CN102076340B - Transdermal patch containing fentanyl or salt thereof - Google Patents
Transdermal patch containing fentanyl or salt thereof Download PDFInfo
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- CN102076340B CN102076340B CN2009801246133A CN200980124613A CN102076340B CN 102076340 B CN102076340 B CN 102076340B CN 2009801246133 A CN2009801246133 A CN 2009801246133A CN 200980124613 A CN200980124613 A CN 200980124613A CN 102076340 B CN102076340 B CN 102076340B
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- 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
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4468—Non condensed piperidines, e.g. piperocaine having a nitrogen directly attached in position 4, e.g. clebopride, fentanyl
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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
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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- 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
- A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
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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
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
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Abstract
Provided is a patch containing fentanyl or a derivative thereof which causes no lowering in the stickiness to the skin, has a high drug-stability, can inhibit the time-dependent deposition of fentanyl crystals, yet little irritates the skin and shows an extremely high skin permeability of fentanyl. A patch containing fentanyl or a derivative thereof consisting of a support, a pressure-sensitive adhesive layer containing fentanyl or a derivative thereof and a release liner, wherein the pressure-sensitive adhesive layer containing fentanyl or a derivative thereof contains 0.01 to 0.5% by mass of an ascorbate such as an L-ascorbate palmitate. A patch containing fentanyl or a derivative thereof further contains a hindered phenol-type antioxidant in an amount sufficient for the inhibition of the deposition of fentanyl or a salt of the same.
Description
Technical field
The present invention relates to contain the percutaneous patch of fentanyl (chemical name: N-(1-phenethyl piperidin-4-yl)-N-Phenylpropionamide) or its salt.Be that the medicine ageing stability is excellent and do not separate out the preparation of fentanyl crystal by the percutaneous patch that contains fentanyl or its salt provided by the invention, this percutaneous patch is expected as the persistent anesthetis of effect, analgesics very much.
Background technology
Fentanyl or its citrate are synthetic opium kind analgesics, are used in mainly as injection in the treatment etc. of acute postoperative pain, chronic cancerous pain.In addition, except injection, also developed the patch (with reference to patent documentation 1) that contains fentanyl, it has obtained preferably effect in clinical.
This patch has reservoir devices (reservoir), and its fentanyl slow-releasing is excellent, compares long action time with injection, is suitable for treating cancerous pain.Its on the other hand, the structure of preparation is made of support, drug storage layer, controlled release layer, adhesive phase and liner, the operation number of making said preparation is many and complicated, and needs high-precision technology.Therefore, comparing manufacturing cost with common patch uprises and need to improve to some extent.
In addition, although the usage that adopts is to use 1 said preparation to stick continuously 3 days, have following problem: since bonding insufficient and in sticking process, peel off or roll, since ethanol through the time volatilization cause the crystallization of fentanyl.In addition, reported that both at home and abroad medicinal liquid is from the spilling of drug storage layer, the misuse example of preparation, abuse, if in the situation of the healthy Person's skin beyond medicinal liquid directly contacts patient or patient, the serious or fatal Health cost such as respiration inhibition may occur in worry.
In recent years, developed the fentanyl patch that contains of matrix type, and it has been applied in the medical scene.Matrix type patch preparations is compared with the reservoir devices patch, and it is simple in structure and manufacture method is easy, therefore can make with low cost.But, because matrix type patch preparations does not have controlled release layer, therefore, compare with the reservoir devices patch, although medicine can be rapidly to cutaneous metastatic usually, the persistence of drug absorption is low, and medicament contg descends, and then in bonding base, separate out gradually medicine crystal etc., thereby need the improvement on the preparation.
Also developed the matrix type fentanyl patch that has improved the problems referred to above.Following patch is for example disclosed: the patch (with reference to patent documentation 2) that contains fentanyl in the bonding base of silicone; Contain fentanyl and contain respectively polyisobutylene, styrene isoprene styrene block copolymer (SIS) and as the patch (with reference to patent documentation 3) of the alicyclic saturated hydrocarbon resin of tackifying resin; The patch (with reference to patent documentation 4) that contains fentanyl, polyisobutylene, mineral oil and absorption enhancer; Contain the patch (with reference to patent documentation 5) of two kinds of different polyisobutylene of molecular weight, adhesive (viscosifier), organic liquor (absorption enhancer) etc.
Wherein, the bonding base of silicone that for example uses in the patent documentation 2, the adhesiveness to skin is not enough usually, peels off when sticking or rolls, and may can not stably throw and medicine for the cancer patient,, may not keep the effective blood drug concentration of medicine that is.
In addition, the patch of patent documentation 3 is the preparations to the adhesiveness excellence of skin, the employed alicyclic saturated hydrocarbon resin of tackifying resin is compared with other tackifying resins, and the compatibility of itself and fentanyl is low, may make the fentanyl time dependent ground recrystallize that is dissolved in the paste layer and separates out.And then the patch of patent documentation 4 and 5 patch that although to be preparation stabilities good and transdermal characteristic is excellent, the adhesiveness to skin in the time of may having diaphoresis, balneation reduces, occurs the problems such as skin irritation.
In order to improve the problem that crystal is separated out in the percutaneous patch of above-mentioned matrix type fentanyl, crystal as fentanyl or its salt is separated out inhibitor, cooperated as the isopropyl myristate in the fatty acid alkyl esters of organic liquor, isooctadecanol in the saturated or undersaturated long-chain branch alcohol, octyldodecanol etc., but the original adhesiveness of bonding base is reduced, thereby cause sticking peeling off or rolling in the process, can't keep effective blood drug level, in addition, the compendency reduction owing to bonding base is created in the cull that occurs mastic on the skin, the problem that patient's compliance (compliance) reduces.Put down in writing on the other hand: in fentanyl percutaneous dosing type patch in the past, can cooperate as any antioxidant of composition is tocopherol and ester derivant thereof, ascorbic acid, stearate, nordihydroguaiaretic acid (nordihydroguaiaretic acid), dibenzylatiooluene (BHT), BHA (BHA) (patent documentation 1), at present, the stabilization effect of these antioxidant remifentanils or its salt is fully unknown.
The prior art document
Patent documentation
Patent documentation 1: Japanese kokai publication sho 61-37725 communique
Patent documentation 2: Japanese Unexamined Patent Application Publication 2006-513160 communique
Patent documentation 3:WO2004/024155 communique
Patent documentation 4:WO2004/035054 communique
Patent documentation 5: TOHKEMY 2006-76994 communique
Patent documentation 6: Japanese kokai publication hei 10-45570 communique
Summary of the invention
The problem that invention will solve
The object of the present invention is to provide the crystal that can suppress fentanyl or its salt through the time separate out and can not reduce skin adherence, medicine stability is excellent and skin irritation is low and the percutaneous patch of the extraordinary fentanyl of the transdermal characteristic of fentanyl or its salt.
For the scheme of dealing with problems
In order to solve above-mentioned problem, the inventor etc. conduct in-depth research, the result is clear and definite first: the percutaneous patch that contains fentanyl or its salt, in its manufacture process with in preserving, generate oxysome on the piperidines ring nitrogen (below be sometimes referred to as " fentanyl-N-oxysome "), and then this fentanyl-N-oxysome, decompose when for example under 60 ℃, keeping 24 hours, generate the N-Phenylpropionamide, N-(1-hydroxy piperidine-4-yl)-N-Phenylpropionamide, (1-phenethyl-2-oxo-piperidine-4-yl)-N-Phenylpropionamide and these four kinds of secondary catabolites of styrene.And, the discoveries such as the inventor, by in containing the percutaneous patch of fentanyl or its salt, cooperating acid ascorbyl ester, thereby suppress catabolite and be fentanyl-N-oxysome, with and pyrolysate be the generation of above-mentioned four kinds of secondary catabolites, can improve the medicine ageing stability, thereby finish the present invention.
In addition, the inventor etc. for provide the crystal that can suppress fentanyl or its salt through the time separate out and can not reduce skin adherence, and medicine stability excellence and skin irritation are low, the percutaneous patch of the extraordinary fentanyl of the transdermal characteristic of fentanyl or its salt and conducting in-depth research, found that: when manufacturing contains the percutaneous patch of fentanyl or its salt, in order not reduce the original adhesiveness of bonding base, and the crystal that suppresses fentanyl through the time separate out, separating out inhibitor as the required fentanyl that the compatibility that improves fentanyl and bonding base is served as a connection or the crystal of its salt, is that antioxidant is the most suitable with hindered phenol.
Namely, the discoveries such as the inventor, adding hindered phenol in the adhesive phase that contains fentanyl or its salt is antioxidant, the crystal that obtains thus suppressing fentanyl through the time separate out and can not reduce the original adhesiveness of bonding base and suppress the good and low percutaneous patch of skin irritation of time dependent transdermal characteristic deteriorated and fentanyl of bonding base, thereby finished the present invention.More specifically, to do not add in the adhesive phase hindered phenol be the preparation of antioxidant and be added with hindered phenol be antioxidant preparation fentanyl crystal through the time separate out inhibitory state and compare observation, found that the preparation that has added hindered phenol and be antioxidant can obviously suppress the crystal of fentanyl and separate out.And then, the crystal of also finding this fentanyl separate out inhibition along with hindered phenol be antioxidant addition increase and increase.
