide à 35 °C. On peut améliorer l'absorbabilité percutanée du constituant actif tout en préservant une forte action couvrante de la peau et une faible irritation de la peau inhérente aux bases de pommades oléagineuses ordinaires, ce qui rend la pommade décrite ici particulièrement bien appropriée pour le traitement des maladies inflammatoires de la peau, telles que notamment le psoriasis.
PCT/JP1992/001716 1991-12-27 1992-12-25 Pommade oleagineuse Ceased WO1993012783A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP36070291 1991-12-27
JP3/360702 1991-12-27

Publications (1)

Publication Number Publication Date
WO1993012783A1 true WO1993012783A1 (fr) 1993-07-08

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ID=18470547

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1992/001716 Ceased WO1993012783A1 (fr) 1991-12-27 1992-12-25 Pommade oleagineuse

Country Status (2)

Country Link
AU (1) AU3172993A (fr)
WO (1) WO1993012783A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020035729A1 (fr) * 2018-08-16 2020-02-20 Dr. Reddy's Laboratories Ltd. Compositions oléagineuses topiques
CN111700857A (zh) * 2020-06-24 2020-09-25 天晴干细胞股份有限公司 一种推注型软膏基质及其制备方法

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS6438045A (en) * 1987-05-29 1989-02-08 Searle & Co Alkoxy substituted dihydrobenzopyran-2-carboxylate derivative

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS6438045A (en) * 1987-05-29 1989-02-08 Searle & Co Alkoxy substituted dihydrobenzopyran-2-carboxylate derivative

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020035729A1 (fr) * 2018-08-16 2020-02-20 Dr. Reddy's Laboratories Ltd. Compositions oléagineuses topiques
CN112566623A (zh) * 2018-08-16 2021-03-26 瑞迪博士实验室有限公司 局部用油质组合物
CN111700857A (zh) * 2020-06-24 2020-09-25 天晴干细胞股份有限公司 一种推注型软膏基质及其制备方法
CN111700857B (zh) * 2020-06-24 2022-12-16 天晴干细胞股份有限公司 一种推注型软膏基质及其制备方法

Also Published As

Publication number Publication date
AU3172993A (en) 1993-07-28

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