JPWO2020046102A5

JPWO2020046102A5 -

Info

Publication number: JPWO2020046102A5
Application number: JP2021537019A
Authority: JP
Publication date: 2022-04-21
Anticipated expiration: 2039-08-23

Description

ここで、溶媒－湿潤剤は、グリセリン、エチルアルコール、Ｔｒａｎｓｃｕｔｏｌ－Ｐ、Ｎ－メチルピロリドン、２－ピロリドン、ＣｒｅｍｏｐｈｏｒＲＨ－４０、プロピレングリコールからなる群から選択され、乳化剤は、セチルアルコール、ステアリルアルコール、セトステアリルアルコール、Ｓｐａｎ８０、Ｓｐａｎ６０、モノステアリン酸グリセリル、ポリエチレングリコールステアレート、ＣｒｅｍｏｐｈｏｒＡ－６、セトステアリルアルコール、セチルアルコール、モノステアリン酸グリセリル、鯨蝋、ＣｒｅｍｏｐｈｏｒＡ－２５からなる群から選択され、増粘皮膚軟化剤は、セトステアリルアルコール、マクロゴールセトステアリルエーテル、Ｃｅｔｅａｒｅｔｈ－２５、セチルアルコール、鯨蝋、蜜蝋、モノステアリン酸グリセリル、固形パラフィン、セチルアルコール及びステアリルアルコールからなる群から選択され、皮膚軟化剤は、ジメチコン、鉱油、アジピン酸イソプロピル、イソヘキサデカン、カプリル／カプリル酸トリグリセリド、ミリスチルグルコシド、ベヘニルアルコール、Ｃ１２～１５安息香酸アルキル、イソステアリン酸イソプロピルからなる群から選択され、保存料は、メチルパラベンナトリウム、プロピルパラベンナトリウム、フェノキシエタノール、ジアゾリジニル尿素、ブチルカルバミン酸ヨウ化プロピニルからなる群から選択され、粘性剤は、プロピルパラベンナトリウムからなる群から選択され、中和剤をトリエタノールアミン又は水酸化ナトリウムとすることができ、安定化剤をクエン酸又は合成ビタミンＣの類から選択することができる。

Here, the solvent-wetting agent is selected from the group consisting of glycerin, ethyl alcohol, Transctool-P, N-methylpyrrolidone, 2-pyrrolidone, Cremophor RH-40, and propylene glycol, and the emulsifier is cetyl alcohol, stearyl alcohol, and the like. Selected from the group consisting of cetostearyl alcohol, Span 80, Span 60, glyceryl monostearate, polyethylene glycol stearate, Cremophor A-6, cetostearyl alcohol, cetyl alcohol, glyceryl monostearate, whale wax, Cremophor A-25. The thickening skin softener is selected from the group consisting of cetostearyl alcohol, macrogol cetostearyl ether, Ceatareth-25 , cetyl alcohol, whale wax, beeswax, glyceryl monostearate, solid paraffin, cetyl alcohol and stearyl alcohol. The skin softening agent is selected from the group consisting of dimethicone, mineral oil, isopropyl adipate, isohexadecane, capril / caprylic acid triglyceride, myristyl glucoside, behenyl alcohol, C12-15 alkyl benzoate, and isopropyl isostearate, and the preservative is sodium methylparaben. , Poxyparaben sodium, phenoxyethanol, diazoridinyl urea, butylcarbamate iodide propynyl selected from the group consisting of propylparaben sodium, the viscous agent selected from the group consisting of propylparaben sodium, and the neutralizing agent being triethanolamine or sodium hydroxide. And the stabilizer can be selected from the class of citric acid or synthetic vitamin C.

Claims

2% -12% pyrphenidone, 20% -60% solvent-wetting agent, 5% -10% one or combination emulsifier, 2% -8% thickening skin softener, 0. 5% to 3% one or various skin softeners, 0.1% to 2% preservatives, 0.05% to 0.2% rheological or viscous agents, 0.05% to 0.2% neutralizer, 0.05% to 0.2% preservative, 0.0005% to 0.003% stabilizer, and optionally 0.008% to 0.8%. A semi-solid pyrphenidone pharmaceutical composition comprising the preservatives / preservatives of.

