WO2013111817A1 - Oil-in-water-type creamy composition containing tacrolimus - Google Patents

Oil-in-water-type creamy composition containing tacrolimus Download PDF

Info

Publication number
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
Authority
WO
WIPO (PCT)
Prior art keywords
composition
tacrolimus
oil
weight
present
Prior art date
Application number
PCT/JP2013/051453
Other languages
French (fr)
Japanese (ja)
Inventor
伊原　幹人
義則 上田
史紀 鳴海
Original Assignee
マルホ株式会社
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 マルホ株式会社 filed Critical マルホ株式会社
Priority to JP2013555305A priority Critical patent/JP6084579B2/en
Publication of WO2013111817A1 publication Critical patent/WO2013111817A1/en

Links

Images

Classifications

    • 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.

Abstract

The purpose of the present invention is to provide a tacrolimus-containing pharmaceutical composition which is a creamy preparation for external application having a good sensation upon use and has high main ingredient stability (a high main ingredient residual ratio). The composition according to the present invention is an oil-in-water-type creamy composition characterized by comprising (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) an anti-oxidative agent.

Description

タクロリムスを含有する水中油型クリーム状組成物Oil-in-water cream composition containing tacrolimus
　本発明は、タクロリムスを含有する水中油型(O/W)クリーム状組成物に関する。 The present invention relates to an oil-in-water (O / W) cream-like composition containing tacrolimus.
　タクロリムス外用剤は、アトピー性皮膚炎に優れた治療効果を有することが知られており、現在、油性基剤を用いた油性軟膏剤としてプロトピック(登録商標)軟膏0.1%及びプロトピック(登録商標)軟膏0.03%小児用が市販されている。しかし、油性軟膏剤は、皮膚保護作用に優れる等のメリットを有する反面、皮膚塗布時にべたつきがあって使用感が悪いため、患者や医療関係者からは、より使用感の良いクリーム状の外用剤が求められている。 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. However, 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.
　クリーム状の外用剤は、油と水とを乳化剤で乳化してなる乳剤性基剤を用いて製造される。しかし、タクロリムスは水に対して不安定であるため、乳剤性基剤を用いると、油性基剤を用いた場合に比べて、タクロリムスの残存率が低くなり有効性(皮内濃度)を維持することが、技術的に困難であるという問題がある。 Cream external preparations are produced using an emulsion base formed by emulsifying oil and water with an emulsifier. However, since tacrolimus is unstable to water, 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. However, there is a problem that it is technically difficult.
　これに対し、従来にも、クリーム状の医薬組成物の調製が試みられており(特許文献1参照)、また、本件出願人も以前にタクロリムスを含有するクリーム状医薬組成物の出願を行っているが(PCT/JP2011/066698)、今なお、使用感が良く、刺激性が少なく、製剤中の主薬安定性が高く、皮膚中のタクロリムスの濃度を至適範囲に調製しやすい組成物を開発することが望まれている。 On the other hand, the preparation of a creamy pharmaceutical composition has been attempted in the past (see Patent Document 1), and the present applicant has previously filed a creamy pharmaceutical composition containing tacrolimus. (PCT / JP2011 / 066698), but still developed a composition that is easy to use, less irritating, has high stability of the active ingredient in the formulation, and can be easily adjusted to the optimal concentration of tacrolimus in the skin. It is hoped to do.
特表2000-513739号公報Special Table 2000-513739
 　したがって、本発明は、使用感の良いクリーム状の外用剤であって、刺激性が少なく、製剤中のタクロリムスの安定性(主薬残存率)が高く、さらに適用部位において所望の経皮吸収性を達成できる、タクロリムス含有医薬組成物(皮膚用外用剤)を提供することを課題とする。 Therefore, 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.
　本発明者らは、上記課題を解決するために検討を重ねた結果、特定の溶解剤(以下、油剤とも称する)および乳化剤を採用し、前記溶解剤にタクロリムスを溶解して、これを内相(油相)とする水中油型組成物を調製することにより、前記課題を効果的に解決できることを見出し、本発明を完成した。 As a result of repeated studies to solve the above problems, the present inventors adopted a specific solubilizer (hereinafter also referred to as an oil agent) and an emulsifier, dissolved tacrolimus in the solubilizer, and used this as an internal phase. It has been found that the above-mentioned problems can be effectively solved by preparing an oil-in-water composition as (oil phase), and the present invention has been completed.
　すなわち、本発明は、水中油型のクリーム状組成物であって、
(A)タクロリムス、その製剤学的に許容される塩、又はその製剤学的に許容される溶媒和物、
(B)セバシン酸ジエチル及び/又はセバシン酸ジイソプロピル、
(C)ポリオキシエチレン硬化ヒマシ油、
(D)親水性高分子、及び
(E)抗酸化剤
を含有することを特徴とする。 That is, 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.