That is, as one of typical scenario of the present invention, for a kind of percutaneous patch that contains fentanyl or its salt, it is characterized in that, contain the acid ascorbyl ester of 0.01～0.5 quality %.
In addition, the example of another typical scenario of the present invention, stabilization method for a kind of fentanyl or its salt is characterized in that, cooperating with respect to percutaneous patch in containing the percutaneous patch of fentanyl or its salt all is the acid ascorbyl ester of 0.01～0.5 quality %.
In addition, the purport of another typical scheme example of the present invention is as described below.
(1) a kind of percutaneous patch, its hindered phenol that contains fentanyl or its salt of effective dose and be enough to suppress this fentanyl or its amount that salts out in mastic is antioxidant.
(2) a kind of percutaneous patch is characterized in that, containing fentanyl or its salt and hindered phenol in the adhesive phase is antioxidant, and this fentanyl or its salt exist with dissolved state in adhesive phase.
(3) a kind of manufacture method that contains the percutaneous patch of fentanyl or its salt, when manufacturing contained the percutaneous patch of fentanyl or its salt, being included in the mastic hindered phenol that cooperates fentanyl or its salt and be enough to suppress this fentanyl or its amount that salts out was the operation of antioxidant.
(4) crystal of a kind of fentanyl or its salt is separated out the inhibition method, and the hindered phenol of the amount that the crystal that it adds in the compositions that contains fentanyl or its salt is enough to suppress fentanyl or its salt is separated out is antioxidant.
(5) crystal of a kind of fentanyl or its salt is separated out inhibitor, and it is that antioxidant is as effective ingredient take hindered phenol.
The present invention can comprise the preferred version of the following stated.
A kind of percutaneous patch that contains fentanyl or its salt, it is to comprise support, contain the adhesive phase of fentanyl or its salt and the percutaneous patch of release liner, and containing with respect to percutaneous patch in the adhesive phase that contains fentanyl or its salt all is the acid ascorbyl ester of 0.01～0.5 quality %.
A kind of percutaneous patch that contains fentanyl or its salt, wherein, acid ascorbyl ester is Ascorbyl Palmitate.
The stabilization method of a kind of fentanyl or its salt is characterized in that, cooperating with respect to percutaneous patch in containing the percutaneous patch of fentanyl or its salt all is the acid ascorbyl ester of 0.01～0.5 quality %.
The stabilization method of a kind of fentanyl or its salt, wherein, acid ascorbyl ester is Ascorbyl Palmitate.
A kind of percutaneous patch that contains fentanyl or its salt, it further contains the hindered phenol that is enough to suppress this fentanyl or its amount that salts out in adhesive phase be antioxidant.
A kind of percutaneous patch that contains fentanyl or its salt, wherein, hindered phenol is that antioxidant is 2,6 ditertiary butyl p cresol or four [3-(3,5-di-t-butyl-4-hydroxyphenyl) propanoic acid] pentaerythritol ester.
The crystal of a kind of fentanyl or its salt is separated out inhibitor, and it is that antioxidant forms by hindered phenol.
The crystal of a kind of fentanyl or its salt is separated out inhibitor, and wherein, hindered phenol is that antioxidant is 2,6 ditertiary butyl p cresol or four [3-(3,5-di-t-butyl-4-hydroxyphenyl) propanoic acid] pentaerythritol ester.
The effect of invention
The percutaneous patch that contains fentanyl or its salt of the application of the invention can obtain preserving for a long time and can not cause the preparation that fentanyl or its salt decompose, thus can be effectively and routinely utilize the pharmacological effect of fentanyl or its salt.
In addition, can provide according to the present invention benefit the crystal that suppresses fentanyl or its salt through the time separate out and can not reduce the percutaneous patch that contains fentanyl or its salt of the original adhesiveness of bonding base and medicine stability excellence.By the present invention, in the percutaneous patch of fentanyl or its salt, can make following percutaneous patch: the crystal that not only can give play to fentanyl or its salt through the time inhibition, low irritant and excellent adhesiveness and the transdermal characteristic of separating out, and the ageing stability of medicine is excellent.Therefore, the percutaneous patch that contains fentanyl or its salt that is obtained by the present invention can become lenitive powerful measure.
The specific embodiment
Below to the percutaneous patch that contains fentanyl or its salt of the present invention, contain the percutaneous patch of fentanyl or its salt stabilization method, suppress fentanyl or its salt crystal through the time hindered phenol of separating out be that antioxidant is elaborated.
As mentioned above, the fentanyl that uses in the percutaneous patch (hereinafter referred to as " containing fentanyl class patch ") of fentanyl or its salt (below be sometimes referred to as " fentanyl class ") that contains of the present invention is synthetic opium kind analgesics, its chemistry N-(1-phenethyl piperidin-4-yl) by name-N-Phenylpropionamide.
In addition, as the salt of fentanyl, so long as the salt that pharmaceutically allows then is not particularly limited, can also can be organic salt for inorganic salt.As representative fentanyl salt, can list citrate, hydrochlorate, fumarate etc.In the middle of these, citric acid fentanyl particularly preferably.In addition, it is two or more that fentanyl or its salt can mix use, but usually take independent use as good.
In the adhesive composition, the effective dose of fentanyl class is preferably 1～15 quality %, the more preferably scope of 1～10 quality %.
As the fentanyl class patch that contains of the present invention, can list the agent shapes such as cataplasma (cataplasm), adhesive tape agent (tape), be preferably the adhesive tape agent.This adhesive tape agent comprises support, adhesive phase, peel ply basically, the hindered phenol of the amount that the crystal that cooperates the fentanyl class of effective dose and be enough to make the acid ascorbyl ester and/or be enough to of the amount of this fentanyl class stabilisation to suppress the fentanyl class in its adhesive phase is separated out is antioxidant, according to conventional method with its preparation, thereby be prepared from.
As the acid ascorbyl ester that in percutaneous patch of the present invention, cooperates, can list Ascorbyl Palmitate, L-ascorbyl stearate, APM, wherein, the compatibility of Ascorbyl Palmitate and fat-soluble base is excellent, so preferred.
The content of acid ascorbyl ester all is 0.01～0.5% with respect to containing fentanyl class patch.When use level is lower than 0.01%, can't obtain sufficient stabilization effect, even surpass 0.5%, stabilization effect does not have difference yet, and because acid ascorbyl ester self crystallize out, it is also nonsensical therefore to increase consumption.
In addition, acid ascorbyl ester is preferably counted 0.0015～0.5 range fit with the mass ratio (acid ascorbyl ester/fentanyl or its salt) with respect to the content of fentanyl or its salt.Be lower than at 0.0015 o'clock, sometimes can't obtaining sufficient stabilization effect, in addition, even be higher than 0.5, sometimes can not confirm the further raising of effect.
In addition, as contain in the fentanyl class patch crystal that shows the fentanyl class through the time inhibition separated out hindered phenol be antioxidant, can list 2,6-ditertbutylparacresol (trade name: Yosinox BHT), 4,4 '-butylidene is two-(the 6-tert-butyl group-3-methylphenol) (trade name: Yosinox BB), 2,2 '-di-2-ethylhexylphosphine oxide-(4-methyl-6-tert-butylphenol) (trade name: Yosinox 2246G), 2,2 '-di-2-ethylhexylphosphine oxide-(4-ethyl-6-tert-butyl phenol) (trade name: Yosinox 425), 2,6-di-t-butyl-4-ethyl-phenol (trade name: Yosinox 250), 1,1,3-three (2-methyl-4-hydroxyl-5-tert-butyl-phenyl) butane (trade name: Yosinox 930), n-octadecane base-3-(3,5-di-t-butyl-4-hydroxyphenyl) propionic ester (trade name: Tominox S S; IRGANOX1076, IRGANOX 1076FD), four [3-(3,5-di-t-butyl-4-hydroxyphenyl) propanoic acid] pentaerythritol ester (also is called four (methylene-3-(3,5-di-t-butyl-4-hydroxyphenyl) propionic ester) methane.Trade name: Tominox TT; IRGANOX 1010, IRGANOX 1010FF), two (3-(3-tertiary butyl-4-hydroxy-5-aminomethyl phenyl) propionic ester) (trade name: the Tominox 917 of triethylene glycol; IRGANOX 245, IRGANOX 245FF), three (3,5-di-tert-butyl-4-hydroxyl benzyl) isocyanuric acid ester (trade name: Yosinox 314; IRGANOX 3114), 1, [3-(3 for 6-hexanediol-two, 5-di-t-butyl-4-hydroxyphenyl) propionic ester] (trade name: IRGANOX 259), 2,4-pair-(positive hot sulfenyl)-6-(4-hydroxyl-3,5-di-tert-butyl amido)-1,3,5-triazine (trade name: IRGANOX 565, IRGANOX 565DD), 2, [3-(3 for 2-sulfo--di ethylene bis, 5-di-t-butyl-4-hydroxyphenyl) propionic ester] (trade name: IRGANOX 1035FF), N, N '-hexa-methylene is two, and [3-(3,5-di-t-butyl-4-hydroxyphenyl) propanoic acid amide] (trade name: IRGANOX 1098), 1,3,5-trimethyl-2,4,6-three (3, the 5-di-tert-butyl-4-hydroxyl benzyl) benzene (trade name: IRGANOX 1330), two (3,5-di-tert-butyl-4-hydroxyl benzyl phosphinic acid ethyl ester) calcium (trade name: IRGANOX1425WL), 2, two [(hot sulfenyl) methyl]-orthoresol (trade names: IRGANOX1520L) of 4-, iso-octyl-3-(3,5-di-t-butyl-4-hydroxyphenyl) propionic ester (trade name: IRGANOX 1135) etc., wherein, preferred 2,6-ditertbutylparacresol or four [3-(3,5-di-t-butyl-4-hydroxyphenyl) propanoic acid] pentaerythritol ester.In addition, " tert-butyl group " refers to " tert-butyl group ".
