WO1995015152A1 - Preparation a usage externe - Google Patents

Preparation a usage externe Download PDF

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Publication number
WO1995015152A1
WO1995015152A1 PCT/JP1994/002015 JP9402015W WO9515152A1 WO 1995015152 A1 WO1995015152 A1 WO 1995015152A1 JP 9402015 W JP9402015 W JP 9402015W WO 9515152 A1 WO9515152 A1 WO 9515152A1
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WO
WIPO (PCT)
Prior art keywords
external preparation
water
preparation according
sol
solution
Prior art date
Application number
PCT/JP1994/002015
Other languages
English (en)
Japanese (ja)
Inventor
Zenichi Ogita
Original Assignee
Zenichi Ogita
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 Zenichi Ogita filed Critical Zenichi Ogita
Priority to AU11198/95A priority Critical patent/AU1119895A/en
Publication of WO1995015152A1 publication Critical patent/WO1995015152A1/fr

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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
    • A61K9/0012—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
    • 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

Definitions

  • the present invention relates to an external preparation for external use such as injection, gargle, compress, spray, application, wiping, disinfection, eye drops, ear drops, nasal drops, etc.More specifically, adhesion and retention during use An external preparation capable of significantly improving the use of the composition.
  • the drug is dissolved in a solvent such as water, ethanol or oil (including water or ethanol extraction and dissolution) or suspended and used for external use.
  • a solvent such as water, ethanol or oil (including water or ethanol extraction and dissolution) or suspended and used for external use.
  • Known liquid preparations for example, injection, gargle, poultice, spray, application, wiping, disinfection, eye drops, ear drops, nasal drops, etc. are known.
  • the present invention solves the problems of conventional external preparations, such as difficulty in use, reduction in adhesion to living body surfaces and reduction in retention, and can be used easily.
  • the purpose of the present invention is to provide a new external preparation which can improve the adhesiveness and retention property on the surface of a living body.
  • the present invention solves the above-mentioned problems, and comprises an aqueous solution of a temperature-sensitive polymer in which the sol-gel transition of the aqueous solution is reversible, and a water-soluble or water-insoluble external drug.
  • It is an external preparation that is formulated and is in a sol state at a temperature lower than the body temperature, becomes a gel state at the temperature of the living body surface, does not dissolve in water in a gel state, and is a sol-gel.
  • An external preparation characterized by being reversible in transition is provided.
  • the external preparation itself may be arbitrary, and may be any of the conventionally known ones, that is, suitable.
  • Various types of water-soluble, water-insoluble, and oil-soluble are used.
  • These topical drugs are used as liquids (sols) dissolved or dispersed in the above-mentioned aqueous polymer solution, or used as gel-like ointments, etc. thing You can do it.
  • water-insoluble external drugs When used, they may be mixed in a water-insoluble medium. In this case, a minimum amount of a dispersing agent may be added. As a matter of course, the external preparation of the present invention may further optionally contain additional components as long as the purpose of the invention is met.
  • topical drugs include, for example, aspirin, sulfenamic acid, mefenamic acid, indomethacin, tolmetin ibuprofen, ketoprofen
  • Non-steroidal anti-inflammatory agents such as benzoquinone, vinyl chloride, and steroloid anti-inflammatory agents such as coltizon and dexamethasone; nitrate; gentamicin; Antibacterial agents such as pyromidic acid and ofloxacin, various vitamins and antihistamines, and naphazolin and tetrahydrozole
  • vasoconstrictors such as benzoquinone, chloramnicol, benzalconium chloride, tetracycline, and various other transdermally absorbable formulations Drugs are used.
  • the external preparation of the present invention is in a sol state at a temperature lower than the biological temperature, becomes a gel state at the temperature of the biological surface, does not dissolve in water in the gel state, and has a sol-gel It is characterized by the reversibility of metastasis, and in this case, it improves adhesion and retention to living organisms during use.
