WO2009096354A1 - フェンタニル含有外用貼付剤 - Google Patents
フェンタニル含有外用貼付剤 Download PDFInfo
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- WO2009096354A1 WO2009096354A1 PCT/JP2009/051172 JP2009051172W WO2009096354A1 WO 2009096354 A1 WO2009096354 A1 WO 2009096354A1 JP 2009051172 W JP2009051172 W JP 2009051172W WO 2009096354 A1 WO2009096354 A1 WO 2009096354A1
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- resin
- fentanyl
- patch
- rosin
- sensitive adhesive
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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
- A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
- A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
- A61K9/7076—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising ingredients of undetermined constitution or reaction products thereof, e.g. rosin or other plant resins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—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
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
-
- 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
- A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
- A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
- A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
- A61K9/7053—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
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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
Definitions
- the present invention relates to a fentanyl-containing external patch having excellent fentanyl skin permeability, high formulation stability during storage, and low irritation to the skin.
- Fentanyl and fentanyl citrate are synthetic narcotic analgesics that have been confirmed to have an analgesic effect about 200 times that of morphine in animal experiments.
- a reservoir-type transdermal absorption-type sustained-release preparation containing fentanyl is commercially available, and the preparation can maintain an effective blood concentration for about 24 to 72 hours.
- the reservoir-type transdermal absorption-type sustained-release preparation has a fairly slow drug absorption after administration, and does not reach an effective blood concentration until 12 to 24 hours after the first administration, so it cannot provide a rapid analgesic effect.
- Patent Documents 1 and 2 percutaneous absorption preparations (Patent Documents 1 and 2) using an acrylic adhesive as a main base have been proposed.
- acrylic adhesives have low drug release properties, and the main drug content in the preparation is reduced.
- a desired drug release property cannot be obtained unless it is increased.
- preparations using polyisobutylene as a main base are disclosed (Patent Documents 3 and 4).
- a fentanyl-containing patch using styrene / isoprene / styrene block copolymer (hereinafter abbreviated as SIS) as a main base is also disclosed (Patent Documents 5 and 6).
- SIS preparation styrene / isoprene / styrene block copolymer
- Patent Documents 5 and 6 A patch that simultaneously satisfies the long-term stable release of the active ingredient, long-term storage stability, and safety to the skin when applied for a long time has not been developed yet.
- a SIS-based preparation containing N-methyl-2-pyrrolidone as an absorption enhancer has been shown to shorten the percutaneous absorption delay time due to the N-methyl-2-pyrrolidone absorption promoting action.
- Patent Document 5 Since methyl-2-pyrrolidone is volatile, there is a problem that N-methyl-2-pyrrolidone volatilizes during storage or pasting and changes the drug release ability (Patent Document 5).
- Patent Document 7 a transdermal patch for administering fentanyl or an analog thereof has been proposed (Patent Document 7).
- This prior art is also a matrix-type preparation comprising a monolayer polymer, but is characterized by being biologically equivalent to the above-mentioned commercially available fentanyl preparation. Similar to the percutaneous absorption type sustained-release preparation, there remains a drawback that a rapid analgesic effect cannot be obtained.
- an object of the present invention is to provide a fentanyl-containing external patch that is excellent in skin permeability of fentanyl, has high formulation stability during storage, and is mild to the skin.
- the present inventors have optimized the blending ratio of fentanyl and rosin resin, which are active ingredients, and the blending ratio of rosin resin and total tackifying resin.
- the present inventors have found that the above problems can be solved. That is, an external patch in which a pressure-sensitive adhesive layer based on SIS is laminated on a support, wherein the pressure-sensitive adhesive layer further comprises a rosin resin and at least one other tackifying resin.
- a softening agent comprising polybutene and liquid paraffin; a fatty acid ester; and an external patch comprising fentanyl as an active ingredient, wherein the ratio of the rosin resin to fentanyl is 1 to 5 times by weight, and By setting the blending ratio of the rosin-based resin to the total amount of the tackifying resin in a weight ratio of 0.1 to 0.6 times, the fentanyl has excellent skin permeability, high formulation stability, and the skin.