In the adhesive composition, it is that the amount of antioxidant is 0.5～8 quality % that above-mentioned being enough to suppresses to contain hindered phenol that the crystal of the fentanyl class of fentanyl class patch separates out, is preferably 1.5～5 quality %.Hindered phenol is that the amount of antioxidant is when being lower than 0.5%, the crystal that can't obtain sufficient fentanyl or its salt through the time separate out inhibition, even surpass 8 quality %, the crystal of fentanyl class through the time inhibition separated out do not have difference yet, it is also nonsensical therefore to increase consumption.
By the available fentanyl class patch that contains of the present invention, at the longer duration of drug effect, can keep aspect the long analgesic effect, be preferred.Embodiments of the present invention contain fentanyl class patch, in adhesive phase, cooperate fentanyl or its salt and as the acid ascorbyl ester of stabilization agent, separating out and further preferably contain hindered phenol for the crystal that suppresses the fentanyl class is antioxidant.
As the bonding base of adhesive phase, preferred hydrophobic is bonding base, can list the bonding base of rubber series, the hydrophobic acrylic acid is bonding base, the bonding base of silicone.As this bonding base, have no particular limits, as preferred example, can list polyisobutylene (PIB), styrene isoprene styrene block copolymer (SIS) (SIS) [for example, the Kraton D-KX401CS of JSR Kraton Elastomer, Kraton D-1107CP, the KaliflexD-1111 that Shell chemicals company makes, Kaliflex TR-1107, the JSR5000 that Japan SYnthetic Rubber Co. Ltd makes, JSR-5002, SR5100, Nippon Zeon Co., Ltd. the Quintac 3421 that makes etc.], isoprene rubber [for example, Nippon Zeon Co., Ltd. NIPOLIR2200], styrene butadiene styrene block copolymer (SBS) (SB S) [for example, the Kaliflex TR-1101 that Shellchemicals company makes etc.], acrylic acid series polymeric compounds (2-EHA, vinylacetate, ethyl acrylate, methacrylate, acrylic acid methoxyl group ethyl ester, at least two kinds copolymer in the acrylic acid, such as (Nippon Carbide Industries Co., Inc. makes) such as PE-300, MAS 811 (can obtain from CosMED), DURO-TAK (DURO-TAK; Registered trade mark) 87-4098 and 87-4287 (can from Henkel Technologies Japan obtain)), polydimethylsiloxane etc., they can be used alone or mixed use of two or more.In the middle of these, preferably use SIS, acrylic acid series polymeric compounds.
Based on all quality of adhesive phase that contain fentanyl class patch, preferably with 0.1～98%, further preferably with 0.1～70%, particularly preferably cooperate the binding agent base with 0.1～50% amount.When the use level of bonding base was lower than 0.1%, the physical property variation of preparation self when surpassing 98%, can't obtain the good adhesion to human body skin sometimes.
In addition, the adhesiveness of the bonding base of rubber series is lower usually, therefore, in order to give the preparation adhesiveness, can further cooperate viscosifier in adhesive phase.As these viscosifier, can list the rosin series resin such as hydrogenated rosin glyceride, poly-terpene and be resin, petroleum line resin, oil-soluble phenolic aldehyde and be the viscosifier etc. of resin as preferred example.As their concrete example, can list Cliaron P-105, Forral105, Alcon P-100, KE-311, KE-100, Super Ester S-100, Tamanol521, YS Resin 75, YS Resin PX 1150N, KR-610 (being trade name) by trade name.Based on all quality of adhesive phase that contain fentanyl class patch of the present invention, preferably with 10～70 quality %, particularly preferably the amount with 20～60 quality % cooperates these viscosifier.
In addition, in order to improve processability, the adjustment adhesiveness that contains fentanyl class patch of the present invention, also can in adhesive phase, cooperate oils and fats as softening agent.As oils and fats, for example preferred liquid paraffin, squalane, olive oil, Camellia oil, peach kernel oil, Semen arachidis hypogaeae wet goods, particularly preferably liquid paraffin.Based on all quality of adhesive phase that contain fentanyl class patch of the present invention, preferably with 1～60 quality %, particularly preferably cooperate oils and fats with the amount of 10～50 quality %.
And then, in the paste layer that contains fentanyl class patch of the present invention, can cooperate as required absorption enhancer.As absorption enhancer, so long as can confirm chemical compound to the absorption enhancement effect of skin, then all can use, for example can list fatty acid, aliphatic alcohol, fatty acid ester or the ether of carbon number 6～20, fragrant family organic acid, fragrant family alcohol, fragrant family organic acid esters or ether.In addition, also can list lactic acid ester, acetates, monoterpene based compound, sesquiterpene based compound, N-dodecyl aza-cyclopentane-2-ketone (trade name: Azone) or derivatives thereof, glycerine fatty acid esters, sorbitan fatty acid ester class, polysorbate system, cithrol class, polyoxyethylene hydrogenated Oleum Ricini system, sucrose-fatty esters etc.Particularly, preferably octanoic acid, capric acid, caproic acid, lauric acid, myristic acid, Palmic acid, stearic acid, oleic acid, linoleic acid, linolenic acid, lauryl alcohol, myristyl alcohol, oleyl alcohol, spermol, methyl laurate, isopropyl myristate, myristyl myristate, myristic acid octyl group dodecane ester, cetin, salicylic acid, methyl salicylate, glycol salicylate, cinnamic acid, methyl cinnamate, cresol, the lactic acid cetyl, ethyl acetate, propyl acetate, geraniol, thymol, acetaminol, terpinol, Menthol, Borneolum Syntheticum, (R)-4-isopropenyl-1-methyl-1-cyclohexene, isoeugenol, isoborneol, nerol, d1-Camphora, glyceryl monolaurate, glyceryl monooleate, sorbitan mono-laurate, sucrose monolaurate, polysorbate20, polyethylene glycol monolaurate, polyethylene glycol mono stearate, castor oil hydrogenated, 1-[2-(sulfenyl in the last of the ten Heavenly stems) ethyl] aza-cyclopentane-2-ketone.
Based on all quality of adhesive phase that contain fentanyl class patch of the present invention, preferably with 0.01～20 quality %, further preferred with 0.1～10 quality %, particularly preferably the amount with 0.5～5 quality % cooperates aforesaid absorption enhancer.When the use level of absorption enhancer surpasses 20 quality %, sometimes can confirm rubescent, edema etc. to the zest of skin, when being lower than 0.01 quality %, sometimes can not obtain cooperating the effect of absorption enhancer, so not preferred.
And then, in order to absorb the water compositions such as antiperspirant that produced by skin, can also cooperate hydrophilic polymer in of the present invention containing in the fentanyl class patch as required.As hydrophilic polymer, preferred light anhydrous silicic acid for example, cellulose derivative (carboxymethyl cellulose (CMC), sodium carboxymethyl cellulose (CMCNa), methylcellulose (MC), hydroxypropyl emthylcellulose (HPMC), hydroxypropyl cellulose (HPC), hydroxyethyl-cellulose (HEC)), starch derivatives (pulullan polysaccharide), polyvinyl alcohol (PVA), polyvinyl pyrrolidone (PVP), vinylacetate (VA), carboxy vinyl polymer (CVP), ethylene-vinyl acetate copolymer (EVA), acrylic acid series polymeric compounds (trade name: Eudragit), gelatin, polyacrylic acid, sodium polyacrylate, the polyisobutylene copolymer-maleic anhydride, alginic acid, sodium alginate, carrageenan, arabic gum, Tragacanth, karaya, polyvinyl methacrylate, particularly preferably light anhydrous silicic acid, cellulose derivative (CMCNa, HPMC, HPC, MC), acrylic acid series polymeric compounds (trade name: Eudragit).Based on all quality of paste layer that contain fentanyl class patch of the present invention, preferably with 0.1～20 quality %, particularly preferably cooperate hydrophilic polymer with the amount of 0.5～10 quality %.