　本発明に係るクリーム状組成物は、内相を油相とする水中油型であって、油相中に主薬である、タクロリムス、その塩、又はその溶媒和物(以下、これらを代表してタクロリムスと称する)を含むため、主薬と水相(外相)の接触を低減させることができ、水に不安定なタクロリムスを安定に保つことができる。また、当該油相を構成する油剤として、セバシン酸ジエチル及び/又はセバシン酸ジイソプロピルを用い、さらに抗酸化剤(好ましくは、ジブチルヒドロキシトルエン)を用いることにより、タクロリムスの溶解性、製剤中のタクロリムスの安定性、タクロリムスの経皮吸収性の全てに優れた水中油型(O/W型)のクリーム状組成物を得ることができる。また、増粘剤として親水性高分子を使用し、乳化剤としてポリオキシエチレン硬化ヒマシ油を用いることにより、優れた分散性を達成することができる。 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). (Referred to as tacrolimus), the contact between the active ingredient and the aqueous phase (external phase) can be reduced, and water-unstable tacrolimus can be kept stable. In addition, by using diethyl sebacate and / or diisopropyl sebacate as the oil constituting the oil phase, and further using an antioxidant (preferably dibutylhydroxytoluene), 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. Moreover, the outstanding dispersibility can be achieved by using a hydrophilic polymer as a thickener and using polyoxyethylene hydrogenated castor oil as an emulsifier.
　本発明によれば、製剤中のタクロリムスを安定に保つことができ、優れた薬効を発揮できるとともに、刺激性が少なく、使用感のよい(べたつきの少ない)クリーム状組成物を提供することができる。 According to the present invention, 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. .
タクロリムスに関するin vitro皮膚透過性試験の結果を示すグラフであって、(a)はヒト角質層中のタクロリムス量を示し、(b)はマウス皮膚中のタクロリムス量を示す。It is a graph which shows the result of the in-vitro skin permeability test regarding tacrolimus, (a) shows the amount of tacrolimus in human stratum corneum, and (b) shows the amount of tacrolimus in mouse skin.
　本発明に係るクリーム状組成物は、タクロリムス(A)を0.01～0.3重量%含むことが好ましい。タクロリムスの含有率が0.01重量%を下回ると、有効性が乏しくなり、0.3重量%を越えると安全性が危惧されるおそれがある。
　タクロリムスの製剤学的に許容される塩としては、無毒の、医薬として許容される慣用の塩を用いることができる。このような塩として、例えばアルカリ金属塩(ナトリウム塩、カリウム塩等)、アルカリ土類金属塩(カルシウム塩、マグネシウム塩等)、アンモニウム塩、アミン塩(トリエチルアミン塩、Ｎ－ベンジル－Ｎ－メチルアミン塩等)のような無機又は有機塩基との塩が挙げられる。
　タクロリムスの製剤学的に許容される溶媒和物としては、水和物及びエタノレートが挙げられる。
　本発明の(A)として特に好ましい化合物は、タクロリムス水和物である。 The cream composition according to the present invention preferably contains 0.01 to 0.3% by weight of tacrolimus (A). When the content of tacrolimus is less than 0.01% by weight, the effectiveness is poor, and when it exceeds 0.3% by weight, there is a risk of safety.
As a pharmaceutically acceptable salt of 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.
　本発明に係るクリーム状組成物では、油相を構成する油剤としてセバシン酸ジエチル及び/又はセバシン酸ジイソプロピル(B)が使用される。本発明では、油相を構成する油剤としてセバシン酸ジエチル及び/又はセバシン酸ジイソプロピルのみを用いてもよく、あるいは、他の油剤を併用してもよい。
　本発明に係る組成物の特に好ましい例は、油相を構成する油剤として、セバシン酸ジエチル又はセバシン酸ジイソプロピルのどちらかのみを含む組成物である。 In the creamy composition according to the present invention, diethyl sebacate and / or diisopropyl sebacate (B) is used as the oil agent constituting the oil phase. In the present invention, only 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.
　組成物におけるセバシン酸ジエチル及び/又はセバシン酸ジイソプロピルの含有率は、合計で5～50重量%であることが好ましい。5重量%を下回った場合は、タクロリムスの安定性と吸収性が損なわれ、50重量%を越えると、水中油型のクリーム状組成物を調製するのが困難である。より好ましい含有率は、5～40重量%であり、特に好ましい含有率は5～25重量%であり、さらに好ましい含有率は10～20重量%である。
　また、さっぱりとした使用感(べたつき感を抑えた軽い滑らかな感触)を達成するには、セバシン酸ジエチル及び/又はセバシン酸ジイソプロピルの含有率は20重量%以下(より好ましくは15重量%以下、特に好ましくは12重量％以下)とすることが好ましい。本発明では、セバシン酸ジエチル及び/又はセバシン酸ジイソプロピルが20重量%以下であっても、優れた経皮吸収性を有する組成物を得ることができる。 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.
Further, in order to achieve a refreshing feeling of use (light smooth feeling with reduced stickiness), 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. In the present invention, even if diethyl sebacate and / or diisopropyl sebacate is 20% by weight or less, a composition having excellent transdermal absorbability can be obtained.
　また、本発明では、セバシン酸ジエチル及び/又はセバシン酸ジイソプロピルの量を増減することによって、タクロリムスの経皮吸収性をコントロールすることが可能である。
　経皮吸収性のコントロールについて、より詳細に述べると、当然のことながら、高い薬効を期待する場合は、タクロリムスの経皮吸収性が高い組成物のほうが好ましい。他方、タクロリムスは、強い免疫抑制作用を有するため、血中濃度の上昇により副作用の発生頻度が高まる可能性がある。例えば、角質層のバリア機能が低下し、経皮吸収性が高まっている皮膚に使用する場合や、特定の患者(例えば小児、妊婦、授乳婦、高齢者、肝障害のある患者等)に使用する場合には、むしろ吸収性を抑えた製剤が望まれることがある。
