WO2013111817A1 - Composition crémeuse de type huile-dans-eau contenant du tacrolimus - Google Patents

Composition crémeuse de type huile-dans-eau contenant du tacrolimus Download PDF

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WO2013111817A1
WO2013111817A1 PCT/JP2013/051453 JP2013051453W WO2013111817A1 WO 2013111817 A1 WO2013111817 A1 WO 2013111817A1 JP 2013051453 W JP2013051453 W JP 2013051453W WO 2013111817 A1 WO2013111817 A1 WO 2013111817A1
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composition
tacrolimus
oil
weight
present
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PCT/JP2013/051453
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Japanese (ja)
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伊原　幹人
義則 上田
史紀 鳴海
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マルホ株式会社
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Priority to JP2013555305A priority Critical patent/JP6084579B2/ja
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    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • 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
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • 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
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/04—Antipruritics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents

Definitions

  • the present invention relates to an oil-in-water (O / W) cream-like composition containing tacrolimus.
  • Tacrolimus topical agent is known to have an excellent therapeutic effect on atopic dermatitis, and currently, Protopic (registered trademark) ointment 0.1% and Protopic (registered trademark) ointment as an oily ointment using an oily base 0.03% for children is commercially available.
  • the oily ointment has the merit of excellent skin protection, but it is sticky when applied to the skin and is uncomfortable to use. Is required.
  • Cream external preparations are produced using an emulsion base formed by emulsifying oil and water with an emulsifier.
  • an emulsion base formed by emulsifying oil and water with an emulsifier.
  • the use of an emulsion base reduces the residual rate of tacrolimus and maintains its effectiveness (intradermal concentration) compared to the case of using an oil base.
  • intradermal concentration Intradermal concentration
  • the present invention is a creamy external preparation with a good feeling of use, has little irritation, high stability of tacrolimus in the preparation (main drug residual ratio), and further has a desired transdermal absorbability at the application site. It is an object of the present invention to provide a tacrolimus-containing pharmaceutical composition (external preparation for skin) that can be achieved.
  • the present invention is an oil-in-water cream composition, (A) tacrolimus, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, (B) diethyl sebacate and / or diisopropyl sebacate, (C) polyoxyethylene hydrogenated castor oil, (D) a hydrophilic polymer, and (E) It contains an antioxidant.
  • the cream-like composition according to the present invention is an oil-in-water type having an internal phase as an oil phase, and is the main agent in the oil phase, tacrolimus, a salt thereof, or a solvate thereof (hereinafter, representative of these).
  • tacrolimus the contact between the active ingredient and the aqueous phase (external phase) can be reduced, and water-unstable tacrolimus can be kept stable.
  • the solubility of tacrolimus, the tacrolimus in the formulation An oil-in-water (O / W type) cream-like composition excellent in all of stability and transdermal absorbability of tacrolimus can be obtained.
  • the outstanding dispersibility can be achieved by using a hydrophilic polymer as a thickener and using polyoxyethylene hydrogenated castor oil as an emulsifier.
  • tacrolimus in a preparation can be stably maintained, an excellent medicinal effect can be exhibited, and a cream-like composition with less irritation and good feeling (less sticky) can be provided. .
  • the cream composition according to the present invention preferably contains 0.01 to 0.3% by weight of tacrolimus (A).
  • tacrolimus a non-toxic, pharmaceutically acceptable conventional salt can be used.
  • examples of such salts include alkali metal salts (sodium salt, potassium salt, etc.), alkaline earth metal salts (calcium salt, magnesium salt, etc.), ammonium salts, amine salts (triethylamine salt, N-benzyl-N-methylamine). Salts with inorganic or organic bases such as salts).
  • Pharmaceutically acceptable solvates of tacrolimus include hydrates and ethanolates.
  • a particularly preferred compound as (A) of the present invention is tacrolimus hydrate.
  • diethyl sebacate and / or diisopropyl sebacate (B) is used as the oil agent constituting the oil phase.