And then, also can cooperate other compositions such as cross-linking agent, antiseptic, UV absorbent according to being desirably in the adhesive phase that contains fentanyl class patch of the present invention.As cross-linking agent, the thermosetting resins such as preferred amino resins, phenolic resins, epoxy resin, alkyd resins, unsaturated polyester (UP), isocyanate compound, block isocyanate compound, the organic system cross-linking agent, metal or metallic compound etc. are inorganic to be cross-linking agent.As antiseptic, preferred ethylparaben, propyl p-hydroxybenzoate, butyl p-hydroxybenzoate etc.As UV absorbent; can list Eusolex 9020; the just own ester of 2-(4-diethylamino-2-hydroxy benzoyl) benzoic acid; Ferulic acid; the branched-chain alkyl ester of Ferulic acid; terephthalylidene-3; 3 '-two Camphoras-10; 10 '-disulfonic acid; 2-(2H-benzotriazole-2-yl)-4-methyl-6-(2-methyl-3-[1; 3; 3; 3-tetramethyl-1-[(trimethyl silyl) oxygen base disiloxanyl] propyl group) dioxo alkyl imidazole base propanoic acid 2-Octyl Nitrite; 1-(3; the 4-Dimethoxyphenyl)-4; 4-dimethyl-1, the 3-pentanedione; 2-(2-hydroxy-5-methyl oxygen base phenyl) benzotriazole; oxybenzone; PABA ethyl ester or Ethylhexyl Methoxycinnamate etc.
Adhesive phase with aforesaid composition also can be made according to known method arbitrarily.For example, when making by solvent method, in the organic solvent solution of the binding agent base that cooperates, add fentanyl or its salt, as the acid ascorbyl ester of stabilization agent, the preferred hindered phenol that further adds as the crystallization inhibitor is antioxidant, after the stirring, be coated on support or the stripping film, make its drying, be cut into arbitrary area, thereby can obtain the fentanyl class patch that contains of the present invention.In addition, when using the rosin series resin as viscosifier, adopt acid ascorbyl ester that the rosin series resin is carried out pretreatment, thereby improve the stabilization effect of remifentanil or its salt.Processing method as adopting acid ascorbyl ester can list acid ascorbyl ester and abietic resin are dissolved into suitable solvent, 1～30 ℃ of lower method of placing 24～72 hours.More specifically, to in benzene,toluene,xylene, hexane equal solvent, dissolving rosin be that the solution that resin forms mixes with the solution that dissolving acid ascorbyl ester in ethanol, isopropyl alcohol equal solvent forms, descend placement after 24～72 hours at 1～30 ℃ mixed solution, add fentanyl or its salt, thereby improve the stabilization effect of remifentanil or its salt.
Coating on support or stripping film, the thickness of the adhesive phase during preferably take drying are coated with as the mode of 10～150 μ m.During the thickness less than 10 μ m of adhesive phase, sometimes can not guarantee the sufficient adhesion of skin, when surpassing 150 μ m, sometimes owing to causing peeling off or rolling of preparation with the clothes friction, so not preferred.
The area of fentanyl class patch when being applied to skin that contain of the present invention is preferably 2.5～60cm
2Area is lower than 2.5cm
2The time, sometimes in treatment, can't obtain the sufficient Percutaneously absorbable of fentanyl, and operability (handling) can reduce also.Area surpasses 60cm
2The time, sometimes stick middle generation sense of discomfort and cancer patient's compliance is reduced.
In addition, of the present inventionly contain fentanyl class patch as long as its adhesive phase is by consisting of aforesaid the composition, then other layers, the composition that consists of other layer have no particular limits, and can be made of layer arbitrarily.For example, of the present invention contain fentanyl class patch can by adhesive phase, support this adhesive phase the support layer, be arranged on peeling liner bed course on the adhesive phase etc. and consist of.The support layer is such as being made of cloth, non-woven fabrics, polyurethane, polyester, polyvinyl acetate, ethylene-vinyl acetate copolymer (EVA), polyvinylidene chloride, polyethylene, polyethylene terephthalate (PET), polybutylene terephthalate (PBT), paper, aluminium flake etc. or their composite.Stripping film such as can be from the thin film made by the macromolecular materials such as polyethylene terephthalate that have been coated with silicone oil, the silicon-coating wet goods forms on paper sheet material choice for use.The duplexer that can use known cutter to make like this is cut into aforesaid arbitrary area, in the packaging material such as inclosure aluminum packaging material.
As one of above such feature that contains fentanyl class patch of the present invention that obtains, the fentanyl class that can list effective dose exists with dissolved state in adhesive phase.Here, the fentanyl class exists with dissolved state and refers to: during visual adhesive phase or when using observation by light microscope, can not observe the crystal of fentanyl class, adhesive phase is in uniform state.Exist with dissolved state in adhesive phase by the fentanyl class that makes effective dose like this, can prevent from more effectively to utilize the pharmacological effect of fentanyl class by containing in the fentanyl class patch in the past generating the problem that crystal produces.
Therefore, according to the fentanyl class patch that contains of the present invention, the fentanyl class routinely is absorbed via skin, therefore, for the patient of the oral administration difficulty of opioid analgesics, is lenitive powerful measure.In addition, namely continue the subcutaneous administration method with invasive medication and compare, non-invasively administration can also alleviate patient's burden.In addition, according to patient's symptom, age, body weight, sex etc. preparation is cut into arbitrary size etc. by the doctor, can easily regulates dosage.
The inventor etc. are by using the technical ability of preparation manufacturing and analytical chemistry, it is clear and definite first: when manufacturing contains the percutaneous patch of fentanyl or its salt, be created on the oxysome on the piperidines ring nitrogen, and then fentanyl-N-oxysome decomposes when for example keeping 24 hours under 60 ℃ of the common temperature when making the adhesive phase of percutaneous patch, as the secondary catabolite, generated the N-Phenylpropionamide, N-(1-hydroxy piperidine-4-yl)-N-Phenylpropionamide, (1-phenethyl-2-oxo-piperidine-4-yl)-N-Phenylpropionamide and these four kinds of materials of styrene.The fentanyl class patch that contains of the present invention, contain acid ascorbyl ester as stabilization agent by special selection, can suppress its catabolite and be fentanyl-N-oxysome, with and pyrolysate be the generation of above-mentioned four kinds of secondary catabolites, the medicine ageing stability is excellent.
Embodiment
Embodiment below is shown the present invention is carried out more specific description, but the present invention is not subjected to the restriction of these embodiment, in the scope that does not break away from technological thought of the present invention, can make various changes.In addition, " % " that occurs among the embodiment do not having to mean " quality % " in the situation about specifying.
Embodiment 1-1 contains fentanyl class patch (1-1)
The percutaneous patch that has prepared following prescription according to following manufacture method.
(prescription)
Fentanyl 1.0%
Styrene isoprene styrene block copolymer (SIS)
*18.2%
Polyisoprene 9.8%
Hydrogenated rosin glyceride
*1.0%
Polyterpene resin
* *41.99%
Polybutene 14.0%
Liquid paraffin 14.0%
Ascorbyl Palmitate 0.01%
Amount to 100%
*：JSR?Kraton?elastomer，Kraton?D-KX401CS
*: waste river chemical industry, Pine Crystal KE-311
* *: waste river chemical industry, Alcon P-100
(method for making)
Add styrene isoprene styrene block copolymer (SIS), polyisoprene, hydrogenated rosin glyceride, polyterpene resin, polybutene, these each compositions of liquid paraffin in the toluene and be dissolved in Ascorbyl Palmitate in the ethanol, mix, and then adding fentanyl, mix, obtain uniform solute.Then use knife type coater that this solute is coated on the stripping film, then air-dry, support and coated face are fitted, be cut into 10.5cm
2Size, be packaged in the aluminum packaging material.
Embodiment 1-2 contains fentanyl class patch (1-2)
The percutaneous patch that has prepared following prescription according to following manufacture method.
(prescription)
Fentanyl 4.0%
Styrene isoprene styrene block copolymer (SIS)
*18.2%
Polyisoprene 9.8%
Hydrogenated rosin glyceride
*5.0%
Polyterpene resin
* *34.98%
Polybutene 14.0%
Liquid paraffin 14.0%
Ascorbyl Palmitate 0.02%
Amount to 100%
*,
*And
* *: identical with embodiment 1-1.
(method for making)
Add styrene isoprene styrene block copolymer (SIS), polyisoprene, hydrogenated rosin glyceride, polyterpene resin, polybutene, these each compositions of liquid paraffin in the toluene and be dissolved in Ascorbyl Palmitate in the ethanol, mix, and then adding fentanyl, further mix, obtain uniform solute.Then use knife type coater that this solute is coated on the stripping film, then air-dry, support and coated face are fitted, be cut into 10.5cm
2Size, be packaged in the aluminum packaging material.
Embodiment 1-3 contains fentanyl class patch (1-3)
The percutaneous patch that has prepared following prescription according to following manufacture method.
(prescription)
Fentanyl 6.0%
Styrene isoprene styrene block copolymer (SIS)
*18.2%
Polyisoprene 9.8%
Hydrogenated rosin glyceride
*10.0%
Polyterpene resin
* *27.5%
Polybutene 14.0%
Liquid paraffin 14.0%
Ascorbyl Palmitate 0.5%
Amount to 100%
*,
*And
* *: identical with embodiment 1-1.