The solvent-wetting agent is selected from the group consisting of glycerin, ethyl alcohol, Transcitol-P, N-methylpyrrolidone, 2-pyrrolidone, Cremophor RH-40, and propylene glycol, and the emulsifier is cetyl alcohol, stearyl alcohol, and cetostearyl alcohol. , Span 80, Span 60, glyceryl monostearate, polyethylene glycol stearate, Cremophor A-6, cetostearyl alcohol, cetyl alcohol, glyceryl monostearate, whale wax, Cremophor A-25. The viscous skin softening agent is selected from the group consisting of cetostearyl alcohol, macrogol cetostearyl ether, Ceatareth-25 , cetyl alcohol, whale wax, beeswax, glyceryl monostearate, solid paraffin, cetyl alcohol and stearyl alcohol, and said skin softening. The agent is selected from the group consisting of dimethicone, mineral oil, isopropyl adipate, isohexadecane, capryl / caprylic acid triglyceride, myristyl glucoside, behenyl alcohol, C12-15 alkyl benzoate, isopropyl isostearate, and the preservatives are methylparaben sodium and propylparaben. The viscous agent may be selected from the group consisting of sodium, phenoxyethanol, diazoridinyl urea, propynyl iodide butylcarbamate, the viscous agent may be selected from the group consisting of sodium propylparaben, and the neutralizing agent may be triethanolamine or sodium hydroxide. It is characterized in that the stabilizer can be selected from the types of citric acid or synthetic vitamin C.
The semi-solid pirfenidone pharmaceutical composition according to claim 1, wherein the semi-solid pharmaceutical composition is in the form of a cream.

The wetting base is propylene glycol, the emulsifiers are Span 60, Cremophor A-6, Cremophor A-25 and Tween 60, the thickening skin softeners are cetyl alcohol and stearyl alcohol, and the skin softener. Is dimethicone, the preservatives are methylparaben sodium and propylparaben sodium, the leology agent or viscous agent is carbomer, the neutralizer is triethanolamine, and the stabilizer is anhydrous citric acid. 2. The semi-solid pyruphenidone pharmaceutical composition in the form of the cream according to claim 2.

Contains 2% -12% pyrphenidone, 50% propylene glycol, 6.382% Span 60, 2% cetyl alcohol, 2% stearyl alcohol, 1% Cremophor A-6, 1 % Cremophor A-25, 1% dimethicone, 0.617% Tween 60, 0.147% methylparaben sodium, 0.1% carbomer, 0.1% triethanolamine, The cream of claim 3, characterized in that it is made with 0.066% propylparaben sodium, 0.001% citric acid and a sufficient amount of water to make it 100%. Semi-solid pyrphenidone pharmaceutical composition in the form of.

A method for producing a semi-solid pirfenidone pharmaceutical composition in the form of a cream according to claim 2, comprising the following steps:
A) Oil phase Span 60, cetyl alcohol, stearyl alcohol, Cremophor A-6, Cremophor A-25 and dimethicone are placed in a reactor, stirred and heated to complete melting (75 ° C-80 ° C).
Identify as oil phase.
B) Mixture A
30% of the total amount of purified water is placed in a stainless steel container of appropriate volume and the carbomer is added slowly with constant stirring until completely moist.
Identify as mixture A.
C) Solution "A"
Put propylene glycol in a pot, heat to (75 ° C-80 ° C) and stir at 131 rpm ± 10%.
Gradually add pirfenidone with constant stirring and continue heating until completely dissolved (75 ° C-80 ° C). Hold for 30 minutes.
(Specify as solution "A")
D) Solution "B"
30% of the total amount of water used is placed in a stainless steel container of appropriate volume and gradually added to the container with constant stirring until the methylparaben sodium, propylparaben sodium, anhydrous citric acid and polysorbate 60 are completely dissolved.
Specify as solution "B".
E) Gradually add the contents of the mixture "A" and the solution "B" to the solution identified as the aqueous phase "A" with constant stirring and continue heating to (75 ° C-80 ° C). Continue stirring at 131 rpm ± 10% and heat until fully incorporated.
Identify as an aqueous phase.
F) Phase mixture The aqueous phase is added to the reactor containing the oil phase at a constant temperature of 75 ° C to 80 ° C with constant stirring. Continue stirring at 71 rpm ± 10% for 20 minutes to reduce the temperature of the mixture to 40 ° C to 45 ° C.
G) Solution "C"
The remaining water is placed in a separate stainless steel container and gradually added to the container with constant stirring until the triethanolamine is completely dissolved.
Specify as solution "C".
H) The final mixture solution C is added to the reactor and stirred at 71 rpm ± 10% for 60 minutes or until a temperature of 30 ° C to 35 ° C is reached.

Use of the semi-solid pirfenidone pharmaceutical composition according to claim 1 for the manufacture of a drug that restores skin defects caused by the loss of collagen and other extracellular matrix proteins such as fibronectin and elastin.