　本発明では、セバシン酸ジエチル及び/又はセバシン酸ジイソプロピルの量を調節することにより、高い製剤安定性を保持したまま、皮膚への吸収性をコントロールすることができるため、これらの要望に対応することが可能である。 In the present invention, 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. As a matter of course, a composition with high transdermal absorbability of tacrolimus is preferable when high drug efficacy is expected. On the other hand, tacrolimus has a strong immunosuppressive effect, and thus the frequency of side effects may increase due to an increase in blood concentration. For example, it is used on skin where the stratum corneum barrier function is reduced and the percutaneous absorption is increased, or on specific patients (for example, children, pregnant women, lactating women, elderly people, patients with liver disorders, etc.) In some cases, preparations with rather low absorbability may be desired.
In 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.
　本発明に係るクリーム状組成物は、水相と油相を乳化し、安定させるための乳化剤(界面活性剤)として、ポリオキシエチレン硬化ヒマシ油(C)を含む。ポリオキシエチレン硬化ヒマシ油を使用することにより、優れた乳化安定性を有する水中油型のクリーム状組成物を調製することが可能である。より好ましいポリオキシエチレン硬化ヒマシ油は10.5～16.5のHLB値を有するものであり、特に好ましいポリオキシエチレン硬化ヒマシ油は12.5～15.0のHLB値を有するものである。
　組成物におけるポリオキシエチレン硬化ヒマシ油の含有率は、0.5～10重量%が好ましい。10重量%を越えた場合は、製剤としての安全性が危惧されるおそれがあり、0.5重量%未満の場合は、安定な水中油型クリーム状組成物を製造することが困難である。より好ましいポリオキシエチレン硬化ヒマシ油の含有率は1～6重量%、特に好ましい含有率は1.5～5重量%、さらに好ましい含有率は2～4重量%である。
　ポリオキシエチレン硬化ヒマシ油は一種のみを用いてもよく、複数を併用してもよい。好ましいポリオキシエチレン硬化ヒマシ油の具体例として、酸化エチレンの付加重合数が20～100であるポリオキシエチレン硬化ヒマシ油が挙げられる。特に好ましいポリオキシエチレン硬化ヒマシ油の一例として、ポリオキシエチレン硬化ヒマシ油60(HLB値14.0)が挙げられる。 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. 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. If it exceeds 10% by weight, the safety of the preparation may be a concern, and if it is less than 0.5% by weight, it is difficult to produce a stable oil-in-water cream composition. A more preferable content of 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).
　本発明に係るクリーム状組成物は、組成物を増粘し、製剤としての安定性を確保する(分離を防ぐ)ため、親水性高分子(D)を含有する。組成物における親水性高分子の含有率は、0.1～10重量%が好ましい。10重量%を越えた場合は、製剤が固くなりすぎて使用し辛くなる可能性があり、0.1重量%未満の場合は、安定な水中油型クリーム状組成物を製造することが困難である。より好ましい親水性高分子の含有率は0.2～2重量%である。
　好ましい親水性高分子の具体例として、カルボキシビニルポリマーや、ヒドロキシエチルセルロース、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、疎水化ヒドロキシプロピルメチルセルロース等の水溶性セルロース誘導体が挙げられる。これらは単独で用いてもよく、併用で用いてもよい。特に好ましい親水性高分子として、カルボキシビニルポリマーが挙げられる。
　本発明に係るクリーム状組成物の粘度は特に限定されないが、一般に10000～200000mPa・sであることが好ましく、20000～100000mPa・sであることがより好ましい。本発明において、粘度とは、Ｂ型粘度計(TVB-10H、ローター7)にて、測定温度25℃、回転数20rpmで30秒間測定した際の粘度を意味する。 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.
Specific examples of preferred 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. In the present invention, 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.
　本発明に係るクリーム状組成物は、タクロリムスの分解を抑制し、主薬安定性を高めるために、抗酸化剤(E)を含有する。組成物における抗酸化剤の含有率は、0.01～0.20重量%が好ましく、0.05～0.15重量%がより好ましい。抗酸化剤が少なすぎる場合にも多すぎる場合にもタクロリムスの安定性を高める効果が弱くなる。 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.
　前記抗酸化剤(E)の具体例として、ジブチルヒドロキシトルエン、亜硝酸ナトリウム、アスコルビン酸、L-アスコルビン酸ステアリン酸エステル、亜硫酸水素ナトリウム、亜硫酸ナトリウム、アルファチオグリセリン、エリソルビン酸、塩酸システイン、乾燥亜硫酸ナトリウム、酢酸トコフェロール、ジクロルイソシアヌール酸カリウム、大豆レシチン、チオグリコール酸ナトリウム、チオリンゴ酸ナトリウム、天然ビタミンE、トコフェロール、d-δ-トコフェロール、濃縮混合トコフェロール、パルミチン酸アスコルビン酸、ピロ亜硫酸ナトリウム、ブチルヒドロキシアニソール、ベンゾトリアゾール、ペンタエリスリチル-テトラキス[3-(3,5-ジ-t-ブチル-4-ヒドロキシフェニル)プロピオネート]、没食子酸プロピル、2-メルカプトベンズイミダゾール、カロテノイド(アスタキサンチン，リコピンなど)、フラボノイド(イソフラボン)、ポリフェノール(アントシアニン，セサミノール，カテキンなど)、コエンザイムQ10が挙げられる。 Specific examples of the antioxidant (E) include dibutylhydroxytoluene, sodium nitrite, ascorbic acid, L-ascorbic acid stearate, sodium bisulfite, sodium sulfite, alphathioglycerin, erythorbic acid, cysteine hydrochloride, and dry sulfite. Sodium, tocopherol acetate, potassium dichloroisocyanurate, soy lecithin, sodium thioglycolate, sodium thiomalate, natural vitamin E, tocopherol, d-δ-tocopherol, concentrated mixed tocopherol, ascorbic acid palmitate, sodium pyrosulfite, butyl Hydroxyanisole, benzotriazole, pentaerythrityl-tetrakis [3- (3,5-di-t-butyl-4-hydroxyphenyl) propionate], propyl gallate, 2-mercaptobenzimidazo Le, carotenoids (astaxanthin, lycopene, etc.), flavonoids (isoflavones), polyphenols (anthocyanins, sesaminol, catechin etc.), and a coenzyme Q10.
　特に好ましい抗酸化剤はジブチルヒドロキシトルエンである。抗酸化剤としてジブチルヒドロキシトルエンを用いた場合、タクロリムスの安定性が非常に高く、且つ、刺激性の非常に少ない組成物を得ることができる。 A particularly preferred antioxidant is dibutylhydroxytoluene. When dibutylhydroxytoluene is used as the antioxidant, a composition with very high stability of tacrolimus and very little irritation can be obtained.