(method for making)
Add styrene isoprene styrene block copolymer (SIS), polyisoprene, hydrogenated rosin glyceride, polyterpene resin, polybutene, these each compositions of liquid paraffin in the toluene and be dissolved in Ascorbyl Palmitate in the ethanol, mix, and then adding fentanyl, further mix, obtain uniform solute.Then use knife type coater that this solute is coated on the stripping film, then air-dry, support and coated face are fitted after, be cut into 10.5cm
2Size, be packaged in the aluminum packaging material.
Embodiment 1-4 contains fentanyl class patch (1-4)
The percutaneous patch that has prepared following prescription according to following manufacture method.
(prescription)
Fentanyl 4.0%
Styrene isoprene styrene block copolymer (SIS)
*18.2%
Polyisoprene 9.8%
Hydrogenated rosin glyceride
*5.0%
Polyterpene resin
* *34.9%
Polybutene 14.0%
Liquid paraffin 14.0%
Ascorbyl Palmitate 0.1%
Amount to 100%
*,
*And
* *: identical with embodiment 1-1.
(method for making)
Add styrene isoprene styrene block copolymer (SIS), polyisoprene, hydrogenated rosin glyceride, polyterpene resin, polybutene, these each compositions of liquid paraffin in the toluene and be dissolved in Ascorbyl Palmitate in the ethanol, mix, and then adding fentanyl, further mix, obtain uniform solute.Then use knife type coater that this solute is coated on the stripping film, then air-dry, support and coated face are fitted after, be cut into 10.5cm
2Size, be packaged in the aluminum packaging material.
Embodiment 1-5 contains fentanyl class patch (1-5)
The percutaneous patch that has prepared following prescription according to following manufacture method.
(prescription)
Fentanyl 4.0%
Styrene isoprene styrene block copolymer (SIS)
*18.2%
Polyisoprene 9.8%
Hydrogenated rosin glyceride
*5.0%
Polyterpene resin
* *33.0%
Polybutene 14.0%
Liquid paraffin 14.0%
Ascorbyl Palmitate 0.1%
3,5-ditertbutylparacresol 1.9%
Amount to 100%
*,
*And
* *: identical with embodiment 1-1.
(method for making)
In toluene, add styrene isoprene styrene block copolymer (SIS), polyisoprene, hydrogenated rosin glyceride, polyterpene resin, polybutene, liquid paraffin, 3, these each compositions of 5-ditertbutylparacresol and the Ascorbyl Palmitate that is dissolved in the ethanol, mix, and then adding fentanyl, further mix, obtain uniform solute.Then use knife type coater that this solute is coated on the stripping film, then air-dry, support and coated face are fitted after, be cut into 10.5cm
2Size, be packaged in the aluminum packaging material.
Embodiment 1-6 contains fentanyl class patch (1-6)
The percutaneous patch that has prepared following prescription according to following manufacture method.
(prescription)
Fentanyl 4.0%
Styrene isoprene styrene block copolymer (SIS)
*18.2%
Polyisoprene 9.8%
Hydrogenated rosin glyceride
*5.0%
Polyterpene resin
* *31.5%
Polybutene 14.0%
Liquid paraffin 14.0%
Ascorbyl Palmitate 0.5%
3,5-ditertbutylparacresol 3.0%
Amount to 100%
*,
*And
* *: identical with embodiment 1-1.
(method for making)
In toluene, add styrene isoprene styrene block copolymer (SIS), polyisoprene, hydrogenated rosin glyceride, polyterpene resin, polybutene, liquid paraffin, 3, these each compositions of 5-ditertbutylparacresol and the Ascorbyl Palmitate that is dissolved in the ethanol, mix, and then adding fentanyl, further mix, obtain uniform solute.Then use knife type coater that this solute is coated on the stripping film, then air-dry, support and coated face are fitted after, be cut into 10.5cm
2Size, be packaged in the aluminum packaging material.
Embodiment 1-7 contains fentanyl class patch (1-7)
The percutaneous patch that has prepared following prescription according to following manufacture method.
(prescription)
Fentanyl 4.0%
Styrene isoprene styrene block copolymer (SIS)
*18.2%
Polyisoprene 9.8%
Hydrogenated rosin glyceride
*5.0%
Polyterpene resin
* *33.0%
Polybutene 14.0%
Liquid paraffin 14.0%
Ascorbyl Palmitate 0.02%
3,5-ditertbutylparacresol 1.98%
Amount to 100%
*,
*And
* *: identical with embodiment 1-1.
(method for making)
In toluene, add styrene isoprene styrene block copolymer (SIS), polyisoprene, hydrogenated rosin glyceride, polyterpene resin, polybutene, liquid paraffin, 3, these each compositions of 5-ditertbutylparacresol and the Ascorbyl Palmitate that is dissolved in the ethanol, mix, and then adding fentanyl, further mix, obtain uniform solute.Then use knife type coater that this solute is coated on the stripping film, then air-dry, support and coated face are fitted after, be cut into 10.5cm
2Size, be packaged in the aluminum packaging material.
Embodiment 1-8 contains fentanyl class patch (1-8)
The percutaneous patch that has prepared following prescription according to following manufacture method.
(prescription)
Fentanyl 4.0%
Styrene isoprene styrene block copolymer (SIS)
*18.2%
Polyisoprene 9.8%
Hydrogenated rosin glyceride
*10.0%
Polyterpene resin
* *26.5%
Polybutene 14.0%
Liquid paraffin 14.0%
Ascorbyl Palmitate 0.5%
3,5-ditertbutylparacresol 3.0%
Amount to 100%
*,
*And
* *: identical with embodiment 1-1.
(method for making)
In toluene, add styrene isoprene styrene block copolymer (SIS), polyisoprene, hydrogenated rosin glyceride, polyterpene resin, polybutene, liquid paraffin, 3, these each compositions of 5-ditertbutylparacresol and the Ascorbyl Palmitate that is dissolved in the ethanol, mix, and then adding fentanyl, further mix, obtain uniform solute.Then use knife type coater that this solute is coated on the stripping film, then air-dry, support and coated face are fitted after, be cut into 10.5cm
2Size, be packaged in the aluminum packaging material.
Comparative example 1-1 contains fentanyl class patch (1-1)
The percutaneous patch that has prepared following prescription according to following manufacture method.
(prescription)
Fentanyl 4.0%
Styrene isoprene styrene block copolymer (SIS)
*18.2%
Polyisoprene 9.8%
Hydrogenated rosin glyceride
*5.0%
Polyterpene resin
* *35.0%
Polybutene 14.0%
Liquid paraffin 14.0%
Amount to 100%
*,
*And
* *: identical with embodiment 1-1.
(method for making)
In toluene, add fentanyl composition in addition, mix, after the dissolving, add again fentanyl fully, further mix, obtain uniform solute.Then use knife type coater that this solute is coated on the stripping film, then air-dry, support and coated face are fitted after, be cut into 10.5cm
2Size, be packaged in the aluminum packaging material.
Comparative example 1-2 contains fentanyl class patch (1-2)
The percutaneous patch that has prepared following prescription according to following manufacture method.
(prescription)
Fentanyl 5.0%
Styrene isoprene styrene block copolymer (SIS)
*18.2%
Polyisoprene 9.8%
Hydrogenated rosin glyceride
*6.0%
Polyterpene resin
* *32.0%
Polybutene 14.0%
Liquid paraffin 14.0%
Ascorbyl Palmitate 1.0%
Amount to 100%
*,
*And
* *: identical with embodiment 1-1.
(method for making)
Add styrene isoprene styrene block copolymer (SIS), polyisoprene, hydrogenated rosin glyceride, polyterpene resin, polybutene, these each compositions of liquid paraffin in the toluene and be dissolved in Ascorbyl Palmitate in the ethanol, mix, and then adding fentanyl, further mix, obtain uniform solute.Then use knife type coater that this solute is coated on the stripping film, then air-dry, support and coated face are fitted after, be cut into 10.5cm
2Size, be packaged in the aluminum packaging material.
Test example 1-1 fentanyl-N-oxide generates inhibitory action
For each preparation that obtains among embodiment 1-2,1-4,1-6 and comparative example 1-1, the 1-2, through the time measured fentanyl, fentanyl-N-oxysome and cinnamic growing amount.Assay method as described below.
To be cut into 10.5cm
2Each 1 of each substances be packaged in the aluminum packaging material, preserve at room temperature, measured by the time fentanyl, fentanyl-N-oxysome and styrene.
Peel off the stripping film of each substances, put in the centrifugal precipition tube of 50mL, add the 5mL oxolane, vibrated 20 minutes, mastic is dissolved fully.In this liquid, add 15mL methanol, vibrated 10 minutes, make the complete coagulation of bonding base composition and precipitation.
Under the following conditions this supernatant is carried out fentanyl, fentanyl-N-oxysome and cinnamic quantitative with high performance liquid chromatography.
The operation of high performance liquid chromatography is carried out under the following conditions.Chromatographic column: the phase chromatography-use octadecyl silylanizing silica gel of filling 3 μ m in the stainless steel tube of internal diameter 4.6mm, long 10cm forms (column temperature: near the uniform temperature 40 ℃); Detect wavelength: 215nm; Mobile phase: dissolving 2.72g potassium dihydrogen phosphate in 1000mL water, and add solution (mobile phase A) and the phase chromatography-use acetonitrile (Mobile phase B) that sodium hydroxide test solution adjusting pH value to 4.7 forms; The conveying of mobile phase: by under the condition mobile phase A and Mobile phase B mixing and controlled concentration gradient being carried out arbitrarily.Its result is summarized in table 1.
