WO1995003352A1 - Compose de polyoxyethylene a terminaison hydroxysilyle, copolymere sequence a terminaison de sel quaternaire et promoteur d'absorption percutanee - Google Patents
Compose de polyoxyethylene a terminaison hydroxysilyle, copolymere sequence a terminaison de sel quaternaire et promoteur d'absorption percutanee Download PDFInfo
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- WO1995003352A1 WO1995003352A1 PCT/JP1994/001109 JP9401109W WO9503352A1 WO 1995003352 A1 WO1995003352 A1 WO 1995003352A1 JP 9401109 W JP9401109 W JP 9401109W WO 9503352 A1 WO9503352 A1 WO 9503352A1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
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- 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
- A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
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- 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
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
- C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
- C08G65/32—Polymers modified by chemical after-treatment
- C08G65/329—Polymers modified by chemical after-treatment with organic compounds
- C08G65/336—Polymers modified by chemical after-treatment with organic compounds containing silicon
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G77/00—Macromolecular compounds obtained by reactions forming a linkage containing silicon with or without sulfur, nitrogen, oxygen or carbon in the main chain of the macromolecule
- C08G77/42—Block-or graft-polymers containing polysiloxane sequences
- C08G77/46—Block-or graft-polymers containing polysiloxane sequences containing polyether sequences
Definitions
- the present invention provides a compound represented by the general formula (I):
- R 1 and R 2 may be the same or different and each have an alkyl group or a phenyl group having 1 to 6 carbon atoms, A is an alkyl group or
- R ′ R 6 may be the same or different and may be an alkyl group or phenyl group having 1 to 6 carbon atoms
- R 7 to R 9 may be the same or different and may be an alkyl group, a substituted alkyl group, a phenyl group Or two or three of R 7 to R 9 may be combined with the nitrogen atom to which they are bonded to form a nitrogen-containing heterocyclic ring
- X— being an anion in a quaternary salt
- Y being alkyl.
- the present invention relates to a polyoxyethylene polyorganosiloxane block copolymer having a quaternary salt at the terminal represented by) and a transdermal absorption enhancer for a drug comprising the copolymer.
- DDS drug delivery systems
- the present inventors have proposed, as transdermal absorption enhancers with low toxicity and irritation to the skin, polymers having a benzalkonium salt in the side chain (Journal of Controlled Release, 13, 63-71 (1990)) and pyridinium salt.
- Polymer having a side chain POLYMER, Vol. 32, No. 11, 2106-2111 (1991)
- -polyorganosiloxane having a methylpyridinium salt at one end POLYMER, Vol. 33, No. 10, 2203-2207 (1992)
- high molecular compounds such as polyorganosynxane (EP-0484857A, US 5200488) having a pyridinium salt or an ammonium salt at one end.
- the present inventors have conducted intensive studies to solve the above-mentioned problems, and in particular, to obtain a transdermal absorption enhancer that exhibits an effective promoting effect even on water-soluble drugs.
- Polyoxyethylene compounds can be synthesized, and polyoxetylene polyorganosiloxane-based xanbutate-based copolymers having a quaternary salt at one end, which is easily derived therefrom, can be used not only for fat-soluble drugs but also for water-soluble drugs. They have found that they show an extremely excellent transdermal absorption promoting action, and have completed the present invention.
- R 1 and R 2 may be the same or different, and are an alkyl group or phenyl group having 1 to 6 carbon atoms, A is an alkyl group or
- a polyoxetylene compound having a hydroxysilyl group at the terminal represented by the following formula:
- R ⁇ R 6 may be the same or different and is an alkyl group or phenyl group having 1 to 6 carbon atoms
- R 7 to R 9 may be the same or different and may be an alkyl group, a substituted alkyl group, Or is a phenyl group
- two or three of R 7 to R 9 may be combined with a nitrogen atom to form a nitrogen-containing heterocyclic ring.