  • the external preparation of the present invention when dropped or applied to the surface of a living body, the external preparation of the present invention instantaneously changes to a gel state due to the sol-gel transition and stably adheres to and stays on the living body surface. And the body temperature If the temperature is lowered to less than 10 ° C., the sol becomes low in viscosity again, so that the external preparation of the present invention can be easily removed.
  • an aqueous solution of a sensitive polymer whose sol-gel transition is reversible in an aqueous solution is blended as an essential component.
  • this sensitive polymer can be presented as a combination of multiple blocks with cloud points and a hydrophilic block. it can.
  • Blocks with a cloud point of n. &. susceptible polymer become insoluble in water at ha. J3 ⁇ 4 above the cloud point and become water soluble at temperatures below the cloud point. Part.
  • thermoreversible sol-gel transition of a susceptible polymer-aqueous solution is due to the nature of the hydrophobic bonds between the blocks, which increases immediately with the increase of the hydrophobic bonds inn3 ⁇ 4, and the change increases with temperature. On the other hand, it is irreversible.
  • the presence of a plurality of blocks having a cloud point in a molecule means that an aqueous solution of an imi-sensitive polymer forms a water-insoluble gel at or above the sol-gel transition temperature.
  • a block having an fc point is preferably a polymer compound having a negative temperature coefficient of solubility in water, and more specifically, a polymer having a fc point.
  • the difference between the acrylamide derivative and other hydrophilic or hydrophobic monomers A polymer compound selected from the group consisting of a copolymer, polyvinyl methyl ether, and polyvinyl alcohol partially acetylated is preferred, and its cloud point is below 0 ° C.
  • the desired cloud point for example, a cloud point higher than 0 and less than or equal to 37 ° C.
  • High molecular compounds can be obtained.
  • aqueous solution of the above-mentioned polymer compound (block having a cloud point)
  • it is cooled to a transparent homogeneous solution, and then gradually heated (temperature rise about l ° C).
  • the point at which the solution first becomes cloudy at first (CZ min) can be taken as the cloud point.
  • the hydrophilic block that constitutes the sensitive polymer is necessary because the aqueous solution of the temperature-sensitive polymer is in a liquid (sol) state below the sol-gel transition temperature. In addition, it prevents the temperature-sensitive polymer from agglomerating and precipitating due to too strong a hydrophobic bond between blocks having a cloud point above the sol-gel transition temperature. Required to maintain state.
  • hydrophilic block examples include methylcellulose, dextran, polyethylene oxide, and polyvinyl alcohol.
  • Poly N-vinyl pi-Ridone, Poly-vinyl pyridine, Polyacrylamide, Polymethylamide, Polyamide, PolyN-methyl Lua acrylamide, polyhydroxymethyl acrylate, polyacrylic acid, polyacrylic acid, polyvinyl sulfonic acid, polyvinyl sulfonate, polyacrylic acid Styrene sulfonate and salts thereof are preferred, but poly UN, N-dimethylamino thiazole methacrylate, poly N, N -N-methyl phenylamine N, N-dimethylaminopropyl mouth Pirua crylamide, and salts thereof may be used.
  • a polymerizable functional group for example, a block
  • the other block can be combined by a simple solid body to give the other block. This is achieved by introducing functional groups (for example, a hydroxyl group, a carboxylic acid group, or an isopropyl group) and linking the two by a chemical reaction. I can do it. At that time, usually, a plurality of reactive functional groups are introduced into the hydrophilic block.
  • the bond between the cloud-opening polypyrene oxide and hydrophilic block is formed by anion polymerization or cation polymerization.
  • D pyrenoxide and the moieties that make up “other water-soluble polymers” Nomer eg, ethylene oxide
  • polypropylene oxide and “other water-soluble polymers” eg, It is possible to obtain a block copolymer to which ethylene oxide is bonded.
  • Such a block copolymer is obtained by introducing a polymerizable group (for example, an acryloyl group) into the terminal of polypropylene oxide and forming a water-soluble polymer. It can also be obtained by copolymerizing nomads.
  • a polymerizable group for example, an acryloyl group