[table 1]
In the table, FEN refers to fentanyl, and the N-oxysome refers to fentanyl-N-oxysome, and styrene is the minimum chemical compound of molecular weight in the fentanyl catabolite.
*1: fentanyl, N-oxysome and cinnamic separately peak area add up to the meansigma methods (determination test material number=3) of 100% value.
*2: the natural law after the manufacturing
By the result of above-mentioned table 1 as can be known, by cooperate Ascorbyl Palmitate in containing the percutaneous patch of fentanyl or its salt, a catabolite that can significantly suppress fentanyl is that fentanyl-N-oxysome and the minimum chemical compound of molecular weight are cinnamic generation.In addition, in the scope of 0.01 quality %～0.5 quality %L-ascorbyl palmitate, this effect increases and increases along with its use level, but when use level was 1 quality %, ascorbyl palmitate self had been separated out crystal (comparative example 1-2).
Embodiment 2-1 contains fentanyl class patch (2-1)
Made according to following composition and method for making and to have contained fentanyl class patch.
(composition)
Fentanyl 1.0%
Styrene isoprene styrene block copolymer (SIS)
*15.8%
Polyisoprene 8.5%
The alicyclic saturated hydrocarbon resin
* * *15.5%
Polyterpene resin
* *34.0%
Liquid paraffin 24.2%
2,6 ditertiary butyl p cresol 1.0%
Amount to 100%
*And
* *: identical with embodiment 1-1.
****：Yasuhara?Chemical，YS?Resin?PX1150N
(method for making)
Add styrene isoprene styrene block copolymer (SIS), polyisoprene, alicyclic saturated hydrocarbon resin, polyterpene resin, liquid paraffin and 2,6 ditertiary butyl p cresol in toluene, mix and blend dissolves it fully.Then, add fentanyl, further mix, obtain uniform solute.Then use knife type coater that this solute is coated on the stripping film (implemented the PET thin film of silicone-treated, rattan lumber industry), then air-dry, support (PET/EVA laminate film, rattan lumber industry) is fitted with coated face after, be cut into 42cm
2Size, be packaged in the aluminum packaging material, thereby obtain patch.
Embodiment 2-2 contains fentanyl class patch (2-2)
Made according to following composition and method for making and to have contained fentanyl class patch.
(composition)
Fentanyl 6.0%
Styrene isoprene styrene block copolymer (SIS)
*15.8%
Polyisoprene 8.5%
The alicyclic saturated hydrocarbon resin
* * *10.5%
Polyterpene resin
* *30.0%
Liquid paraffin 24.2%
2,6 ditertiary butyl p cresol 5.0%
Amount to 100%
*And
* *: identical with embodiment 1-1.
* * *: identical with embodiment 2-1.
(method for making)
Add styrene isoprene styrene block copolymer (SIS), polyisoprene, alicyclic saturated hydrocarbon resin, polyterpene resin, liquid paraffin and 2,6 ditertiary butyl p cresol in toluene, mix and blend dissolves it fully.Then, add fentanyl, further mix, obtain uniform solute.Then use knife type coater that this solute is coated on the stripping film (implemented the PET thin film of silicone-treated, rattan lumber industry), then air-dry, support (PET/EVA laminate film, rattan lumber industry) is fitted with coated face after, be cut into 42cm
2Size, be packaged in the aluminum packaging material, thereby obtain patch.
Embodiment 2-3 contains fentanyl class patch (2-3)
Made according to following composition and method for making and to have contained fentanyl class patch.
(composition)
Fentanyl 3.0%
Styrene isoprene styrene block copolymer (SIS)
*15.8%
Polyisoprene 8.5%
The alicyclic saturated hydrocarbon resin
* * *12.5%
Polyterpene resin
* *34.0%
Liquid paraffin 24.2%
4,4 '-butylidene is two-(the 6-tert-butyl group-3-methylphenol) 2.0%
Amount to 100%
*And
* *: identical with embodiment 1-1.
* * *: identical with embodiment 2-1.
(method for making)
In toluene, add styrene isoprene styrene block copolymer (SIS), polyisoprene, alicyclic saturated hydrocarbon resin, polyterpene resin, liquid paraffin and 4,4 '-butylidene is two-and (the 6-tert-butyl group-3-methylphenol), mix and blend dissolves it fully.Then, add fentanyl, further mix, obtain uniform solute.Then use knife type coater that this solute is coated on the stripping film (implemented the PET thin film of silicone-treated, rattan lumber industry), then air-dry, support (PET/EVA laminate film, rattan lumber industry) is fitted with coated face after, be cut into 42cm
2Size, be packaged in the aluminum packaging material, thereby obtain patch.
Embodiment 2-4 contains fentanyl class patch (2-4)
Made according to following composition and method for making and to have contained fentanyl class patch.
(composition)
Fentanyl 1.0%
Styrene isoprene styrene block copolymer (SIS)
*15.8%
Polyisoprene 8.5%
The alicyclic saturated hydrocarbon resin
* * *14.5%
Polyterpene resin
* *34.0%
Liquid paraffin 24.2%
2,2 '-di-2-ethylhexylphosphine oxide-(4-ethyl-6-tert-butyl phenol) 2.0%
Amount to 100%
*And
* *: identical with embodiment 1-1.
* * *: identical with embodiment 2-1.
(method for making)
In toluene, add styrene isoprene styrene block copolymer (SIS), polyisoprene, alicyclic saturated hydrocarbon resin, polyterpene resin, liquid paraffin and 2,2 '-di-2-ethylhexylphosphine oxide-(4-ethyl-6-tert-butyl phenol), mix and blend dissolves it fully.Then, add fentanyl, further mix, obtain uniform solute.Then use knife type coater that this solute is coated on the stripping film (implemented the PET thin film of silicone-treated, rattan lumber industry), then air-dry, support (PET/EVA laminate film, rattan lumber industry) is fitted with coated face after, be cut into 42cm
2Size, be packaged in the aluminum packaging material, thereby obtain patch.
Embodiment 2-5 contains fentanyl class patch (2-5)
Made according to following composition and method for making and to have contained fentanyl class patch.
(composition)
Fentanyl 2.0%
Styrene isoprene styrene block copolymer (SIS)
*15.8%
Polyisoprene 8.5%
The alicyclic saturated hydrocarbon resin
* * *12.5%
Polyterpene resin
* *34.0%
Liquid paraffin 24.2%
Four [3-(3,5-di-t-butyl-4-hydroxyphenyl) propanoic acid] pentaerythritol ester 3.0%
Amount to 100%
*And
* *: identical with embodiment 1-1.
* * *: identical with embodiment 2-1.
(method for making)
Add styrene isoprene styrene block copolymer (SIS), polyisoprene, alicyclic saturated hydrocarbon resin, polyterpene resin in the toluene, [3-(3 for liquid paraffin and four, 5-di-t-butyl-4-hydroxyphenyl) propanoic acid] pentaerythritol ester, stir, it is dissolved fully.Then, add fentanyl, further mix, obtain uniform solute.Then use knife type coater that this solute is coated on the stripping film (implemented the PET thin film of silicone-treated, rattan lumber industry), then air-dry, support (PET/EVA laminate film, rattan lumber industry) is fitted with coated face after, be cut into 42cm
2Size, be packaged in the aluminum packaging material, thereby obtain patch.
Embodiment 2-6 contains fentanyl class patch (2-6)
Made according to following composition and method for making and to have contained fentanyl class patch.
(composition)
Fentanyl 10.0%
Acrylic acid series polymeric compounds
+87.0%
2,6 ditertiary butyl p cresol 3.0%
Amount to 100%
+: 2-EHA, 2-Ethylhexyl Methacrylate and lauryl methacrylate copolymer (proportion d=about 0.94)
(method for making)
In the ethyl acetate solution of acrylic acid series polymeric compounds, add 2,6 ditertiary butyl p cresol and fentanyl, it is mixed, obtain uniform solute.Then use knife type coater that this solute is coated on the stripping film (implemented the PET thin film of silicone-treated, rattan lumber industry), then air-dry, support (PET/EVA laminate film, rattan lumber industry) is fitted with coated face after, be cut into 42cm
2Size, be packaged in the aluminum packaging material, thereby obtain patch.
Embodiment 2-7 contains fentanyl class patch (2-7)
Made according to following composition and method for making and to have contained fentanyl class patch.
(composition)
Fentanyl 3.0%
Styrene isoprene styrene block copolymer (SIS)
*15.8%
Polyisoprene 8.5%
The alicyclic saturated hydrocarbon resin
* * *14.5%
Polyterpene resin
* *34.0%
Liquid paraffin 22.7%
Four [3-(3,5-di-t-butyl-4-hydroxyphenyl) propanoic acid] pentaerythritol ester 1.5%
Amount to 100%
*And
* *: identical with embodiment 1-1.
* * *: identical with embodiment 2-1.