  • diethyl sebacate and / or diisopropyl sebacate may be used as the oil constituting the oil phase, or other oil may be used in combination.
  • a particularly preferable example of the composition according to the present invention is a composition containing only diethyl sebacate or diisopropyl sebacate as an oil agent constituting the oil phase.
  • the total content of diethyl sebacate and / or diisopropyl sebacate in the composition is preferably 5 to 50% by weight. If it is less than 5% by weight, the stability and absorbability of tacrolimus are impaired, and if it exceeds 50% by weight, it is difficult to prepare an oil-in-water cream composition.
  • a more preferable content is 5 to 40% by weight, a particularly preferable content is 5 to 25% by weight, and a still more preferable content is 10 to 20% by weight.
  • the content of diethyl sebacate and / or diisopropyl sebacate is 20% by weight or less (more preferably 15% by weight or less, Particularly preferably, it is preferably 12% by weight or less.
  • diethyl sebacate and / or diisopropyl sebacate is 20% by weight or less, a composition having excellent transdermal absorbability can be obtained.
  • the percutaneous absorbability of tacrolimus can be controlled by increasing or decreasing the amount of diethyl sebacate and / or diisopropyl sebacate.
  • the control of transdermal absorbability will be described in more detail.
  • a composition with high transdermal absorbability of tacrolimus is preferable when high drug efficacy is expected.
  • tacrolimus has a strong immunosuppressive effect, and thus the frequency of side effects may increase due to an increase in blood concentration.
  • the present invention by adjusting the amount of diethyl sebacate and / or diisopropyl sebacate, it is possible to control the absorbability to the skin while maintaining high formulation stability. Is possible.
  • the creamy composition according to the present invention contains polyoxyethylene hydrogenated castor oil (C) as an emulsifier (surfactant) for emulsifying and stabilizing an aqueous phase and an oil phase.
  • C polyoxyethylene hydrogenated castor oil
  • emulsifier surfactant
  • polyoxyethylene hydrogenated castor oil By using polyoxyethylene hydrogenated castor oil, it is possible to prepare an oil-in-water cream composition having excellent emulsion stability. More preferred polyoxyethylene hydrogenated castor oil has an HLB value of 10.5 to 16.5, and particularly preferred polyoxyethylene hydrogenated castor oil has an HLB value of 12.5 to 15.0.
  • the content of polyoxyethylene hydrogenated castor oil in the composition is preferably 0.5 to 10% by weight.
  • polyoxyethylene hydrogenated castor oil is 1 to 6% by weight, a particularly preferable content is 1.5 to 5% by weight, and a further preferable content is 2 to 4% by weight.
  • Polyoxyethylene hydrogenated castor oil may be used alone or in combination. Specific examples of preferable polyoxyethylene hydrogenated castor oil include polyoxyethylene hydrogenated castor oil having an addition polymerization number of ethylene oxide of 20 to 100. An example of a particularly preferred polyoxyethylene hydrogenated castor oil is polyoxyethylene hydrogenated castor oil 60 (HLB value 14.0).
  • the cream-like composition according to the present invention contains a hydrophilic polymer (D) in order to increase the viscosity of the composition and ensure the stability as a preparation (prevent separation).
  • the content of the hydrophilic polymer in the composition is preferably 0.1 to 10% by weight. If it exceeds 10% by weight, the preparation may be too hard to use, and if it is less than 0.1% by weight, it is difficult to produce a stable oil-in-water cream composition.
  • a more preferable content of the hydrophilic polymer is 0.2 to 2% by weight.
  • hydrophilic polymers include carboxyvinyl polymers and water-soluble cellulose derivatives such as hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, and hydrophobized hydroxypropyl methyl cellulose. These may be used alone or in combination.
  • a particularly preferred hydrophilic polymer is a carboxyvinyl polymer.
  • the viscosity of the creamy composition according to the present invention is not particularly limited, but it is generally preferably 10,000 to 200,000 mPa ⁇ s, more preferably 20000 to 100,000 mPa ⁇ s.
  • the viscosity means a viscosity when measured with a B-type viscometer (TVB-10H, rotor 7) at a measurement temperature of 25 ° C. and a rotation speed of 20 rpm for 30 seconds.
  • a B-type viscometer (TVB-10H, rotor 7) at a measurement temperature of 25 ° C. and a rotation speed of 20 rpm for 30 seconds.
  • the cream composition according to the present invention contains an antioxidant (E) in order to suppress the decomposition of tacrolimus and enhance the stability of the active ingredient.