- the present invention has been completed by finding that a patch with low irritation can be obtained.
- the present invention is an external patch in which an adhesive layer based on SIS is laminated on a support, and the adhesive layer further comprises a rosin resin and at least one other tackifying resin.
- a rosin resin preferably 30-60% by weight, softener consisting of polybutene and liquid paraffin, preferably 5-40% by weight, fatty acid ester, preferably 1-20% by weight, and fentanyl 1-10% by weight.
- the blending ratio of the rosin resin to fentanyl is 1 to 5 times by weight, and the blending ratio of the rosin resin to the total tackifying resin blending ratio is 0.1 to 0.6 times by weight.
- the present invention relates to a fentanyl-containing external patch.
- the patch of the present invention provides a patch having excellent fentanyl skin permeability, high formulation stability during storage, and low irritation to the skin. There are effects such as being able to. Furthermore, when the tackifying resin is composed of a rosin resin and a petroleum resin, the balance of solubility of fentanyl in the preparation, active ingredient release and skin adhesiveness is good. Moreover, the skin permeability of fentanyl can be enhanced by blending fatty acid esters, particularly isopropyl myristate, into the pressure-sensitive adhesive layer as an absorption accelerator.
- liquid paraffin and polybutene are blended in the pressure-sensitive adhesive layer as a softening agent, the balance between the adhesiveness to the skin and the main drug solubility in the preparation is good, and the blending ratio of liquid paraffin and polybutene is 0.5: 1 to It was found that a patch having the highest effect in the range of 3: 1 and preventing crystallization of the active ingredient in the preparation and having low skin irritation can be obtained. Furthermore, it was also found that the adhesive patch of the present invention having better skin adhesiveness can be obtained by setting the blending amount of the tackifying resin to 30% or more based on the entire pressure-sensitive adhesive layer.
- the blending amount of the SIS used as a main base for the pressure-sensitive adhesive layer of the present invention with respect to the whole pressure-sensitive adhesive layer is preferably 5 to 50% by weight, more preferably 10 to 30% by weight.
- the tackifier resin blended in the pressure-sensitive adhesive layer of the present invention gives adhesiveness to the skin by mixing with SIS.
- rosin resin petroleum resin, polyterpene resin, phenol resin
- examples include terpene phenol resins and xylene resins.
- the rosin resin include rosin ester, hydrogenated rosin, glycerin rosin ester, hydrogenated rosin glycerin ester, rosin acid, and polymerized rosin, and hydrogenated rosin glycerin ester is particularly preferable.
- Examples of petroleum resins include aliphatic saturated hydrocarbon resins, alicyclic saturated hydrocarbon resins, and aromatic hydrocarbon resins. However, alicyclic saturated hydrocarbon resins are more preferred.
- the tackifying resin is blended in a proportion of 30 to 60% by weight based on the weight of the entire pressure-sensitive adhesive layer. If it is less than 30% by weight, the adhesive physical properties as a patch deteriorate, and if it exceeds 60% by weight, the adhesive tack becomes so strong that it causes physical skin irritation when peeled off from the skin, which is not preferable.
- the rosin resin may be added in an amount of 1 to 5 times, preferably 2 to 4 times the blending ratio (weight ratio) with respect to fentanyl. It is effective. If the amount of rosin resin added is more than 5 times the amount of fentanyl, the drug permeability to the skin will decrease, and if it is less than 1 time the drug solubility will decrease, and the pharmacological properties such as crystallization of the active ingredient will be preferable. There is no influence. Furthermore, the blending ratio (weight ratio) of the rosin resin to the total amount of the tackifying resin is preferably 0.1 to 0.6 times, more preferably 0.2 to 0.4 times.
- the amount of rosin resin added is more than 0.6 times the total amount of tackifying resin, the drug's skin permeability will decrease, and if it is less than 0.1 times the drug solubility will decrease. Unfavorable effects on the physical properties of the preparation, such as crystallization of the components.
- the fatty acid ester blended in the pressure-sensitive adhesive layer of the present invention acts as an absorption accelerator and is not particularly limited, and examples thereof include isopropyl myristate, diisopropyl adipate, diethyl sebacate, and the like. Isopropyl acid is particularly preferred.