- X— is an anion in a quaternary salt
- Y is an alkyl group or the following general formula ( ⁇ ⁇ )
- the present invention relates to a polyoxyethylene Z polyorganosiloxane block copolymer having a quaternary salt represented by the formula (1) at the terminal, and use of the copolymer as a transdermal absorption enhancer for a drug.
- the present invention also provides a transdermal drug comprising a drug, an effective amount of the polyoxyethylene / polyorganosiloxane block copolymer of the present invention, and a pharmaceutically acceptable carrier, auxiliary or a combination thereof. It relates to a preparation for absorption.
- the present invention provides a drug obtained by mixing a drug and an effective amount of the polyoxyethylene Z polyorganosiloxane block copolymer of the present invention with a pharmaceutically acceptable carrier, auxiliary or a combination thereof.
- a method for promoting transdermal or transmucosal absorption of a drug comprising applying the composition to the skin or mucosa.
- Examples of the substituent represented by the general formula (I) ⁇ (!!) Medium R ⁇ R 41, methylation group, Echiru group, propyl group, butyl group, a pentyl group, a hexyl group, an isopropyl group, t- An alkyl group such as a butyl group or a phenyl group can be exemplified.
- An alkyl group such as a butyl group or a phenyl group can be exemplified.
- represented by the general formula ( ⁇ ) of the present invention When a block copolymer having a quaternary salt at its terminal is used as a percutaneous absorption enhancer, those having a methyl group as the above substituent are preferable in terms of ease of synthesis and the properties of the polysiloxane chain. preferable.
- the anion in the quaternary salt represented by the above general formula ( ⁇ ) or (X in DO) is a conjugate base of brenstead acid, ie, F—, C 1—, Br—, I—, etc.
- Conjugate bases of mineral acids such as halogen ions, hydroxyl ions, carbonate ions, sulfate ions, hydrogen sulfate ions, sulfite ions, nitrate ions, phosphate ions, etc., carboxylate ions, sulfonate ions, phosphonate ions, etc. Examples thereof include conjugate bases of organic acids, etc.
- the polyoxyethylene having a hydroxysilyl group at the terminal of the present invention represented by the general formula (I) can be produced, for example, by the following method. That is, the following general formula (IV)
- Equation (V) Equation (V)
- p is an integer of 2 to 6
- the average value of the polymerization degree m is a real number of 3 to 100.
- the polyoxyethylene compound having an alkenyl group at the terminal represented by the following formula is synthesized, and the polyoxyethylene compound represented by the general formula (VI) is further converted to a compound represented by the following general formula (VD R 1
- R 1 and R 2 may be the same or different and each may be an alkyl group or a phenyl group having 1 to 6 carbon atoms, and X 2 is a halogen atom or a lower alkoxy group).
- R 1 and R 2 may be the same or different and may be an alkyl group or a phenyl group having 1 to 6 carbon atoms, X 2 is a halogen atom or a lower alkoxy group, A 3 is an alkyl group or-(CH ⁇ p -Si ⁇ I ⁇ X 2 , p is an integer of 2 to 6, average degree of polymerization m is a real number of 3 to 100.) Polyoxyethylene having a terminal silyl group The compound is synthesized, and is obtained by hydrolyzing a halogen atom or a lower alkoxy group on a terminal silyl group of the obtained polyoxyethylene compound.
- the strong base used in the above reaction is methyllithium, n- Organic lithium compounds such as butyllithium, sec-butyllithium, t-butyllithium, phenol, lithium diisopropylamide, bistrimethylsilyllithium amide, sodium hydride, water Metal hydrides such as aluminum hydro
- Hydroxyl of the polyoxyethylene compound represented by the general formula (IV) as a raw material Use approximately 1 equivalent per group.
- the reaction is preferably carried out at a relatively low temperature from 180 to room temperature from the viewpoint of suppressing side reactions.