  • the content of the antioxidant in the composition is preferably 0.01 to 0.20% by weight, more preferably 0.05 to 0.15% by weight. Whether the amount of antioxidant is too small or too large, the effect of increasing the stability of tacrolimus is weakened.
  • antioxidant (E) examples include dibutylhydroxytoluene, sodium nitrite, ascorbic acid, L-ascorbic acid stearate, sodium bisulfite, sodium sulfite, alphathioglycerin, erythorbic acid, cysteine hydrochloride, and dry sulfite.
  • a particularly preferred antioxidant is dibutylhydroxytoluene.
  • dibutylhydroxytoluene is used as the antioxidant, a composition with very high stability of tacrolimus and very little irritation can be obtained.
  • the cream composition according to the present invention preferably has a pH value in the range of 4-7.
  • the pH value is less than 4, there is a risk of safety as a preparation, and when the pH value exceeds 7, there is a risk of hydrolysis of diethyl sebacate and / or diisopropyl sebacate.
  • the above pH value is an optimum pH in terms of the stability of tacrolimus. A more preferred pH range is 5-6.
  • Examples of the pH adjusting agent for adjusting the composition to a pH value in the above range include lactic acid, citric acid, and phosphoric acid, which are used to adjust to the low pH region, and adjust to the high pH region.
  • Examples of those used include sodium hydroxide, potassium hydroxide, sodium lactate, sodium citrate, L-arginine, and diisopropanolamine.
  • a particularly preferred pH adjusting agent is diisopropanolamine.
  • the cream-like composition according to the present invention may contain a wetting agent, a preservative, a thickening aid, an emulsification aid and the like in addition to the above components.
  • wetting agent examples include 1,3-butylene glycol, glycerin, propylene glycol, dipropylene glycol and the like.
  • a particularly preferred wetting agent is 1,3-butylene glycol.
  • the content of the wetting agent in the composition is preferably in the range of 0.01 to 30% by weight, more preferably 1 to 20% by weight.
  • the preservative examples include methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, sodium benzoate, phenoxyethanol and the like.
  • the preservative may be used alone or in combination.
  • the content of the preservative in the composition is preferably in the range of 0.01 to 2% by weight, and more preferably in the range of 0.1 to 1.0% by weight. If it exceeds 2% by weight, the safety of the preparation may be a concern, and if it is less than 0.01% by weight, it is difficult to exert sufficient storage efficacy.
  • thickening aid examples include sodium edetate hydrate, tetrasodium edetate hydrate, tetrasodium edetate tetrahydrate, sodium metaphosphate and the like.
  • the content of the thickening aid in the composition is preferably in the range of 0.005 to 1% by weight, more preferably in the range of 0.01 to 0.5% by weight. If it exceeds 1% by weight, the safety of the preparation may be a concern, and if it is less than 0.005% by weight, it will provide sufficient thickening support for hydrophilic polymers (thickeners). Is difficult.
  • a particularly preferred thickening aid is sodium edetate hydrate.
  • the emulsification aid examples include cetanol, stearyl alcohol, cetostearyl alcohol, and behenyl alcohol.
  • a particularly preferred emulsification aid is cetanol.
  • the content of the emulsification aid in the composition is preferably in the range of 0.1 to 5% by weight, more preferably 0.5 to 3% by weight, if necessary.
  • the cream-like composition according to the present invention contains water (purified water) constituting an aqueous phase.
  • the water content in the composition varies depending on the content of other components, but is preferably about 45 to 85% by weight, more preferably about 55 to 82% by weight.
  • the cream composition according to the present invention preferably does not contain a lower monohydric alcohol (monohydric alcohol having 1 to 3 carbon atoms) such as ethanol. This is because a lower monohydric alcohol such as ethanol has a high volatility, and there is a concern that the effect on the skin due to the addition to an external preparation is concerned.
  • compositions according to the present invention include tacrolimus hydrate as the main agent, 5 to 25% by weight of diethyl sebacate and / or diisopropyl sebacate (preferably either) as the oil agent, and polyoxyethylene hydrogenated castor as the emulsifier.
  • examples include oil 60, a composition containing carboxyvinyl polymer as a thickener and dibutylhydroxytoluene as an antioxidant.
  • examples of more preferable compositions include, in addition to the above, 1,3-butylene glycol as a wetting agent, and / or diisopropanolamine as a pH adjusting agent, and / or sodium edetate as a thickening aid.