　本発明に係るクリーム状組成物は、4～7の範囲のpH値を有することが好ましい。pH値が4未満の場合は、製剤としての安全性が危惧されるおそれがあり、pH値が7を超えた場合は、セバシン酸ジエチル及び/又はセバシン酸ジイソプロピルの加水分解が危惧される。また、上記pH値は、タクロリムスの安定性の面でも、至適pHである。より好ましいpHの範囲は5～6である。 The cream composition according to the present invention preferably has a pH value in the range of 4-7. When 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. Further, the above pH value is an optimum pH in terms of the stability of tacrolimus. A more preferred pH range is 5-6.
　組成物を上記範囲のpH値に調節するためのpH調節剤としては、低pH領域に調節するために使用されるものとして、乳酸、クエン酸、リン酸などが挙げられ、高pH領域に調節するため使用されるものとして、水酸化ナトリウム、水酸化カリウム、乳酸ナトリウム、クエン酸ナトリウム、L-アルギニン、ジイソプロパノールアミンなどが挙げられる。特に好ましいpH調節剤として、ジイソプロパノールアミンが挙げられる。 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.
　本発明に係るクリーム状組成物は、上記成分の他に、湿潤剤、保存剤、増粘補助剤、乳化助剤等を含むことができる。 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.
　上記湿潤剤の例としては、1,3-ブチレングリコール、グリセリン、プロピレングリコール、ジプロピレングリコールなどが挙げられる。特に好ましい湿潤剤として、1,3-ブチレングリコールが挙げられる。組成物における湿潤剤の含有率は、0.01～30重量%の範囲とすることが好ましく、1～20重量%がより好ましい。 Examples of the wetting agent 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.
　上記保存剤の例としては、パラオキシ安息香酸メチル、パラオキシ安息香酸エチル、パラオキシ安息香酸プロピル、安息香酸ナトリウム、フェノキシエタノールなどが挙げられる。上記保存剤は、一種のみを用いてもよく、複数を併用してもよい。組成物における保存剤の含有率は、0.01～2重量%の範囲とすることが好ましく、0.1～1.0重量%の範囲とすることがより好ましい。2重量%を越えた場合は、製剤としての安全性が危惧されるおそれがあり、0.01重量%未満の場合は、十分な保存効力を発揮することが困難である。 Examples of the preservative 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.
　上記増粘補助剤の例としては、エデト酸ナトリウム水和物、エデト酸四ナトリウム水和物、エデト酸四ナトリウム四水塩、メタリン酸ナトリウムなどが挙げられる。組成物における増粘補助剤の含有率は、0.005～1重量%の範囲とすることが好ましく、0.01～0.5重量%の範囲とすることがより好ましい。1重量%を越えた場合は、製剤としての安全性が危惧されるおそれがあり、0.005重量%未満の場合は、親水性高分子(増粘剤)に対して十分な増粘補助作用を発揮することが困難である。特に好ましい増粘補助剤として、エデト酸ナトリウム水和物が挙げられる。 Examples of the above thickening aid 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.
　上記乳化助剤の例としては、セタノール、ステアリルアルコール、セトステアリルアルコール、ベヘニルアルコールなどが挙げられる。特に好ましい乳化助剤として、セタノールが挙げられる。組成物における乳化助剤の含有率は、必要に応じて0.1～5重量%の範囲とすることが好ましく、0.5～3重量%がより好ましい。 Examples of the emulsification aid 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.
　本発明に係るクリーム状組成物は、水相を構成する水(精製水)を含む。組成物における水の含有率は、他の成分の含有率によっても変動するが、45～85重量%程度が好ましく、55～82重量%程度がより好ましい。
　なお、本発明に係るクリーム状組成物は、エタノール等の低級一価アルコール(炭素数1～3の一価アルコール)を含まないことが好ましい。エタノールのような低級一価アルコールは揮発性が高く、外用剤に添加することによる皮膚への影響が懸念されるという問題があるためである。 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.
　本発明に係る組成物の好ましい例として、主薬としてタクロリムス水和物、油剤として5～25重量%のセバシン酸ジエチル及び/又はセバシン酸ジイソプロピル(好ましくはどちらか一方)、乳化剤としてポリオキシエチレン硬化ヒマシ油60、増粘剤としてカルボキシビニルポリマー、抗酸化剤としてジブチルヒドロキシトルエンを含む組成物が挙げられる。また、より好ましい組成物の例として、上記に加えて、さらに湿潤剤として1,3-ブチレングリコール、及び/又は、pH調節剤としてジイソプロパノールアミン、及び/又は、増粘補助剤としてエデト酸ナトリウム水和物を含む組成物が挙げられる。 Preferred examples of the composition 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. Examples include compositions containing hydrates.
　なお、先行する段落において、本発明の組成物に使用される必須成分および任意成分の好ましい化合物名を記載してきたが、本発明の組成物には、これらを任意に組み合わせて得られる組成物が含まれ、且つ、各成分について記載した濃度範囲を任意に組み合わせて得られる組成物も含まれる。また、先行する段落において記載した濃度、粘度、pH値等の数値範囲も任意に組み合わせ可能であり、数値範囲が複数記載されている場合、各数値範囲の上限値または下限値も任意に組み合わせ可能である。 In the preceding paragraphs, the names of preferred compounds of the essential components and optional components used in the composition of the present invention have been described. However, the 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. In addition, 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.
　本発明に係る組成物の皮膚への塗布量・塗布頻度は、皮膚の症状、組成物中のタクロリムスの濃度、患者の年齢等に応じて適宜調節すればよい。通常、一日1～2回の塗布が適切であり、一日の使用量は、成人の場合5mg以下(組成物ではなく、タクロリムスのmgを示す。以下、この段落において同じ)、小児の場合1.5mg以下が適切である(小児の年齢や体重によって適宜減量する。例えば、20kg未満の小児の場合、一日の使用量は0.3mg以下、20～30kgの小児の場合、一日の使用量は0.6mg以下が適切である)。 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).
　以下、実施例により本発明をより詳細に説明するが、本発明は実施例により限定されるものではない。
［実施例１］タクロリムス水和物を含有するO/W型クリーム状組成物の調製
　以下の方法により表1に示す組成を有するO/W型クリーム状組成物を調製した。
　あらかじめ、カルボキシビニルポリマーを精製水に膨潤させ、カルボキシビニルポリマー水溶液とした。また、ジイソプロパノールアミンを精製水に溶解させ、ジイソプロパノールアミン水溶液とした。
　処方に応じて、タクロリムス水和物、ジブチルヒドロキシトルエン(以下、実施例中においてBHTと表記する)、パラオキシ安息香酸プロピル及びセタノールを油剤に溶解させ、ポリオキシエチレン硬化ヒマシ油を加え、油相部とした。一方、カルボキシビニルポリマー水溶液、1,3-ブチレングリコール、パラオキシ安息香酸メチル、エデト酸ナトリウム水和物及び精製水を合わせ、水相部とした。
　油相部、水相部をそれぞれ70～90℃に加温し、溶解させた後、油相部に水相部を加え、ホモミキサーを用いて乳化処理を行なった。次いで、ジイソプロパノールアミン水溶液を加えた後、品温が室温になるまで撹拌棒で撹拌し、均質なクリーム剤を製した(粘度30000～60000mPa・s)。