- This reaction is preferably performed in an organic solvent, and as the solvent used, tetrahydrofuran, dimethyloxetane, dioxane, benzene, toluene, hexane and the like are preferably used. Further, this reaction is desirably performed in an atmosphere of an inert gas such as argon-nitrogen.
- Examples of the alkenyl compound represented by the general formula (V) include vinyl chloride, vinyl bromide, aryl chloride, aryl bromide, aryl oxide, 4-bromobutene, 5-bromopentene, and 6-bromohexene. Can be illustrated.
- Examples of the hydrosilane compound represented by the general formula (W) include dimethylchlorosilane, dimethylmethoxysilane, dimethylethoxysilane, dimethylchlorosilane, dimethylmethoxysilane, dipropylethoxysilane, diisopropylethoxysilane, dibutylethoxysilane, and dibutylethoxysilane.
- Examples thereof include 1-butylethoxysilane, dipentylethoxysilane, dihexylethoxysilane, methylpropylmethoxysilane, methylphenylmethoxysilane, diphenylchlorosilane, and diphenylmethoxysilane.
- a polyoxyethylene compound having an alkenyl group represented by the general formula (VI) is reacted with a hydrosilane compound represented by the general formula (VI), and represented by the general formula 01).
- a hydrosilylation catalyst used for producing a polyoxetylene compound it is most common to use a platinum-based catalyst such as platinum, platinum carbon, chloroplatinic acid, and dicyclopentagel platinum platinum dichloride.
- platinum-based catalyst such as platinum, platinum carbon, chloroplatinic acid, and dicyclopentagel platinum platinum dichloride.
- other metal complexes containing palladium and rhodium can be used.
- (Ph 3 P) 4 Pd, (Ph 3 P) 2 PdCl 2 , (PhCN) 2 PdCl 2 , (Ph 3 P) 3 RhCl, (Ph 2 PH) 2 RhCl, (Ph 3 P) 2 (CO) RhCl, [(C 2 H 5 ) 3 P] 2 (C0) RhCl can be used as a catalyst.
- the amount of the catalyst used is usually 1/100 to the alkenyl group of the compound represented by the general formula (VI).
- reaction temperature is usually ⁇ ⁇ .
- the temperature is preferably set in the following temperature range, and is preferably set in an atmosphere of an inert gas such as argon or nitrogen.
- the hydrolysis reaction carried out when the polyoxyethylene compound represented by the general formula (I) of the present invention is derived from the polyoxyethylene compound represented by the general formula (wo) generally comprises a basic or acidic substance.
- the reaction proceeds smoothly in the presence of the compound.
- Basic or acidic substances used herein include lithium hydroxide, potassium hydroxide, sodium hydroxide, aluminum hydroxide, carbonated lime, and sodium carbonate.
- Basic substances such as potassium acetate, sodium acetate, etc. or acidic substances such as hydrochloric acid, sulfuric acid, nitric acid, acetic acid, calcium sulfate, calcium nitrate, magnesium sulfate, etc. are preferably used.
- a basic or weakly acidic substance which is represented by the above general formula (I).
- the reaction is preferably performed in the range of 0.1 to 5.0 equivalents with respect to the compound, and it is essential to carry out this reaction in the presence of water, but methanol, ethanol, propanol, acetone, tetrahydrofuran, Acetonitrile, etc.
- the reaction proceeds favorably when a water-soluble organic solvent is used in combination.
- the reaction temperature is usually sufficient around room temperature, but the temperature is high and the dimer of silanol, the target product, is dimer.
- a siloxane compound may be obtained as a by-product.
- it is necessary to control the reaction temperature in the range of 100 to room temperature in order to minimize the amount of by-products generated.
- a copolymer of the present invention having a quaternary salt at the terminal represented by the general formula (II) is obtained.