Use of the semi-solid pirfenidone pharmaceutical composition in the form of a cream according to claim 2 in the manufacture of a drug that restores skin defects caused by the loss of collagen and other extracellular matrix proteins such as fibronectin and elastin.

The wetting base is propylene glycol, the emulsifiers are Span 60, Cremophor A-6, Cremophor A-25 and Tween 60, the thickening skin softeners are cetyl alcohol and stearyl alcohol, and the antiseptic / preservative. The agent is modified diallyl disulfide oxide (M-DDO), and the thickening base is solid white vaseline.
The semi-solid pirfenidone pharmaceutical composition according to claim 1, wherein the semi-solid pharmaceutical composition is in the form of an ointment.

10% Propylene Glycol, 18.234% Span 60, 1% Cremophor A-6, 1% Cremophor A-25, 2.122% Solid 60, 1% Stearyl Alcohol, Half of the ointment form of claim 8, characterized by containing 1% stearyl alcohol, 0.016% M-DDO, and a sufficient amount of solid white petrolatum to make 100%. Solid pirfenidone pharmaceutical composition.

A method for producing a semi-solid pirfenidone pharmaceutical composition in the form of an ointment according to claim 8, which comprises the following steps:
A) Oil phase Span 60, cetyl alcohol, stearyl alcohol, Cremophor A-6, Cremophor A-25 and solid white vaseline are placed in a reactor, stirred and heated to complete melting (75 ° C-80 ° C). ..
Identify as oil phase.
B) Solution "A"
Put propylene glycol in a pot, heat to 75 ° C to 80 ° C, stir at 131 rpm ± 10%, and stir. Gradually add pirfenidone with constant stirring and continue heating until completely dissolved (75 ° C-80 ° C). Keep under stirring, heat for 20 minutes, slowly add 2% M-DDO, stir for 10 minutes, add Tween 60 and stir for 10 minutes.
C) Phase mixture The entire contents of the aqueous phase are added to the reactor containing the oil phase at 71 rpm for 20 minutes with constant stirring. Reduce the temperature to 30 ° C to 35 ° C.

Use of the semi-solid pirfenidone pharmaceutical composition in the form of an ointment according to claim 8 for the manufacture of a drug that restores skin defects caused by the loss of collagen and other extracellular matrix proteins such as fibronectin and elastin.

The wetting base is propylene glycol, the emulsifier is Span 60, the emulsifier is Tween 60, the thickening emollient is stearyl alcohol, the preservative is M-DDO, and the thickening. The agent is a solid white petrolatum, characterized by containing a sufficient amount of water to impart consistency to the formulation.
The semi-solid pirfenidone pharmaceutical composition according to claim 1, wherein the semi-solid pharmaceutical composition is in the form of a plaster.

The formulation is 2% -12% pirfenidone, 45% propylene glycol, 18.234% Span 60, 3% stearyl alcohol, 17% solid white petrolatum, 1.764% Tween 60, 0.001%. The semi-solid pirfenidone pharmaceutical composition in the form of a plaster according to claim 12, characterized by containing 0.016% M-DDO of citric acid.

A method for producing a semi-solid pirfenidone pharmaceutical composition in the form of a plaster according to claim 12, which comprises the following steps:
A) Oil phase Span 60, stearyl alcohol and solid white petrolatum are placed in a reactor, stirred and heated to complete melting (75 ° C-80 ° C).
Identify as oil phase.
B) Solution "A"
Put propylene glycol in a pot, heat to 75 ° C to 80 ° C, stir at 131 rpm ± 10%, and stir. Gradually add pirfenidone with constant stirring and continue heating until completely dissolved (75 ° C-80 ° C). Keep under stirring, heat for 20 minutes, slowly add 2% M-DDO, stir for 10 minutes, add Tween 60 and stir for 10 minutes.
C) Solution "B"
Purified water is placed in a stainless steel container of appropriate volume and citric acid and polysorbate 60 are gradually added.
D) Water phase Gradually add the solution "B" to the solution specified as "A" with constant stirring, continue heating to 75 ° C-80 ° C and hold for 30 minutes.
E) Aquatic phase The aqueous phase is added to the reactor containing the oil phase while constantly stirring at a constant temperature for 20 minutes.

Use of the semi-solid pirfenidone pharmaceutical composition in the form of a plaster according to claim 12 in the manufacture of a drug that restores skin defects caused by the loss of collagen and other extracellular matrix proteins such as fibronectin and elastin.

2. 13. The method comprising administering the semi-solid pirfenidone pharmaceutical composition according to any one of 13.