　ただし、O/W型クリーム状組成物の調製方法はこれに限定されない。 EXAMPLES Hereinafter, although an Example demonstrates this invention in detail, this invention is not limited by an Example.
[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.
According to the formulation, 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. On the other hand, 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. Next, an aqueous solution of diisopropanolamine was added, and the mixture was stirred with a stirring bar until the product temperature reached room temperature to produce a homogeneous cream (viscosity 30000-60000 mPa · s).
However, the method for preparing the O / W type creamy composition is not limited to this.
Figure JPOXMLDOC01-appb-T000001
Figure JPOXMLDOC01-appb-T000001
　表1に示す組成物はいずれもクリーム状であり、外観上分離等は認められず、良好なO/W型クリーム状組成物を調製することが可能であった。 All of the 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.
［実施例2］タクロリムス水和物を含有するO/W型クリーム状組成物の安定性評価
　実施例1で調製したクリーム状組成物No.2～4、No.6、No.8～10を所定の条件下で3ヶ月保管し、タクロリムス水和物含量を「第16改正日本薬局方 一般試験法 液体クロマトグラフィー＜2.01＞」に従って測定し、下記の式1により、クリーム状組成物中のタクロリムス水和物の残存率を算出し、組成物中の主薬安定性を評価した。結果を表2に示す。
Figure JPOXMLDOC01-appb-M000002
 [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.
Figure JPOXMLDOC01-appb-M000002
Figure JPOXMLDOC01-appb-T000003
Figure JPOXMLDOC01-appb-T000003
　クリーム状組成物の安定性試験を行った結果、油剤としてセバシン酸ジエチルまたはセバシン酸ジイソプロピルを用いた組成物(No.2～No.4，No.6、No.8)のほうが、油剤として中鎖脂肪酸トリグリセリドとサリチル酸エチレングルコールを用いた組成物(No.9および10)よりも高い主薬安定性を示した。また、油剤としてセバシン酸ジエチルまたはセバシン酸ジイソプロピルを用いた組成物どうしを比較すると、抗酸化剤を含まない組成物No.8と比べて、抗酸化剤(BHT)を含む組成物No.2、No.3、No.4、No.6のほうが高い主薬安定性を示した。 As a result of the stability test of the creamy composition, it was found that the 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.
　さらに、組成物No.2～4、No.6、No.7、No.9、No.10について経時的に行った安定性試験の結果を表3に示す。 Furthermore, 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.
Figure JPOXMLDOC01-appb-T000004
Figure JPOXMLDOC01-appb-T000004
　表3に示すように、組成物No.9およびNo.10は、保存条件が「25℃、相対湿度60%」若しくは「30℃、相対湿度65%」の場合は6ヶ月保存した後も、95%以上の主薬残存率を示したが、保存条件が「40℃、相対湿度75%」と過酷な場合には、3ヶ月経過後の主薬残存率は90%を切り、6ヶ月経過後には80%程度となった。これに対し、本発明の組成物である組成物No.2～4、No.6、No.7は、保存条件を「40℃、相対湿度75%」とした場合でも、3ヶ月後の主薬残存率が95%以上及び/又は6ヶ月後の主薬残存率が90%以上となり、過酷な条件下でも長期間の保存に耐えうることが明らかになった。
　本実施例の結果から、セバシン酸ジエチルやセバシン酸ジイソプロピルが、主薬の分解を長期間に渡り抑制するのに非常に好適な油剤であることが分かった。 As shown in Table 3, 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%. In contrast, 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.
［実施例3］O/W型クリーム状組成物の有効性 (in vitroヒト皮膚透過性評価)
　上記組成物No.2、No.7及びプロトピック(登録商標)軟膏0.1%(以下、実施例中および図中においてP軟膏と示す)を正常ヒト皮膚(HAB研究機構を通じて入手)に適用したときの、適用後24時間における角質中量を比較した。
　フランツ型セルにヒト背部皮膚(1.77cm2)を装着し、10mgの前記組成物No.2、No.7或いはP軟膏を密閉適用した。所定時間後にレセプター液(1w/v%ウシ血清アルブミン含有リン酸緩衝生理食塩水)を採取し、適用24時間後の角層中タクロリムス量を定量した。 [Example 3] Effectiveness of O / W type creamy composition (in vitro human skin permeability evaluation)
When the above compositions No. 2, No. 7 and Protopic (registered trademark) ointment 0.1% (hereinafter referred to as P ointment in the examples and figures) were applied to normal human skin (obtained through HAB Research Organization) The stratum corneum content at 24 hours after application was compared.
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.
　結果を表4および図1(a)に示す。組成物No.2(油剤：セバシン酸ジエチル)、組成物No.7(油剤：セバシン酸ジイソプロピル)とも、市販のタクロリムス製剤であるP軟膏と同程度の角層中薬物量を示した。 The results are shown in Table 4 and Fig. 1 (a). Composition No. 2 (oil agent: diethyl sebacate) and composition No. 7 (oil agent: diisopropyl sebacate) showed a drug amount in the stratum corneum similar to that of P ointment, which is a commercially available tacrolimus preparation.
Figure JPOXMLDOC01-appb-T000005
Figure JPOXMLDOC01-appb-T000005
［実施例4］O/W型クリーム状組成物の有効性 (in vitroマウス皮膚透過性評価)
　上記組成物No.1～4及びP軟膏をヘアレスマウス皮膚(星野試験動物飼育所を通じて入手)に適用したときの、適用後24時間における皮膚中量を比較した。
　フランツ型セルにラボスキン(1.77 cm2)を装着し、10mgの前記組成物No.1～4或いはP軟膏を密閉適用した。所定時間後にレセプター液(1w/v%ウシ血清アルブミン含有リン酸緩衝生理食塩水)を採取し、適用24時間後の皮膚中タクロリムス量を定量した。結果を表5および図1(b)に示す。 [Example 4] Effectiveness of O / W type creamy composition (in vitro mouse skin permeability evaluation)