- the following method can be applied to manufacture the union. That is, a polyoxyethylene compound having a hydroxysilyl group at the terminal represented by the general formula (I) is reacted with a strong base to form a silanolate anion, and then the following general formula (K)
- R 3 and R 4 may be the same or different and each is an alkyl group having 1 to 6 carbon atoms or a phenyl group.
- the compound is reacted with a cyclotrisiloxane compound represented by the following general formula (X):
- R 5 and R 6 may be the same or different and may be an alkyl group or a phenyl group having 1 to 6 carbon atoms, X 3 is a halogen atom, q is 1 to 6 Is an integer.
- the reaction is stopped by using a chlorosilane compound represented by the following general formula (XI).
- ⁇ 6 may be the same or different and may be an alkyl group or a phenyl group having 1 to 6 carbon atoms, X 3 is a halogen atom, Y 1 is an alkyl group or the following general formula ( ⁇ )
- R 7 to R 9 may be the same or different and each represents an alkyl group, a substituted alkyl group, or a phenyl group, or a nitrogen atom to which two or three of R 7 to R 9 are bonded. And a nitrogen-containing heterocyclic ring may be formed together with the compound of formula (1). By doing so, it is possible to produce a polyoxyethylene / polyorganosiloxane block copolymer having a quaternary salt represented by the general formula (II) at one end, wherein X- is a halogen ion.
- a conjugate base such as a mineral acid or an organic acid corresponding to the halogen ion which is a counter anion of the copolymer represented by the above general formula ( ⁇ ) is obtained. It can be easily obtained by ion-exchange.
- Examples of the strong base used in the above reaction include organic lithium compounds such as methyllithium, n-butyllithium, sec-butyllithium, t-butyllithium, phenol, lithium diisopropylamide, bistrimethylsilyllithium amide, and the like.
- Examples thereof include sodium, hydrogenated metal hydride such as hydrogenated metal hydride, and methyl compounds such as methylmagnesium iodide, chilled magnesium bromide, and phenylmagnesium bromide.
- These strong bases are generally used in an amount of about 1 equivalent relative to the hydrocyanic acid group of the polyoxyethylene compound represented by the above general formula (I) as a raw material.
- the reaction is preferably carried out at a relatively low temperature from 180 to room temperature in order to suppress side reactions.
- This reaction is preferably performed in an organic solvent, and as the solvent used, tetrahydrofuran, dimethoxetane, dioxane, benzene, toluene, hexane and the like are preferably used. Further, this reaction is preferably performed in an atmosphere of an inert gas such as argon or nitrogen.
- Examples of the cyclotrisiloxane compound represented by the general formula (K), which is a monomer for forming a polysiloxane skeleton, include hexmethylcyclotrisiloxane, hexethylcyclotrisiloxane, and hexethylcyclotrisiloxane.
- Xaprovir cyclotrisiloxane Hexaisopropyl cyclotrisiloxane, Hexabutyltrisiloxane, Hexapentylcyclotrisiloxane, Hexahexylcycl trisiloxane, Hexaphenylcyclotrisiloxane, 1,3,5- Trimethinole-1,3,5-triethylcyclotrisiloxane, 1,3,5-trimethyl-1,3,5-tri-1-pentynolecyclotrisiloxane, 1,3,5-trimethyl-1,3 Examples thereof include 5-tripropyl cyclotrisiloxane, 1,3,5-trimethyl-1,3,5-triphenylcyclotrisiloxane, and the like. In addition, these cyclosiloxane compounds may use a mixture of two or more kinds in this reaction.
- chlorosilane compound represented by the general formula (X) to be used as the reaction terminator examples include chloromethyldimethylchlorosilane, bromomethyldimethylchlorosilane, p-methyldimethylchlorosilane, 2-couproethyldimethylchlorosilane, and 3-chloropropyl.