- the blending amount in the pressure-sensitive adhesive layer is preferably 1 to 20% by weight, more preferably 2 to 10% by weight. When the blending amount of the fatty acid ester is 1% by weight or less, the skin permeability of the drug is not sufficient, and when it is 20% by weight or more, the cohesive force of the adhesive layer is lowered and the base remains on the skin.
- the softening agent composed of liquid paraffin and polybutene blended in the pressure-sensitive adhesive layer of the present invention improves the followability to the skin by softening the pressure-sensitive adhesive, adjusts the adhesive force, and stimulates physical skin irritation. It is blended for the purpose of reduction, and is blended in consideration of the effect on fentanyl solubility and the physical properties of the preparation, and the blending amount is preferably 5 to 40% by weight, more preferably 10 to 30% by weight. When the amount is less than 5% by weight, the followability to the skin is poor and the film is easily peeled off.
- the fentanyl solubility of liquid paraffin and polybutene is greater with polybutene and can also adjust the solubility of the active ingredient in the formulation.
- the blending amount of liquid paraffin is more than 3: 1, the solubility of fentanyl in the preparation is lowered, unfavorable effects such as crystallization of the active ingredient, and the adhesion of the preparation to the skin are further lowered.
- it is less than 0.5: 1 the adhesive strength becomes too strong and the skin irritation becomes strong.
- a component usually used when preparing a pressure-sensitive adhesive layer of a patch as necessary for adjusting the adhesiveness and stability of the base Is appropriately selected and added.
- water-absorbing polymers such as polyvinyl pyrrolidone and polyvinyl pyrrolidone / vinyl acetate copolymer, inorganic fillers such as titanium dioxide and silica, and dibutylhydroxytoluene (BHT) can be appropriately contained.
- the amount of fentanyl blended in the adhesive layer of the present invention is preferably 0.1 to 10% by weight, more preferably 1 to 8% by weight, and particularly preferably 3 to 8% by weight.
- the thickness of the pressure-sensitive adhesive layer according to the present invention is not particularly limited, but if it becomes too thin, the adhesive strength decreases, and if it becomes too thick, the number of drugs that are not used in the plaster increases, resulting in high costs and rubbing of clothes. For example, 20 to 100 ⁇ m is desirable because it is easy to peel off.
- a support having high flexibility and stretchability is used.
- a support having high flexibility and stretchability.
- examples of such a support include a low density polymer film, a nonwoven fabric, a woven fabric, etc.
- a polyethylene terephthalate film is desirable from the viewpoint of properties.
- the thickness of the film is preferably from 0.1 to 100 ⁇ m. When applied to the skin, when the thickness is 100 ⁇ m or more, the patch cannot follow the unevenness or movement of the skin due to the rigidity of the polyethylene terephthalate film, resulting in a decrease in the skin absorbability of the drug.
- the patch of the present invention has a release liner on the upper surface of the pressure-sensitive adhesive layer.
- a release liner polyethylene terephthalate, polypropylene, paper or the like is used.
- the release liner is siliconized as necessary to optimize the release force.
- the patch of the present invention can be produced, for example, by the following method.
- a base component containing a tackifier is dissolved in an organic solvent such as toluene and then mixed with another component dissolved in an appropriate organic solvent.
- the obtained solution is applied on a silicon-treated release liner and dried at 90 ° C. for 10 minutes to form a 20 to 100 ⁇ m adhesive layer.
- the percutaneously absorbable preparation of the present invention can be obtained by cutting into an appropriate size and shape.
- Comparative Examples 1-9 From the formulations shown in Table 3-1 and Table 3-2, external patches of Comparative Examples 1 to 6 were prepared according to the above production method. In Comparative Example 7, a patch was produced with reference to Example 1 of WO2004 / 024155. Comparative Example 8 is a test example No. 2006-76994. A patch was produced with reference to 6. In Comparative Example 9, the patch could not be produced due to insufficient cohesive strength.
- Test Example 1 In Vitro Rat Skin Permeability Test
- Examples 1, 3, 4, 5, 6, 7, Reference Examples 1-5 and Comparative Examples 3-8 were used in rats.