  • compositions containing hydrates include 1,3-butylene glycol as a wetting agent, and / or diisopropanolamine as a pH adjusting agent, and / or sodium edetate as a thickening aid.
  • composition of the present invention includes a composition obtained by arbitrarily combining them. Also included are compositions obtained by arbitrarily combining the concentration ranges described for each component.
  • numerical ranges such as concentration, viscosity, pH value, etc. described in the preceding paragraph can be arbitrarily combined. When multiple numerical ranges are described, the upper limit value or lower limit value of each numerical range can be arbitrarily combined. It is.
  • the amount and frequency of application of the composition according to the present invention to the skin may be appropriately adjusted according to skin symptoms, the concentration of tacrolimus in the composition, the age of the patient, and the like. In general, it is appropriate to apply 1 to 2 times a day, and the daily dose is 5 mg or less for adults (indicating mg of tacrolimus, not the composition; the same applies in this paragraph), for children 1.5mg or less is appropriate (Dose as appropriate depending on the age and weight of the child. For example, for children under 20kg, the daily usage is 0.3mg or less, and for children between 20 and 30kg, the daily usage. 0.6 mg or less is appropriate).
  • Example 1 Preparation of O / W type creamy composition containing tacrolimus hydrate An O / W type creamy composition having the composition shown in Table 1 was prepared by the following method. In advance, the carboxyvinyl polymer was swollen in purified water to obtain an aqueous carboxyvinyl polymer solution. Further, diisopropanolamine was dissolved in purified water to obtain a diisopropanolamine aqueous solution.
  • tacrolimus hydrate, dibutylhydroxytoluene (hereinafter referred to as BHT in the examples), propyl paraoxybenzoate and cetanol are dissolved in the oil, polyoxyethylene hydrogenated castor oil is added, and the oil phase part It was.
  • BHT dibutylhydroxytoluene
  • an aqueous carboxyvinyl polymer solution, 1,3-butylene glycol, methyl paraoxybenzoate, sodium edetate hydrate and purified water were combined to form an aqueous phase part.
  • the oil phase part and the water phase part were each heated to 70 to 90 ° C. and dissolved, and then the water phase part was added to the oil phase part and emulsified using a homomixer.
  • compositions shown in Table 1 were creamy, and no separation or the like was observed in appearance, and it was possible to prepare a good O / W type creamy composition.
  • Example 2 Stability evaluation of O / W type creamy composition containing tacrolimus hydrate Cream Nos. 2 to 4, No. 6, No. 8 to 10 prepared in Example 1 Store for 3 months under specified conditions, and measure tacrolimus hydrate content according to "16th revised Japanese Pharmacopoeia General Test Method Liquid Chromatography ⁇ 2.01>". The residual rate of hydrate was calculated, and the stability of the active ingredient in the composition was evaluated. The results are shown in Table 2.
  • composition using No. 2 to No. 4, No. 6, No. 8 and No. 8 as the oil agent was more suitable as the oil agent. It showed higher stability of the active ingredient than the compositions using chain fatty acid triglycerides and ethylene glycol salicylate (No. 9 and 10). Further, when comparing compositions using diethyl sebacate or diisopropyl sebacate as an oil agent, composition No. 2 containing an antioxidant (BHT) compared to composition No. 8 containing no antioxidant, No.3, No.4 and No.6 showed higher active ingredient stability.
  • BHT antioxidant
  • Table 3 shows the results of stability tests conducted over time for compositions Nos. 2 to 4, No. 6, No. 7, No. 9, and No. 10.
  • compositions No. 9 and No. 10 were stored for 6 months when the storage conditions were ⁇ 25 ° C., relative humidity 60% '' or ⁇ 30 ° C., relative humidity 65% ''
  • the residual rate of the active ingredient was 95% or more, but when the storage conditions were severe, ⁇ 40 ° C, relative humidity 75% '', the residual rate of active ingredient after 3 months was less than 90% and after 6 months, About 80%.
  • compositions Nos. 2 to 4, No. 6, and No. 7, which are the compositions of the present invention are the main drug after 3 months even when the storage conditions are “40 ° C. and relative humidity 75%”.
  • the residual rate was 95% or higher and / or the residual rate of the active ingredient after 6 months was 90% or higher, which proved that it could withstand long-term storage even under harsh conditions. From the results of this Example, it was found that diethyl sebacate and diisopropyl sebacate are very suitable oil agents for suppressing the decomposition of the main agent over a long period of time.