- the amount of the cyclotrisiloxane compound represented by the general formula (K) is adjusted to obtain a polyoxyethylene / polyoxyethylene / polyalkyl ester having a haloalkyl group represented by the general formula (XI) at a terminal. It is possible to control the degree of polymerization n of the liorganosiloxane block copolymer and the polyoxyethylene phenol polyorganosiloxane block copolymer having a quaternary salt represented by the general formula (II) of the present invention at the terminal. it can.
- the copolymers represented by the general formulas ( ⁇ ) and (XI) are mixtures of polyorganosiloxanes having different degrees of polymerization n, the measured degrees of polymerization are average values (real numbers). ).
- the amount of the cyclotrisiloxane compound represented by the general formula (K) is at least 1 equivalent to the amount of the silanolate anion used as the initiator. It is necessary to use the above.
- solvents include hexane, benzene, toluene, getyl ether, dioxane, tetrahydrofuran, acetone, methyl ethyl ketone, chloroform, methylene chloride, N, N-dimethylformamide, ⁇ , ⁇ -dimethylacetate.
- solvents include amide, dimethylformamide, and ⁇ -methylpyrrolidone.
- the terminal halogen atom represented by X 3 in the copolymer represented by the general formula (XI) is chlorine
- the quaternization reaction hardly proceeds, and the Ordinary halogen using sodium iodide or sodium iodide It is desirable to perform quaternization after replacing with bromine or iodine by an exchange reaction.
- the compound represented by the general formula (ring) used in the quaternization reaction includes trimethylamine, triethylamine, tripropylamine, triisopropylamine, tributylamine, triisobutylamine, tripentylamine.
- the polyoxyethylene / polyorganosiloxane block copolymer having a quaternary salt at the terminal represented by the general formula ( ⁇ ) of the present invention obtained by the above-mentioned production method is used as a drug transdermal absorption enhancer.
- the copolymer is a compound having a quaternary salt as a polar group, a polyoxyethylene chain as another hydrophilic group, and a polyorganosiloxane chain as a hydrophobic group. have. Therefore, in addition to the use of the drug of the present invention as a transdermal absorption enhancer, it can be applied to detergents, bactericides, preservatives, cosmetics, and the like.
- the average degree of polymerization has a large effect on the promotion effect, and differs depending on the drug used in order to exhibit a high promotion effect.
- the average value of the degree of polymerization represented by m and n is preferably in the range of 3 to 100, and more preferably in the range of 5 to 50.
- the tertiary salt-terminated polyoxyethylenenopolyorganosiloxane block copolymer of the present invention or the transdermal absorption enhancer of a drug comprising this copolymer should be administered.
- the drug is mixed with a pharmaceutically acceptable carrier and a pharmaceutically acceptable carrier or adjuvant, and used as a preparation (composition) for transdermal absorption of the drug.
- a pharmaceutically acceptable carrier and a pharmaceutically acceptable carrier or adjuvant include a tincture dissolved in a solvent such as water or alcohol together with a drug together with the above-mentioned copolymer, an ointment, an ointment mixed with a cream base, a cream, and a polymer film or an adhesive. It can be used in any form such as a tape preparation mixed therein.
- the content of the copolymer or transdermal absorption enhancer of the present invention in the preparation varies depending on the use form. Made, but generally 0.1 wt% to 50 wt%, preferably 1 wt Q '0 to 20 by weight%.
- the content is small, the absorption promoting effect is small, and when the content is large, side effects such as skin irritation become remarkable and the release of the drug is sometimes suppressed.
- the drug used in the present invention may be any drug for humans or animals.
- an anti-inflammatory analgesic acetoaminophenone, aspirin, methyl salicylate, choline salicylate, choline salicylate, 1-glycol, Menthol, camphor, mefenamic acid, flufenamic acid, antipyrine, indomethacin, diclofenac, diclofenac sodium, alclofenac, ibuprofen, ketoprofen, naproxen, planoprofen, fenobrofen, fenprofen, flurbiprofen, flurbiprofen Fen, Funchiazac, Tolmetin, Sprofen, Benza Duck, Bufoxamac, Piroxicam, Phenylbutazone, Oxyfenbutazone, Clofuzone, Penta Zozin, mepyrizole, etc .