- In vitro skin permeability test was performed. The skin removed from the abdomen of the depilated rat was set in a Franz-type cell, filled with phosphate buffered saline, and warm water at 37 ° C. was refluxed in the water jacket. Each preparation was punched into a circle ( ⁇ 16 mm), rat skin was affixed, the receptor fluid was sampled over time, the amount of fentanyl permeation was measured by liquid chromatography, and the permeation rate (4 to 12 hr) was calculated. The results are shown in Table 4-1, Table 4-2, and Table 4-3.
- Test Example 2 Stability test Table 5 shows the results of visual observation of the appearance of the preparations after Examples 1, 2, 3, 4 and Comparative Examples 1 to 8 after storage at room temperature for 3 months.
- the preparation with crystal precipitation is indicated by x, and the preparation without crystal precipitation is indicated by ⁇ .
- Test Example 3 Adhesive strength test For Examples 1, 2, 3, 4, 5, 6, 7, Reference Examples 1-5 and Comparative Examples 1-8, a tensile tester (Rheometer CR500DX manufactured by Sun Scientific Co., Ltd.) was used. The adhesive strength was evaluated by performing a 180 ° peel test. The results are shown in Table 6-1, Table 6-2 and Table 6-3.
- Test Example 4 Rabbit skin temporary irritation test The rabbit skin primary irritation test was performed on Example 1, Example 2 and Comparative Example 8. Each patch was applied to the back of the rabbit from which the hair had been removed for 72 hours, and the stimulation index (PII) was determined from the skin symptoms at 1 hour, 24 hours and 48 hours after peeling. The evaluation criteria and results are shown in Table 7-1 and Table 7-2, respectively.
- Comparative Example 7 had a low release of the active ingredient and a low tackiness. Further, Comparative Example 8 was found to have high adhesiveness but low release of the active ingredient, crystallized active ingredient in the preparation, and high skin irritation.
- Test Example 5 Rabbit Plasma Concentration Measurement Test A fentanyl rabbit plasma concentration measurement test was conducted on Example 1 and a commercially available product (reservoir type patch in which fentanyl was dissolved in ethanol) (dose of 5 mg each). Each patch was applied to the back of the rabbit from which hair had been removed for 72 hours, blood was collected over time, and the concentration of fentanyl in plasma was measured by liquid chromatography. The result is shown in FIG. The patch of the present example was found to be a preparation that has almost the same durability as a commercially available product, but has a rapid rise in blood drug concentration.