When 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).
Figure JPOXMLDOC01-appb-T000006
Figure JPOXMLDOC01-appb-T000006
　実験の結果、セバシン酸ジエチルの含有率が5重量%である組成物No.1および10重量%である組成物No.2のほうが、セバシン酸ジエチルの含有率が20重量%である組成物No.3および40重量%である組成物No.4よりタクロリムス水和物の皮膚透過量が高いことが分かった。また、組成物No.1およびNo.2はP軟膏よりも高い皮膚透過量を示した。 As a result of the experiment, the 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.
　本実施例の結果から、本発明の組成物では、少ない油剤でP軟膏を超える高い主薬経皮吸収性を達成できることが分かった。油剤を少量に抑えることにより、べたつきが少なく、さっぱりとした感触を有するクリーム状組成物を調製できるため、本発明によれば、高い薬効を有し、且つ使用感の非常に良い組成物を提供することができる。
　また、本実施例の結果から、本発明によれば油剤の添加量により皮膚吸収性をコントロールすることができ、P軟膏よりもタクロリムス含量を減らしても同等の薬効を示す、より安全な製剤の開発が可能であることが分かった。 From the results of the present example, it was found that 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.
［実施例5］O/W型クリーム状組成物の刺激性(皮膚累積刺激性の評価)
　組成物No.2及びNo.7の皮膚累積刺激性を雌性ウサギ(Kbl:NZW)を用いて検討した。
　除毛したウサギの背部皮膚に1匹当たり2.5×2.5 cmの投与部位(損傷皮膚)を4ヶ所設け、上記組成物0.05mL/siteを1日約23時間、14日間連続で開放投与した(n=3)。皮膚反応の判定は、Draize,J.H.(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)の基準に従って実施し、各判定日における平均評点の投与期間の平均値をもとに皮膚累積刺激性の程度を評価した。
　試験の結果を表6・表7に示す。表7から分かるように、各組成物の投与期間の平均値は、組成物No.2が0.7、組成物No.7が1.1であり、いずれも「弱い刺激物」に分類された。 [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).
Four sites of 2.5 × 2.5 cm administration sites (damaged skin) were provided on the back skin of rabbits with hair removal, and 0.05 mL / site of the above composition was administered openly for about 23 hours a day for 14 consecutive days (n = 3). 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”.
Figure JPOXMLDOC01-appb-T000007
Figure JPOXMLDOC01-appb-T000007
［実施例6］O/W型クリーム状組成物の刺激性(眼粘膜一次刺激性の評価)
　組成物No.2及びNo.7の眼粘膜一次刺激性を雌性ウサギ(Kbl:NZW)を用いて検討した。
　ウサギの結膜嚢内に上記組成物 0.1 mL/eyeを単回投与し、洗眼は実施しなかった(n=3）。眼反応の判定は、投与後1、24及び48時間にDraize,J.H.(Appraisal of the safety of chemicals in foods, drugs and cosmetics, Association of Food and Drug Officials of the United States, 49-51, 1959)の判定基準に従って行い、AFNORの評価基準(Association Francaise de Normalisation, Evaluation de I’ Irritation et/ou de la Corrosion Oculaires chez le Lapin, NF T03-264, 1982)に従って眼粘膜刺激性強度を評価した。
　試験の結果を表8に、評価基準を表9に示す。表8から分かるように、各組成物の総平均評点の最高値は、組成物No.2が0.7、組成物No.7が1.3を示し、いずれも「無刺激物」に分類された。 [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 above composition 0.1 mL / eye was administered once into the conjunctival sac of the rabbit, and eye washing was not performed (n = 3). 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 Oculaires chez le Lapin, NF T03-264, 1982).
The test results are shown in Table 8, and the evaluation criteria are shown in Table 9. As can be seen from Table 8, 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”.
Figure JPOXMLDOC01-appb-T000008
Figure JPOXMLDOC01-appb-T000008
　実施例5および6の結果とP軟膏の刺激性データ(皮膚刺激性は当社実施の検討試験結果1)、眼粘膜刺激性はP軟膏の申請資料2)を参考)を比較したところ、組成物No.2及び組成物No.7の刺激性の程度は、両組成物ともP軟膏と同一の評価区分(皮膚刺激性:「弱い刺激物」、眼粘膜一次刺激性:「無刺激物」)に分類された。このことから、本発明に係る組成物は、刺激性が低く、臨床使用上問題ないことが実証された。
　1) ウサギを用いた14日間皮膚累積刺激性試験の結果、P軟膏の投与1日から14日までの平均評点は0.2であり、「弱い刺激物」に分類された。
　2) ウサギ眼粘膜一次刺激性試験において、P軟膏の刺激性所見は認められなかった。 Comparing the results of Examples 5 and 6 with P ointment irritation data (for skin irritation, refer to the examination test results 1) , and for ocular mucosal irritation, refer to P ointment application data 2)) . The degree of irritation of No.2 and composition No.7 is the same evaluation category for both compositions as P ointment (skin irritation: `` weak irritant '', ocular mucosa primary irritation: `` irritant '') It was classified into. From this, it was demonstrated that the composition according to the present invention has low irritation and no problem in clinical use.
1) As a result of a 14-day skin irritation test using rabbits, the average score from day 1 to day 14 of administration of P ointment was 0.2, and the substance was classified as “weak irritant”.
2) In rabbit eye mucosa primary irritation test, no irritating findings of P ointment were observed.
　本発明によれば、タクロリムスの安定性が良好であり、刺激性が少なく、さらに、主薬の皮膚中濃度を容易にコントロール可能なクリーム状組成物を提供することができる。本発明に係るクリーム状組成物は、特にアトピー性皮膚炎の治療薬として好適である。 According to 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.