  • Example 3 Effectiveness of O / W type creamy composition (in vitro human skin permeability evaluation)
  • P ointment 0.1% Protopic (registered trademark) ointment 0.1%
  • Human back skin (1.77 cm 2 ) was attached to a Franz-type cell, and 10 mg of the composition No. 2, No. 7 or P ointment was hermetically applied.
  • a receptor solution (1 w / v% bovine serum albumin-containing phosphate buffered saline) was collected after a predetermined time, and the amount of tacrolimus in the stratum corneum 24 hours after application was quantified.
  • composition No. 2 oil agent: diethyl sebacate
  • composition No. 7 oil agent: diisopropyl sebacate
  • Example 4 Effectiveness of O / W type creamy composition (in vitro mouse skin permeability evaluation)
  • the above compositions No. 1 to 4 and P ointment were applied to hairless mouse skin (obtained through Hoshino test animal breeding house)
  • the amounts in the skin 24 hours after application were compared.
  • Lab skin (1.77 cm 2 ) was attached to a Franz-type cell, and 10 mg of the above composition No. 1 to 4 or P ointment was hermetically applied.
  • a receptor solution (1 w / v% bovine serum albumin-containing phosphate buffered saline) was collected after a predetermined time, and the amount of tacrolimus in the skin 24 hours after application was quantified. The results are shown in Table 5 and FIG. 1 (b).
  • composition No. 1 having a diethyl sebacate content of 5% by weight and the composition No. 2 having a diethyl sebacate content of 20% by weight were more preferable. It was found that the amount of tacrolimus hydrate permeated through the skin was higher than that of Composition No. 4 which was .3 and 40% by weight. Compositions No. 1 and No. 2 showed a higher skin permeation amount than P ointment.
  • the composition of the present invention can achieve high drug transdermal absorbability exceeding P ointment with a small amount of oil. By suppressing the oil agent to a small amount, a creamy composition with less stickiness and a refreshing feel can be prepared. According to the present invention, a composition having a high medicinal effect and a very good feeling of use is provided. can do. Further, from the results of this example, according to the present invention, the skin absorbability can be controlled by the amount of oil added, and a safer formulation that exhibits the same medicinal effect even if the tacrolimus content is reduced as compared with P ointment. It turns out that development is possible.
  • Example 5 Irritation (evaluation of cumulative skin irritation) of O / W type creamy composition
  • the cumulative skin irritation of compositions No. 2 and No. 7 was examined using female rabbits (Kbl: NZW).
  • Kbl: NZW female rabbits
  • Skin reaction was determined according to the criteria of Draize, JH (Appraisal of the safety of chemicals in foods, drugs and cosmetics, The Association of Food and Drug Officials of the United States, Topeka, Kansas, 46-59, 1965).
  • the degree of cumulative skin irritation was evaluated based on the average value of the administration period of the average score on each judgment day.
  • the test results are shown in Tables 6 and 7. As can be seen from Table 7, the average value of the administration period of each composition was 0.7 for composition No. 2 and 1.1 for composition No. 7, both of which were classified as “weak stimulants”.
  • Example 6 Irritation of O / W cream type composition (Evaluation of primary irritation of ocular mucosa)
  • the primary irritation of ocular mucosa of compositions No. 2 and No. 7 was examined using female rabbits (Kbl: NZW).
  • the ocular reaction was determined by Draize, JH (Appraisal of the safety of chemicals in foods, drugs and cosmetics, Association of Food and Drug Officials of the United States, 49-51, 1959) at 1, 24 and 48 hours after administration.
  • the ocular mucosal irritation intensity was evaluated according to AFNOR evaluation criteria (Association Francaise de Normalisation, Evaluation de I'Irritation et / ou de la Corrosion O vides sheep le Lapin, NF T03-264, 1982).
  • the test results are shown in Table 8, and the evaluation criteria are shown in Table 9.
  • the highest total average score of each composition was 0.7 for composition No. 2 and 1.3 for composition No. 7, both of which were classified as “irritant”.
  • the present invention it is possible to provide a cream-like composition that has good stability of tacrolimus, little irritation, and can easily control the concentration of the active ingredient in the skin.
  • the cream-like composition according to the present invention is particularly suitable as a therapeutic agent for atopic dermatitis.