(method for making)
Add styrene isoprene styrene block copolymer (SIS), polyisoprene, alicyclic saturated hydrocarbon resin, polyterpene resin in the toluene, [3-(3 for liquid paraffin and four, 5-di-t-butyl-4-hydroxyphenyl) propanoic acid] pentaerythritol ester, stir, it is dissolved fully.Then, add fentanyl, further mix, obtain uniform solute.Then use knife type coater that this solute is coated on the stripping film (implemented the PET thin film of silicone-treated, rattan lumber industry), then air-dry, support (PET/EVA laminate film, rattan lumber industry) is fitted with coated face after, be cut into 42cm
2Size, be packaged in the aluminum packaging material, thereby obtain patch.
Embodiment 2-8 contains fentanyl class patch (2-8)
Made according to following composition and method for making and to have contained fentanyl class patch.
(composition)
Fentanyl 2.0%
Styrene isoprene styrene block copolymer (SIS)
*15.8%
Polyisoprene 8.5%
The alicyclic saturated hydrocarbon resin
* * *15.5%
Polyterpene resin
* *34.0%
Liquid paraffin 22.7%
2,6 ditertiary butyl p cresol 1.5%
Amount to 100%
*And
* *: identical with embodiment 1-1.
* * *: identical with embodiment 2-1.
(method for making)
Add styrene isoprene styrene block copolymer (SIS), polyisoprene, alicyclic saturated hydrocarbon resin, polyterpene resin, liquid paraffin and 2,6 ditertiary butyl p cresol in toluene, mix and blend dissolves it fully.Then, add fentanyl, further mix, obtain uniform solute.Then use knife type coater that this solute is coated on the stripping film (implemented the PET thin film of silicone-treated, rattan lumber industry), then air-dry, support (PET/EVA laminate film, rattan lumber industry) is fitted with coated face after, be cut into 42cm
2Size, be packaged in the aluminum packaging material, thereby obtain patch.
Embodiment 2-9 contains fentanyl class patch (2-9)
Made according to following composition and method for making and to have contained fentanyl class patch.
(composition)
Fentanyl 6.0%
Styrene isoprene styrene block copolymer (SIS)
*15.8%
Polyisoprene 8.5%
The alicyclic saturated hydrocarbon resin
* * *9.5%
Polyterpene resin
* *30.0%
Liquid paraffin 24.2%
2,6 ditertiary butyl p cresol 5.0%
Oleyl alcohol 1.0%
Amount to 100%
*And
* *: identical with embodiment 1-1.
* * *: identical with embodiment 2-1.
(method for making)
Add styrene isoprene styrene block copolymer (SIS), polyisoprene, alicyclic saturated hydrocarbon resin, polyterpene resin, liquid paraffin, 2,6 ditertiary butyl p cresol and oleyl alcohol in toluene, mix and blend dissolves it fully.Then, add fentanyl, further mix, obtain uniform solute.Then use knife type coater that this solute is coated on the stripping film (implemented the PET thin film of silicone-treated, rattan lumber industry), then air-dry, support (PET/EVA laminate film, rattan lumber industry) is fitted with coated face after, be cut into 42cm
2Size, be packaged in the aluminum packaging material, thereby obtain patch.
Embodiment 2-10 contains fentanyl class patch (2-10)
Made according to following composition and method for making and to have contained fentanyl class patch.
(composition)
Fentanyl 6.0%
Styrene isoprene styrene block copolymer (SIS)
*15.8%
Polyisoprene 8.5%
The alicyclic saturated hydrocarbon resin
* * *5.5%
Polyterpene resin
* *30.0%
Liquid paraffin 24.2%
2,6 ditertiary butyl p cresol 5.0%
Polyvinyl pyrrolidone
++5.0%
Amount to 100%
*And
* *: identical with embodiment 1-1.
* * *: identical with embodiment 2-1.
++: polyvinyl pyrrolidone K-30 (Nippon Shokubai Co., Ltd's manufacturing)
(method for making)
Add styrene isoprene styrene block copolymer (SIS), polyisoprene, alicyclic saturated hydrocarbon resin, polyterpene resin, liquid paraffin, 2,6 ditertiary butyl p cresol and polyvinyl pyrrolidone in toluene, mix and blend dissolves it fully.Then, add fentanyl, further mix, obtain uniform solute.Then use knife type coater that this solute is coated on the stripping film (implemented the PET thin film of silicone-treated, rattan lumber industry), then air-dry, support (PET/EVA laminate film, rattan lumber industry) is fitted with coated face after, be cut into 42cm
2Size, be packaged in the aluminum packaging material, thereby obtain patch.
Comparative example 2-1 contains the comparison patch (2-1) of fentanyl class
Made the comparison patch that contains the fentanyl class according to following composition and method for making.
(composition)
Fentanyl 1.0%
Styrene isoprene styrene block copolymer (SIS)
*15.8%
Polyisoprene 8.5%
The alicyclic saturated hydrocarbon resin
* * *14.5%
Polyterpene resin
* *34.0%
Liquid paraffin 26.2%
Amount to 100%
*And
* *: identical with embodiment 1-1.
* * *: identical with embodiment 2-1.
(method for making)
Get styrene isoprene styrene block copolymer (SIS), polyisoprene, alicyclic saturated hydrocarbon resin, polyterpene resin and liquid paraffin, with they mix and blends, make its fully dissolving in toluene.Then, add fentanyl, further mix, obtain uniform solute.Then use knife type coater that this solute is coated on the stripping film (implemented the PET thin film of silicone-treated, rattan lumber industry), then air-dry, support (PET/EVA laminate film, rattan lumber industry) is fitted with coated face after, be cut into 42cm
2Size, be packaged in the aluminum packaging material, thereby obtain the comparison patch.
Comparative example 2-2 contains the comparison patch (2-2) of fentanyl class
Made the comparison patch that contains the fentanyl class according to following composition and method for making.
(composition)
Fentanyl 3.0%
Styrene isoprene styrene block copolymer (SIS)
*15.8%
Polyisoprene 8.5%
The alicyclic saturated hydrocarbon resin
* * *14.5%
Polyterpene resin
* *34.0%
Liquid paraffin 24.2%
Amount to 100%
*And
* *: identical with embodiment 1-1.
* * *: identical with embodiment 2-1.
(method for making)
Get styrene isoprene styrene block copolymer (SIS), polyisoprene, alicyclic saturated hydrocarbon resin, polyterpene resin and liquid paraffin, with they mix and blends, make its fully dissolving in toluene.Then, add fentanyl, further mix, obtain uniform solute.Then use knife type coater that this solute is coated on the stripping film (implemented the PET thin film of silicone-treated, rattan lumber industry), then air-dry, support (PET/EVA laminate film, rattan lumber industry) is fitted with coated face after, be cut into 42cm
2Size, be packaged in the aluminum packaging material, thereby obtain the comparison patch.
Comparative example 2-3 contains the comparison patch (2-3) of fentanyl class
Made the comparison patch that contains the fentanyl class according to following composition and method for making.
(composition)
Fentanyl 6.0%
Styrene isoprene styrene block copolymer (SIS)
*15.8%
Polyisoprene 8.5%
The alicyclic saturated hydrocarbon resin
* * *14.5%
Polyterpene resin
* *34.0%
Liquid paraffin 21.2%
Amount to 100%
*And
* *: identical with embodiment 1-1.
* * *: identical with embodiment 2-1.
(method for making)
Get styrene isoprene styrene block copolymer (SIS), polyisoprene, alicyclic saturated hydrocarbon resin, polyterpene resin and liquid paraffin, with their mix and blend, make its fully dissolving in toluene.Then, add fentanyl, further mix, obtain uniform solute.Then use knife type coater that this solute is coated on the stripping film (implemented the PET thin film of silicone-treated, rattan lumber industry), then air-dry, support (PET/EVA laminate film, rattan lumber industry) is fitted with coated face after, be cut into 42cm
2Size, be packaged in the aluminum packaging material, thereby obtain the comparison patch.
Comparative example 2-4 contains the comparison patch (2-4) of fentanyl class
Made the comparison patch that contains the fentanyl class according to following composition and method for making.
(composition)
Fentanyl 10.0%
Acrylic acid series polymeric compounds
+90.0%
Amount to 100%
+: identical with embodiment 2-6.
(method for making)
In the ethyl acetate solution of acrylic acid series polymeric compounds, add fentanyl, it is mixed, obtain uniform solute.Then use knife type coater that this solute is coated on the stripping film (implemented the PET thin film of silicone-treated, rattan lumber industry), then air-dry, support (PET/EVA laminate film, rattan lumber industry) is fitted with coated face after, be cut into 42cm
2Size, be packaged in the aluminum packaging material, thereby obtain the comparison patch.
Comparative example 2-5 contains the comparison patch (2-5) of fentanyl class
Made the comparison patch that contains the fentanyl class according to following composition and method for making.
(composition)
Fentanyl 4.0%
Styrene isoprene styrene block copolymer (SIS)
*15.8%
Polyisoprene 8.5%
The alicyclic saturated hydrocarbon resin
* * *12.5%
Polyterpene resin
* *30.0%
Liquid paraffin 24.2%
Octyldodecanol 5.0%
Amount to 100%
*And
* *: identical with embodiment 1-1.