- Steroid-type anti-inflammatory agents include hydrocortisone, predn
- vitamins A, B, C, D, E, K and their derivatives calcidrol, mecovalamine, etc .
- antitumor agents 5-fluorouracil and its derivatives, adriamycin, krestin, picibanani Lecithin, ancitabine, cytarabine, etc .
- enzymes such as perokinase; herbal medicines or herbal extracts such as licorice, aloe, and purple root; anti-ulcer agents such as allantoin, argioxa, and alcroxa;
- Other examples include prostaglandins and antidiabetic agents. If necessary, two or more of these drugs can be used in combination.
- the preparation (composition) of the above-mentioned drug containing the block copolymer of the present invention is applied to the skin or mucous membrane (oral cavity, nasal cavity, rectum, vagina) of each part of the human body in a required amount according to the purpose, or applied or patched. It can facilitate transdermal or transdermal absorption of the drug. For example, if it is for the local treatment of trauma, skin ulcer, myalgia, arthritis, etc., it is directly at or near the affected area, or for systemic treatment of internal organs, etc. For example, it is preferably applied to a site where keratin is not developed.
- the above preparations When used for cosmetics, the above preparations may be used as they are, or may be selected from the above-mentioned drugs, or may contain any known cosmetic ingredients.These may be used for washing, packing, countermeasures against sunburn or rough skin, moisturizing, etc. Can be used in BEST MODE FOR CARRYING OUT THE INVENTION
- D 3 represents hexamethylcyclotrisiloxane.
- IR (neat, cm- 1 ); 2880, 1720, 1460, 1360, 1110, 940, 840.
- An n-butyllithium hexane solution (1.6 mol / l) was added at 0, and the mixture was stirred for 1 hour.
- Table 4 the amount of tetrahydrofuran solution of D 3 according added, at room temperature, and stirred for 12 hours. Further, 1.5 equivalents of 3-chloropropyldimethylchlorosilane relative to polyoxyethylene was added, and the mixture was stirred for 3 hours.
- IR (neat, cm- 1 ); 3480 (SiOH), 2880, 1460, 1350, 1300, 1250, 1100, 9 40,880, 840,680.
- IR (neat, cm-unit; 2980, 2900, 1740, 1460, 1420, 1360, 1260, 1100, 1 030, 880,710. Examples 12, 13 Skin permeation experiment of diclovena.
- a heron abdominal exfoliated skin was sandwiched between two -chamber one-diffusion cell with water jacket (effective cross-sectional area 0.95 cm 2 ), and the anti-inflammatory agent diclofenac sodium 20 mg was obtained in the donor part, obtained in Examples 2 and 3.
- 2 ml of a 50% aqueous solution of ethyl alcohol containing a polyoxetylenenopolyorganosiloxane block copolymer having a quaternary salt at the end (percutaneous absorption enhancer) (5 wt.3 ⁇ 4), and ⁇ 7 ⁇ 2 ml of phosphate buffer adjusted to 4 was added. 37 constant temperature water was circulated in the water jacket to keep the temperature constant.
- Table 1 shows the permeation measurement results obtained by using the polyoxyethylenenopolyorganosiloxane block copolymer having a quaternary salt at the terminal obtained in Examples 2 and 3 as a transdermal absorption enhancer, respectively. .
- the case where these block copolymers are not added is shown as Comparative Example 1 in Table 7.
- ⁇ As can be seen from Table 1, the polyoxyethylene Z polyorganosiloxane block having a quaternary salt at the terminal thereof is used.
- Table 8 shows the results of permeation measurement obtained using the polyoxyethylene polyorganosiloxane block copolymer having a quaternary salt at the terminal obtained in Examples 2 and 3 as a transdermal absorption enhancer, respectively.