Claims (4)

  1. (A) タクロリムス、その製剤学的に許容される塩、又はその製剤学的に許容される溶媒和物、
    (B) セバシン酸ジエチル及び/又はセバシン酸ジイソプロピル、
    (C) ポリオキシエチレン硬化ヒマシ油、
    (D) 親水性高分子、及び
    (E) 抗酸化剤
    を含有することを特徴とする、水中油型のクリーム状組成物。     (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) An oil-in-water cream composition comprising an antioxidant.
  2. 　セバシン酸ジエチル及び/又はセバシン酸ジイソプロピル(B)の含有率が合計で5～25重量%であることを特徴とする、請求項１に記載の組成物。 The composition according to claim 1, wherein the total content of diethyl sebacate and / or diisopropyl sebacate (B) is 5 to 25% by weight.
  3. 　抗酸化剤(E)がジブチルヒドロキシトルエンであることを特徴とする、請求項１または２に記載の組成物。 The composition according to claim 1 or 2, wherein the antioxidant (E) is dibutylhydroxytoluene.
  4. 　親水性高分子(D)が、カルボキシビニルポリマー、ヒドロキシエチルセルロース、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース及び疎水化ヒドロキシプロピルメチルセルロースからなる群から選択される1種又は2種以上であることを特徴とする、請求項１～３のいずれか１項に記載の組成物。 The hydrophilic polymer (D) is one or more selected from the group consisting of carboxyvinyl polymer, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose and hydrophobized hydroxypropylmethylcellulose, The composition according to any one of claims 1 to 3.
PCT/JP2013/051453 2012-01-25 2013-01-24 Oil-in-water-type creamy composition containing tacrolimus WO2013111817A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP2013555305A JP6084579B2 (en) 2012-01-25 2013-01-24 Oil-in-water cream composition containing tacrolimus