  • the 3 ⁇ 4 ⁇ -sensitive polymer introduces a functional group capable of binding and reacting with a functional group (for example, a hydroxyl group) at the terminal of poly (propylene oxide) in a water-soluble polymer and reacts the two. You can also get it by using the product, and Polypropylene oxide and Polyethylene oxide ⁇ , the brand name ⁇ Bluronic F
  • -127 J can also be obtained by connecting materials such as J (manufactured by Asahi Denka Kogyo Co., Ltd.).
  • the sol-gel transition temperature of the temperature-sensitive polymer aqueous solution that is, the sol-gel transition temperature of the agent for external use of the present invention can be controlled.o Depending on the component added to the agent for external application.
  • the sol-gel transition temperature can also be controlled, and preferably the sol-gel transition temperature is controlled to be higher than 0 and lower than 37 ° C.
  • the temperature-sensitive polymer as described above is used in the present invention. It is formulated as an aqueous solution, and the aqueous solution in this case is an aqueous solution containing the temperature-sensitive polymer, and further contains a solvent or a water-soluble substance that is compatible with water. It is good.
  • solvents that are compatible with water include alcohols such as ethanol, glycerin, propylene glycol, and acetone. Illustrated.
  • water-soluble substance examples include various salts and water-soluble polymers.
  • water-insoluble medium that can be used in the compounding of the above-mentioned water-insoluble topical drug means a solvent that is incompatible with water.
  • examples include hydrocarbons such as hexane and liquid paraffin, vegetable oils, waxes, petrolatum, polyesters, and the like.
  • the suspending aid is a substance having an effect of enhancing the suspendability of a water-insoluble drug or a water-insoluble solvent containing the drug in a temperature-sensitive polymer aqueous solution.
  • various surfactants described below are used, but nonionic surfactants are particularly preferably used.
  • anionic surfactants include alkyl sulfates such as sodium dodecyl sulfate, and polyoxyethylene alkyl ether sulfate. Salts, poloxyshethylene alkylphenyl ether sulfates, fatty acid salts, alkylsulfonates, alkylbenzensulfonates, alkyls Lunafurethren sulfonate, alkyl linoleate, polyoxyethylene alkenyl monoterinate, polyoxyethylene alkyne two
  • cationic surfactants include ruthel phosphate and quaternary anions such as dodecinoletrimethinoleanmonium chloride.
  • amphoteric surfactants include, for example, N, N—dimethyl-N—dodecyl-N—kammonium salt, primary to tertiary fatty amine salts, and the like.
  • non-ionic surfactants include betaines such as ruboxime methyl ammonium betaine, and polyoxythienyl nonylphenyl. ⁇ Polyoxyethylenyl ether, polyoxyethylene alkyl ether, polyoxyethylene fatty acid ester, polyoxyethylene Roxyshethylene Polyhydric alcohol fatty acid partial ester etc. can be listed.o
  • the amount of the topical drug is, for example, generally in the range of about 0.01 to 30 parts by weight based on 100 parts by weight of the temperature-sensitive polymer of the present invention. .
  • the amount of addition depends on the type, but is generally based on 100 parts by weight of the external preparation.
  • the above-mentioned external preparations are applied in a liquid form by dropping or coating.
  • it has an excellent effect of greatly improving the adhesion and retention properties of the water-insoluble topical drug due to the change to a gel state.
  • the effect of remarkably improving the suspension stability of an external preparation containing a water-insoluble medium containing it is particularly noteworthy. This is because the temperature-sensitive polymer aqueous solution effectively blocks the mutual aggregation of a water-insoluble drug or a water-insoluble medium containing the same, which gels and suspends on the surface of a living body. It is.
  • Polypropylene oxide triamino compound (Propylene oxide; molecular weight: about 300,000, manufactured by Digifaron Chemical Co., USA): Difarmi T — 300 000) 10 g and polyaminopolyamide at both ends (a molecular weight of about 600,000, manufactured by Kawaken Fine Chemical Co., Ltd.) ) Dissolve 30 g in 900 ml of the mouth opening solution, and use tri-isolate (colonet T-1).
  • This polymer compound was dissolved in distilled water at a concentration of 8 wt% under ice cooling. Further, when the aqueous solution of the polymer compound was gradually heated, the viscosity gradually increased from 10 and solidified at about 14 ° C. to form a gel.
  • the gel when the gel was cooled, it was returned to an aqueous solution at 10 ° C. However, the gel was poured into a large amount of distilled water at 25 ° C, but did not dissolve.