* * *: identical with embodiment 2-1.
(method for making)
Get styrene isoprene styrene block copolymer (SIS), polyisoprene, alicyclic saturated hydrocarbon resin, polyterpene resin, liquid paraffin and octyldodecanol, with they mix and blends, make its fully dissolving in toluene.Then, add fentanyl, further mix, obtain uniform solute.Then use knife type coater that this solute is coated on the stripping film (implemented the PET thin film of silicone-treated, rattan lumber industry), then air-dry, support (PET/EVA laminate film, rattan lumber industry) is fitted with coated face after, be cut into 42cm
2Size, be packaged in the aluminum packaging material, thereby obtain the comparison patch.
The crystal of test example 2-1 fentanyl is separated out inhibitory action
To each preparation that obtains among embodiment 2-1～2-8 and the comparative example 2-1～2-5, estimated the fentanyl crystal through the time inhibitory action separated out.Evaluation methodology as described below.
At first, will be cut into 42cm
2Each test preparation each 1 be packaged in the aluminum packaging material, be kept under 4 ℃, by visual valuation the fentanyl crystal through the time precipitation state.In addition, the relevant evaluation, existing situation that few crystal separates out as △, take confirm situation that considerable crystal separates out as *, not have situation that crystal separates out fully as zero.Its result is summarized in table 2.
[table 2]
Test example 2-2
Stick test:
For the patch for preparing among embodiment 2-2 and the comparative example 2-5, prepared blank patch (only having removed the patch of fentanyl), implement it and used the test of sense.About test, preparation to be measured is sticked on 12 male's of health adult chest 3 days, according to following benchmark evaluation the state that sticks of this moment and the cull of the mastic that occurs at skin when peeling off.The results are shown in table 3.
(sticking the scoring formula of situation)
Estimate
◎: peel off or roll less than 10%
Peel off or roll more than zero: 10% and less than 20%
△: peel off or roll more than 20% and less than 50%
*: peel off or roll (scoring formula of cull) more than 50%
Estimate
Nothing: without the cull of mastic
Have: the cull that mastic is arranged
[table 3]
By the result of above-mentioned table 2 and table 3 as can be known, be antioxidant, especially 2 by adding hindered phenol, [3-(3 for 6-ditertbutylparacresol or four, 5-di-t-butyl-4-hydroxyphenyl) propanoic acid] pentaerythritol ester as the crystal that suppresses fentanyl through the time fentanyl class separated out crystal separate out inhibitor, compare with the situation of using organic liquor to separate out inhibitor as the crystal of fentanyl or its salt, obviously has excellent adhesiveness, and the preparation of separating out inhibitor with the crystal of mismatching fentanyl or its salt is compared, the crystal that can suppress fentanyl through the time separate out.
Utilizability on the industry
Contain acid ascorbyl ester as the fentanyl class patch that contains of the present invention of stabilization agent, can preserve for a long time and can not cause the decomposition of fentanyl or its salt, thus can be effectively and routinely utilize the pharmacological effect of fentanyl or its salt.In addition because to have cooperated hindered phenol be that antioxidant is separated out inhibitor as crystal, the crystal that therefore can give play to fentanyl or its salt through the time inhibition, low irritant and excellent adhesiveness and the transdermal characteristic of separating out.
Claims (7)
1. percutaneous patch that contains fentanyl, this percutaneous patch comprises support, contains adhesive phase and the release liner of fentanyl, contains hindered phenol and is antioxidant in containing the adhesive phase of fentanyl and all be the Ascorbyl Palmitate of 0.01～0.5 quality % with respect to percutaneous patch.
2. the percutaneous patch that contains fentanyl according to claim 1 is characterized in that, in the mass ratio with respect to the content of fentanyl, the content of Ascorbyl Palmitate is in 0.0015～0.5 scope.
3. the percutaneous patch that contains fentanyl according to claim 1 and 2, wherein, containing bonding base contained in the adhesive phase of fentanyl is the bonding base of rubber series.
4. percutaneous patch that does not contain the crystal of fentanyl, this percutaneous patch comprises support, adhesive phase and release liner, contain fentanyl with the bonding base of rubber series with the state that dissolves in the described adhesive phase, containing with respect to percutaneous patch in containing the adhesive phase of fentanyl all is the Ascorbyl Palmitate of 0.01～0.5 quality %.
5. one kind is suppressed catabolite of fentanyl and/or the method that the secondary catabolite generates, it is characterized in that, in containing the percutaneous patch of fentanyl, with respect to all Ascorbyl Palmitates that cooperates 0.01～0.5 quality % of percutaneous patch.
6. the method that generates of inhibition fentanyl according to claim 5 catabolite and/or secondary catabolite is characterized in that a catabolite is fentanyl-N-oxysome.
7. according to claim 5 or the method that generates of catabolite of 6 described inhibition fentanyls and/or secondary catabolite, it is characterized in that the secondary catabolite is any in N-Phenylpropionamide, N-(1-hydroxy piperidine-4-yl)-Phenylpropionamide, (1-phenethyl-2-oxo-piperidine-4-yl)-N-Phenylpropionamide and the styrene.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2008169211A JP4856125B2 (en) | 2008-06-27 | 2008-06-27 | Stabilized fentanyl or salt-containing composition, pharmaceutical preparation using the same, and method for stabilizing fentanyl or salt thereof |
| JP2008-169211 | 2008-06-27 | ||
| JP2008191840A JP2010030909A (en) | 2008-07-25 | 2008-07-25 | Transdermal absorption-type patch containing fentanyls, method for producing the same, method for inhibiting crystal deposition of fentanyls, and crystal deposition inhibitor |
| JP2008-191840 | 2008-07-25 | ||
| PCT/JP2009/061853 WO2009157586A1 (en) | 2008-06-27 | 2009-06-29 | Transdermal patch containing fentanyl or salt thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102076340A CN102076340A (en) | 2011-05-25 |
| CN102076340B true CN102076340B (en) | 2013-01-23 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2009801246133A Active CN102076340B (en) | 2008-06-27 | 2009-06-29 | Transdermal patch containing fentanyl or salt thereof |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN102076340B (en) |
| WO (1) | WO2009157586A1 (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NZ596398A (en) * | 2009-07-24 | 2013-08-30 | Teikoku Seiyaku Kk | Fentanyl-containing adhesive preparation for external use |
| EP2462927A1 (en) * | 2010-12-03 | 2012-06-13 | Hexal AG | Transdermal therapeutic system comprising fentanyl |
| ES2805342T3 (en) * | 2015-10-26 | 2021-02-11 | Hisamitsu Pharmaceutical Co | Adhesive skin patch |
| US9650338B1 (en) | 2016-07-29 | 2017-05-16 | VDM Biochemicals, Inc. | Opioid antagonist compounds and methods of making and using |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1346265A (en) * | 1999-04-13 | 2002-04-24 | 久光制药株式会社 | Preparations for percutaneous absorption |
Family Cites Families (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS63159315A (en) * | 1986-12-22 | 1988-07-02 | Yuutoku Yakuhin Kogyo Kk | Cataplasm |
| GB9213322D0 (en) * | 1992-06-23 | 1992-08-05 | Efamol Holdings | Antioxidant compositions |
| JPH07277917A (en) * | 1994-04-01 | 1995-10-24 | Nisshin Oil Mills Ltd:The | Cosmetic good in oxidation stability |
| JP3836566B2 (en) * | 1996-05-13 | 2006-10-25 | 久光製薬株式会社 | Fentanyl-containing transdermal administration tape formulation |
| JP4136029B2 (en) * | 1997-05-12 | 2008-08-20 | 帝國製薬株式会社 | Patch containing isosorbide nitrate |
| WO1999051230A1 (en) * | 1998-04-02 | 1999-10-14 | Novartis Ag | Method for stabilizing pharmaceutical compositions by special use of an antioxidant |
| JP4205778B2 (en) * | 1998-04-17 | 2009-01-07 | 久光製薬株式会社 | Patch preparation |
| US6353029B1 (en) * | 2000-08-24 | 2002-03-05 | Bristol-Myers Squibb Company | Storage stable tretinoin and 4-hydroxyanisole containing topical composition |
| EP1548077A1 (en) * | 2003-12-26 | 2005-06-29 | Biotechnology Institute BTI I+D | cyanoacrylic-based adhesive composition for sealing biological tissues |
| JP5114042B2 (en) * | 2005-10-19 | 2013-01-09 | ニプロパッチ株式会社 | Patch and method for producing the patch |
| EP1948145A2 (en) * | 2005-10-24 | 2008-07-30 | Ciba Holding Inc. | Protection of oxidizable agents |
-
2009
- 2009-06-29 WO PCT/JP2009/061853 patent/WO2009157586A1/en active Application Filing
- 2009-06-29 CN CN2009801246133A patent/CN102076340B/en active Active
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1346265A (en) * | 1999-04-13 | 2002-04-24 | 久光制药株式会社 | Preparations for percutaneous absorption |
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| WO2009157586A1 (en) | 2009-12-30 |
| CN102076340A (en) | 2011-05-25 |
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