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2012012953 2012-01-25
JP2012-012953 2012-01-25

Publications (1)

Publication Number Publication Date
WO2013111817A1 true WO2013111817A1 (en) 2013-08-01

Family

ID=48873529

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2013/051453 WO2013111817A1 (en) 2012-01-25 2013-01-24 Oil-in-water-type creamy composition containing tacrolimus

Country Status (2)

Country Link
JP (1) JP6084579B2 (en)
WO (1) WO2013111817A1 (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019082873A1 (en) * 2017-10-23 2019-05-02 マルホ株式会社 Coating-forming topical agent

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2000513739A (en) * 1997-02-20 2000-10-17 藤沢薬品工業株式会社 Pharmaceutical composition
JP2005500269A (en) * 2001-05-28 2005-01-06 藤沢薬品工業株式会社 Pharmaceutical composition for preventing or treating skin diseases containing a tricyclo compound
WO2012011566A1 (en) * 2010-07-23 2012-01-26 マルホ株式会社 Tacrolimus-containing oil-in-water type creamy composition

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH06345646A (en) * 1993-06-08 1994-12-20 Fujisawa Pharmaceut Co Ltd Lotion preparation
NZ295170A (en) * 1994-10-26 1999-02-25 Novartis Ag Topical pharmaceutical compositions comprising a fk506 class compound, an unsaturated fatty alcohol, water and diether alcohol, alkanediol or ether diol as a solvent

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2000513739A (en) * 1997-02-20 2000-10-17 藤沢薬品工業株式会社 Pharmaceutical composition
JP2005500269A (en) * 2001-05-28 2005-01-06 藤沢薬品工業株式会社 Pharmaceutical composition for preventing or treating skin diseases containing a tricyclo compound
WO2012011566A1 (en) * 2010-07-23 2012-01-26 マルホ株式会社 Tacrolimus-containing oil-in-water type creamy composition
WO2012011192A1 (en) * 2010-07-23 2012-01-26 マルホ株式会社 Tacrolimus-containing oil-in-water type creamy composition

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019082873A1 (en) * 2017-10-23 2019-05-02 マルホ株式会社 Coating-forming topical agent

Also Published As

Publication number Publication date
JPWO2013111817A1 (en) 2015-05-11
JP6084579B2 (en) 2017-02-22

Similar Documents

Publication Publication Date Title
JP5453093B2 (en) Antifungal pharmaceutical composition
WO2012011566A1 (en) Tacrolimus-containing oil-in-water type creamy composition
JP4549006B2 (en) Gel ointment
JP5052558B2 (en) Gel ointment
WO2015075640A1 (en) Stable pharmaceutical formulation(s) of tetracycline antibiotic
JP6666068B2 (en) External composition
JP2013541557A (en) Methods of increasing the solubility of poorly soluble compounds and methods of making and using such compounds
CA3020157A1 (en) Topical composition comprising tacrolimus
JP6753312B2 (en) Topical skin preparation for medical use
JP4972895B2 (en) Urea formulation for external use
JP6084579B2 (en) Oil-in-water cream composition containing tacrolimus
JP6503626B2 (en) Pharmaceutical composition
JP6503627B2 (en) Pharmaceutical liquid composition
EP2116237A1 (en) Compositions for treating rosacea comprising chitosan and a dicarboxylic acid
JP2017178798A (en) External composition
WO2016116909A2 (en) Non-staining topical gel compositions of nimesulide
JP5338030B2 (en) Adapalene-containing external preparation composition
WO2007086582A1 (en) OIL-IN-WATER TYPE EMULSION LOTION CONTAINING 22-OXA-1α,25-DIHYDROXYVITAMIN D3 AND METHOD OF TREATING SKIN DISEASE BY USING THE SAME
JP2007262031A (en) Ameliorating agent for hyperesthetic itchy feeling on skin
JP7092495B2 (en) External composition for suppressing pigmentation
JP5695310B2 (en) External preparation composition containing γ-oryzanol
JP6779730B2 (en) Topical composition
JP2017095362A (en) Liranaftate-containing external composition
JP5674786B2 (en) Oil-in-water cream composition containing tacrolimus
JP5980171B2 (en) Adapalene-containing external preparation composition

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 13741225

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 2013555305

Country of ref document: JP

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 13741225

Country of ref document: EP

Kind code of ref document: A1