  • the polymer compound was dissolved in distilled water at a concentration of 8 wt% under ice-cooling. When the aqueous solution of the polymer compound was slowly heated, the viscosity gradually increased from 5 ° C, and solidified at about 10 ° C to form a gel.
  • the polymer mixture was completely dissolved under ice-cooling and stirring with the above mixture to prepare a mouthwash and a mouthwash.
  • the sol-gel transition temperature of the mouthwash and mouthwash was measured by a change in fluidity, and as a result, it was about 13 ° C.
  • Purified water was added to 100 ml of Isosinger Garnole, 25 ml of nodulating water, and 25 g of the polymer compound (P) obtained in Reference Example 1 to make a total volume of 500 ml.
  • the polymer compound was completely dissolved under ice-cooling and stirring to prepare a mouthwash and a mouthwash.
  • the sol-gel transition temperature of the gargle and mouthwash was measured by a change in fluidity, and was found to be about 10 ° C.
  • the sol-gel transition temperature of the poultice was measured by a change in fluidity, and was found to be about 14 ° C.
  • the sol-gel transition temperature of the nasal solution was measured by a change in fluidity, and as a result, it was about 12 ° C.
  • the sol-gel transition temperature of the eardrop was measured by a change in fluidity, and was found to be about 12 ° C.
  • the sol-gel transition temperature of the eye drop was measured by a change in fluidity, and as a result, it was about 11 ° C.
  • Solution A and Solution B were thoroughly mixed with ice cooling and stirring to prepare an eyewash (PH 8.2) for contact lenses.
  • the sol-gel transition temperature of this suspension was about 14. Also, when the gelled suspension was observed with a microscope, the particle size distribution of the dispersed liquid paraffin was from 100 m to 100 m Was about 500 m. The liquid paraffin particles in the suspension are stable for a long time without any agglomeration, without agglomeration, even without the use of surfactants. The effect of gelling was confirmed. The resulting suspension could be used as an ointment to prevent purulent dermatitis, burns and trauma. If the suspension is cooled to about 14 ° C or less when applied, the suspension becomes a sol and is very easy to apply, and when it adheres to the skin, it becomes a gel at body temperature. Therefore, the adhesiveness was very good, and it could be used comfortably without any discomfort.
  • the average was about 100 m from 100 m, and the average was about 500 m.
  • the liquid paraffin particles in the suspension do not clump or coagulate without the use of surfactants, and do not agglomerate for a long period of time. The effect of gelling the suspension was observed.
  • the suspension thus obtained could be used as an oral ointment. If the suspension is cooled to about 14 C or less when applied to the oral cavity, the suspension becomes a sol, so it can be applied to the oral cavity using Jet No.5. In addition, when the suspension adheres to the oral cavity, the suspension turns into a gel at body temperature, and has excellent adhesion or retention in the oral cavity, and is comfortable without feeling uncomfortable. It could be used.
  • Example 8 5% of the polymer compound (P) in the suspension shown in Example 8 was replaced with 2% of carboxymethylphenol (CMC), The same operation was performed to obtain a similar suspension.
  • the particle size distribution of the dispersed fluid paraffin was 100 mm! It ranged from 11 to 1000 m, with an average of about 500 m.
  • the liquid paraffin particles in the suspension do not use surfactants, so if left undisturbed, they will gradually aggregate in 10 minutes and eventually complete Separated into two phases.
  • this suspension had a relatively high viscosity and had fluidity, when applied to the skin, the suspension flowed down and had poor retention.
  • the topical preparation of the present invention contains a temperature-sensitive polymer aqueous solution having a property of sol-gel transfer above the surface temperature of the living body, it forms a solution (sol-like) in a cool and dark place, When heated at (25 to 35 ° C), it immediately changes to a gel and accumulates. As a result, the use of external preparations becomes remarkably easy, the adhesion and retention on the surface of the living body are remarkably improved, and the sustainability of the drug can be remarkably enhanced. Furthermore, since the sol-gel transition temperature is higher than 0 ° C and lower than 37 ° C, there is no thermal damage to the living body surface.