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  • Medicinal Preparation (AREA)

Abstract

L'objet de la présente invention consiste en une composition pharmaceutique contenant du tacrolimus qui est une préparation crémeuse destinée à une application externe donnant une sensation agréable lors de l'utilisation et qui présente une stabilité élevée de l'ingrédient principal (un rapport ingrédient principal/résidu élevé). La composition selon la présente invention consiste en une composition crémeuse de type huile-dans-eau caractérisée en ce qu'elle comprend (A) du tacrolimus, un sel pharmaceutiquement acceptable de celui-ci ou un solvate pharmaceutiquement acceptable de celui-ci, (B) du sébacate de diéthyle et/ou du sébacate de diisopropyle, (C) du polyoxyéthylène-huile de ricin hydrogénée, (D) un polymère hydrophile et (E) un agent antioxydant.
PCT/JP2013/051453 2012-01-25 2013-01-24 Composition crémeuse de type huile-dans-eau contenant du tacrolimus WO2013111817A1 (fr)

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JP2013555305A JP6084579B2 (ja) 2012-01-25 2013-01-24 タクロリムスを含有する水中油型クリーム状組成物

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019082873A1 (fr) * 2017-10-23 2019-05-02 マルホ株式会社 Agent topique formant un revêtement

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2000513739A (ja) * 1997-02-20 2000-10-17 藤沢薬品工業株式会社 医薬組成物
JP2005500269A (ja) * 2001-05-28 2005-01-06 藤沢薬品工業株式会社 トリシクロ化合物を含有する皮膚疾患の予防または治療のための医薬組成物
WO2012011566A1 (fr) * 2010-07-23 2012-01-26 マルホ株式会社 Composition crémeuse de type huile dans eau contenant du tacrolimus

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH06345646A (ja) * 1993-06-08 1994-12-20 Fujisawa Pharmaceut Co Ltd ローション剤
CN1089233C (zh) * 1994-10-26 2002-08-21 诺瓦蒂斯有限公司 药物组合物

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2000513739A (ja) * 1997-02-20 2000-10-17 藤沢薬品工業株式会社 医薬組成物
JP2005500269A (ja) * 2001-05-28 2005-01-06 藤沢薬品工業株式会社 トリシクロ化合物を含有する皮膚疾患の予防または治療のための医薬組成物
WO2012011566A1 (fr) * 2010-07-23 2012-01-26 マルホ株式会社 Composition crémeuse de type huile dans eau contenant du tacrolimus
WO2012011192A1 (fr) * 2010-07-23 2012-01-26 マルホ株式会社 Composition crémeuse de type huile dans l'eau contenant du tacrolimus

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019082873A1 (fr) * 2017-10-23 2019-05-02 マルホ株式会社 Agent topique formant un revêtement

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JPWO2013111817A1 (ja) 2015-05-11

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