- the case where these block copolymers were not added is shown as Comparative Example 1 in Table 8.
- Comparative Example 1 it is clear that the polyoxyethylene polyorganosiloxane block copolymer having a quaternary salt at its terminal has an excellent transdermal absorption promoting effect on such water-soluble drugs.
- a heron abdominal exfoliated skin was sandwiched between a two -chamber one diffusion cell (effective area: 0.95 cm 2 ) with a water jacket, and the anti-inflammatory agent antipyrine 20 mg was applied to the donor part.
- Examples 2 to 5, 8, 9 and 11 2 ml of a 50% aqueous solution of ethyl alcohol containing the obtained polyoxoxethylennopolyorganosiloxane block copolymer having a quaternary salt (percutaneous absorption enhancer) (2 wt.%) was added to the receptor.
- 2 ml of the phosphate buffer adjusted to pH 7.4 was added. 37 constant temperature water was circulated in the water jacket to keep the temperature constant.
- Example 1 1 0.558 ⁇ 0.069 2.229 ⁇ 0.112 Comparative Example 2 None 0.069 ⁇ 0.0013 0.269 ⁇ 0.041
- a heron abdominal exfoliated skin was sandwiched between a 2- diffused diffusion cell (effective area: 0.95 cm 2 ) with a water jacket, and an anti-inflammatory agent, indomethacin 20 mg, was partially applied to the donna, and was obtained in Examples 2 to 4 and 7 to 9.
- 2 ml of a 503 ⁇ 4 aqueous solution of ethyl alcohol containing a polyoxetylenenopolyorganosiloxane block copolymer (percutaneous absorption enhancer) (2 wt.3 ⁇ 4) containing a quaternary salt at the terminal 2, 2 ml of the phosphate buffer adjusted to 7.4. 37 constant temperature water was circulated in the water jacket to keep the temperature constant.
- novel hydroxysilyl-terminated polyoxyethylene compound-terminated polyoxyethylene compound-terminated tertiary salt-terminated polyoxyethylenenopolyorganosiloxane block copolymer promotes the penetration and absorption of drugs through the skin It can be used as a transdermal absorption enhancer.
- a surfactant since it has the property of a surfactant, it can be applied to detergents, bactericides, preservatives, cosmetics, and the like.
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Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US08/537,867 US5624680A (en) | 1993-07-23 | 1994-07-07 | Hydroxysilyl-terminated polyoxyethylene compound, quaternary-salt-terminated block copolymer, and percutaneous absorption-promoting agent |
EP94919868A EP0710688A4 (en) | 1993-07-23 | 1994-07-07 | POLYOXYETHYLENE COMPOUND WITH HYDROXYSILYL TERMINATION, SEQUENCE COPOLYMER WITH QUATERNARY SALT TERMINATION AND PERCUTANEOUS ABSORPTION PROMOTER |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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JP20196693A JP3414446B2 (ja) | 1993-07-23 | 1993-07-23 | ヒドロキシシリル基を末端に有するポリオキシエチレン化合物、四級塩を末端に有するブロック共重合体、および経皮吸収促進剤 |
JP5/201966 | 1993-07-23 |
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WO1995003352A1 true WO1995003352A1 (fr) | 1995-02-02 |
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PCT/JP1994/001109 WO1995003352A1 (fr) | 1993-07-23 | 1994-07-07 | Compose de polyoxyethylene a terminaison hydroxysilyle, copolymere sequence a terminaison de sel quaternaire et promoteur d'absorption percutanee |