Abstract

L'invention concerne une préparation a usage externe qui adhère facilement à un organisme vivant, reste longtemps dans ledit organisme, et dont la stabilité en suspension peut être améliorée. Ladite préparation comprend une solution aqueuse d'un polymère thermosensible et d'un médicament soluble ou non soluble dans l'eau, pour usage externe. Cette préparation se présente sous la forme d'un sol à une température inférieure à celle de l'organisme vivant mais se transforme en gel à la température de la surface dudit organisme vivant. Ledit gel est non soluble dans l'eau, et la transformation sol-gel est réversible.
PCT/JP1994/002015 1993-11-30 1994-11-30 Preparation a usage externe WO1995015152A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU11198/95A AU1119895A (en) 1993-11-30 1994-11-30 External preparation

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP32968493 1993-11-30
JP5/329684 1993-11-30

Publications (1)

Publication Number Publication Date
WO1995015152A1 true WO1995015152A1 (fr) 1995-06-08

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Application Number Title Priority Date Filing Date
PCT/JP1994/002015 WO1995015152A1 (fr) 1993-11-30 1994-11-30 Preparation a usage externe

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AU (1) AU1119895A (fr)
WO (1) WO1995015152A1 (fr)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6011744A (en) * 1997-07-16 2000-01-04 Altera Corporation Programmable logic device with multi-port memory
US6034857A (en) * 1997-07-16 2000-03-07 Altera Corporation Input/output buffer with overcurrent protection circuit
JP2006111585A (ja) * 2004-10-15 2006-04-27 Mebiol Kk 徐放性組成物およびその徐放方法
US7456275B2 (en) 2002-04-18 2008-11-25 Chugai Seiyaku Kabushiki Kaisya Hyaluronic acid modification product
JP2016153423A (ja) * 2008-05-14 2016-08-25 オトノミ—，インク． 制御放出型コルチコステロイド組成物、および耳の疾患を処置する方法
US9867778B2 (en) 2008-07-21 2018-01-16 Otonomy, Inc. Controlled release antimicrobial compositions and methods for the treatment of otic disorders
US11040004B2 (en) 2016-09-16 2021-06-22 Otonomy, Inc. Otic gel formulations for treating otitis externa

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS52125619A (en) * 1976-02-26 1977-10-21 Flow Pharma Inc Pharmaceutical vehicle
JPS59219217A (ja) * 1983-05-16 1984-12-10 メルク　エンド　カムパニー　インコーポレーテツド 熱硬化性ゲルを利用する薬剤送達系

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS52125619A (en) * 1976-02-26 1977-10-21 Flow Pharma Inc Pharmaceutical vehicle
JPS59219217A (ja) * 1983-05-16 1984-12-10 メルク　エンド　カムパニー　インコーポレーテツド 熱硬化性ゲルを利用する薬剤送達系

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6011744A (en) * 1997-07-16 2000-01-04 Altera Corporation Programmable logic device with multi-port memory
US6034857A (en) * 1997-07-16 2000-03-07 Altera Corporation Input/output buffer with overcurrent protection circuit
US6151258A (en) * 1997-07-16 2000-11-21 Quickturn Design Systems, Inc. Programmable logic device with multi-port memory
US6259588B1 (en) 1997-07-16 2001-07-10 Altera Corporation Input/output buffer with overcurrent protection circuit
US7456275B2 (en) 2002-04-18 2008-11-25 Chugai Seiyaku Kabushiki Kaisya Hyaluronic acid modification product
JP2006111585A (ja) * 2004-10-15 2006-04-27 Mebiol Kk 徐放性組成物およびその徐放方法
JP2016153423A (ja) * 2008-05-14 2016-08-25 オトノミ—，インク． 制御放出型コルチコステロイド組成物、および耳の疾患を処置する方法
US9744126B2 (en) 2008-05-14 2017-08-29 Otonomy, Inc. Controlled release corticosteroid compositions and methods for the treatment of otic disorders
US9867778B2 (en) 2008-07-21 2018-01-16 Otonomy, Inc. Controlled release antimicrobial compositions and methods for the treatment of otic disorders
US10772828B2 (en) 2008-07-21 2020-09-15 Otonomy, Inc. Controlled release antimicrobial compositions and methods for the treatment of otic disorders
US11369566B2 (en) 2008-07-21 2022-06-28 Alk-Abelló, Inc. Controlled release antimicrobial compositions and methods for the treatment of otic disorders
US11040004B2 (en) 2016-09-16 2021-06-22 Otonomy, Inc. Otic gel formulations for treating otitis externa

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Publication number Publication date
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