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US (1) | US5624680A (ja) |
EP (1) | EP0710688A4 (ja) |
JP (1) | JP3414446B2 (ja) |
WO (1) | WO1995003352A1 (ja) |
Families Citing this family (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB9814272D0 (en) * | 1998-07-01 | 1998-09-02 | Johnson & Son Inc S C | Silicone compounds and process for making them |
US6238684B1 (en) * | 1998-12-10 | 2001-05-29 | Osi Specialties, Inc. | Terminally modified, amino, polyether siloxanes |
DE19954394A1 (de) * | 1999-11-12 | 2001-05-17 | Bayer Ag | Verwendung von Polysiloxanen mit quartären Aminogruppen als Formulierungshilfe und Mittel enthalten dieselben |
EP1369449B1 (de) * | 2002-06-06 | 2004-02-11 | Wacker-Chemie GmbH | Verfahren zur Herstellung von Polydiorganosiloxanen |
JP4551073B2 (ja) * | 2003-10-06 | 2010-09-22 | 日東電工株式会社 | 皮膚貼付用の粘着シート |
JP5046404B2 (ja) * | 2009-09-25 | 2012-10-10 | 信越化学工業株式会社 | ω末端にポリアルキレンオキシド基を有する片末端反応性オルガノポリシロキサン及びその製造方法。 |
WO2013066911A1 (en) * | 2011-11-04 | 2013-05-10 | Dow Corning Corporation | Hydrophilic organosilanes |
JP2015124274A (ja) * | 2013-12-26 | 2015-07-06 | 日本ゼオン株式会社 | ポリエーテルゴムの製造方法 |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS55131021A (en) * | 1979-03-30 | 1980-10-11 | Shin Etsu Chem Co Ltd | Preparation of silicone-modified polyoxyalkylene polyether |
JPH05936A (ja) * | 1990-10-25 | 1993-01-08 | Kanegafuchi Chem Ind Co Ltd | 経皮吸収製剤 |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS55123648A (en) * | 1979-03-16 | 1980-09-24 | Shin Etsu Chem Co Ltd | Cold-setting composition |
DE3719086C1 (de) * | 1987-06-06 | 1988-10-27 | Goldschmidt Ag Th | Diquartaere Polysiloxane,deren Herstellung und Verwendung in kosmetischen Zubereitungen |
GB8917323D0 (en) * | 1989-07-28 | 1989-09-13 | Inverni Della Beffa Spa | Methods and pharmaceutical compositions for the treatment of ophthalmic diseases |
US5087715A (en) * | 1989-08-07 | 1992-02-11 | Dow Corning Corporation | Alkanolanmino functional siloxane compositions |
DE69126002T2 (de) * | 1990-11-06 | 1997-08-28 | Sagami Chem Res | An einem Kettenende mit einem quaternären Salz abgeschlossenes Polyorganosiloxan und Mittel zur Förderung der perkutanen Absorption |
US5115049A (en) * | 1991-02-19 | 1992-05-19 | Siltech Inc. | Fatty carboxylic silicone amine salts |
-
1993
- 1993-07-23 JP JP20196693A patent/JP3414446B2/ja not_active Expired - Fee Related
-
1994
- 1994-07-07 EP EP94919868A patent/EP0710688A4/en not_active Ceased
- 1994-07-07 US US08/537,867 patent/US5624680A/en not_active Expired - Fee Related
- 1994-07-07 WO PCT/JP1994/001109 patent/WO1995003352A1/ja not_active Application Discontinuation
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS55131021A (en) * | 1979-03-30 | 1980-10-11 | Shin Etsu Chem Co Ltd | Preparation of silicone-modified polyoxyalkylene polyether |
JPH05936A (ja) * | 1990-10-25 | 1993-01-08 | Kanegafuchi Chem Ind Co Ltd | 経皮吸収製剤 |
Non-Patent Citations (1)
Title |
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See also references of EP0710688A4 * |
Also Published As
Publication number | Publication date |
---|---|
EP0710688A4 (en) | 1998-01-07 |
EP0710688A1 (en) | 1996-05-08 |
JPH0733870A (ja) | 1995-02-03 |
JP3414446B2 (ja) | 2003-06-09 |
US5624680A (en) | 1997-04-29 |
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