- the fentanyl-containing external patch according to the present invention is excellent in skin permeability of fentanyl, has high formulation stability during storage, is hypoallergenic to the skin, and can be used as a treatment for pain such as cancer.
Abstract
Description
即ち、支持体にSISを基剤とする粘着剤層が積層された外用貼付剤であって、該粘着剤層に、さらにロジン系樹脂と他の少なくとも1種の粘着付与樹脂からなる粘着付与樹脂;ポリブテンと流動パラフィンからなる軟化剤;脂肪酸エステル;及び活性成分としてフェンタニルを配合してなる外用貼付剤において、ロジン系樹脂のフェンタニルに対する配合割合を、重量比で1~5倍量にし、かつ、ロジン系樹脂の全粘着付与樹脂配合量に対する配合割合を重量比で0.1~0.6倍量とすることにより、フェンタニルの皮膚透過性に優れ、製剤安定性が高く、かつ皮膚に対して低刺激性である貼付剤を得られることを見出し、本発明を完成した。
さらに、粘着付与樹脂がロジン系樹脂と石油系樹脂から成る場合、フェンタニルの製剤中への溶解性、主薬放出性及び皮膚接着性のバランスが良好である。また脂肪酸エステル類、特にミリスチン酸イソプロピルを吸収促進剤として粘着剤層に配合することにより、フェンタニルの皮膚透過性を高めることができる。さらに軟化剤として流動パラフィン並びにポリブテンを粘着剤層に配合した場合、皮膚に対する粘着性と製剤中の主薬溶解性とのバランスが良好で、特に流動パラフィンとポリブテンの配合比が0.5:1~3:1の範囲において最も効果が高く、製剤中での主薬の結晶化を防止できるとともに、皮膚に対する低刺激性を兼ね備えた貼付剤を得ることができることが判明した。
さらには粘着付与樹脂の配合量を粘着剤層全体に対して30%以上にすることにより、皮膚粘着性において、より優れた本発明の貼付剤が得られることも判明した。
ロジン系樹脂以外の他の粘着付与樹脂としては石油系樹脂を使用するのが好ましく、石油系樹脂には脂肪族飽和炭化水素樹脂、脂環族飽和炭化水素樹脂、芳香族炭化水素樹脂等が挙げられるが、脂環族飽和炭化水素樹脂がより好ましい。
粘着付与樹脂は粘着剤層全体の重量に対して30~60重量%の割合で配合する。30重量%未満では貼付剤としての粘着物性が悪くなり、60重量%を越えると粘着タックが強くなりすぎて皮膚から剥がすとき、物理的な皮膚刺激を生じるため好ましくない。
さらにロジン系樹脂の全粘着付与樹脂配合量に対する配合割合(重量比)は、好ましくは0.1~0.6倍量、さらに好ましくは0.2~0.4倍量である。ロジン系樹脂の添加量が、全粘着付与樹脂配合量に対して0.6倍量より多いと薬物の皮膚透過性が低下し、0.1倍量より少ないと薬物溶解性が低下し、主薬成分の結晶化等、製剤物性に対する好ましくない影響がでる。
粘着付与剤を含む基剤成分をトルエン等の有機溶媒に溶解した後、適当な有機溶媒に溶解させた他の成分と攪拌混合する。得られた溶液をシリコン処理された剥離ライナー上に塗布し、90℃で10分間乾燥し、20~100μmの粘着層を形成する。得られた粘着層に支持体のポリエチレンテレフタレート面をラミネートした後、適当な大きさと形状に切断して本発明の経皮吸収製剤を得ることができる。
表3-1及び表3-2に記載の処方より、上記の製造法に従い比較例1~6の外用貼付剤を作製した。比較例7は、WO2004/024155実施例1を参考にして貼付剤を製造した。比較例8は、特開2006-76994試験例No.6を参考にして貼付剤を製造した。比較例9は凝集力不足のため貼付剤を製造できなかった。
フェンタニルの薬物放出性を検討するため、実施例1、3、4、5、6、7、参考例1~5、及び比較例3~8につきラットにおけるin vitro皮膚透過性試験を行った。
除毛ラット腹部摘出皮膚をフランツ型セルにセットし、その内側にはリン酸緩衝生理食塩水を満たし、ウォータージャケットには、37℃の温水を還流した。各製剤を円状(φ16mm)に打ち抜き、ラット摘出皮膚を貼付し、経時的にレセプター液をサンプリングし、液体クロマトグラフ法によりフェンタニル透過量を測定し、透過速度(4~12hr)を計算した。その結果を、表4-1、表4-2及び表4-3に示す。
実施例1、2、3、4及び比較例1~8について、室温保存3ヶ月経過後の製剤の外観を目視で観察した結果を表5に示す。結晶析出している製剤を×、結晶析出していない製剤を○で表す。
実施例1、2、3、4、5、6、7、参考例1~5及び比較例1~8について引っ張り試験器(レオメーターCR500DX サン科学社製)を用い、180°剥離試験を行うことにより粘着力を評価した。結果を表6-1、表6-2及び表6-3に示す。
実施例1、実施例2及び比較例8についてウサギ皮膚一次刺激性試験を行った。それぞれの貼付剤を除毛したウサギ背部に72時間貼付し、剥離後1時間目、24時間目及び48時間目の皮膚症状から刺激指数(P.I.I)を求めた。その評価基準及び結果を、それぞれ表7-1、表7-2に示す。
(1)表4-1~表4-3に示す結果より、本発明の実施例の貼付剤は、優れた薬物放出性を示した。特に薬物含有量が同濃度の比較例に比べ、薬物放出性が優れていることが判明した。比較例3~5、7及び8は、薬物放出性において本発明の実施例の貼付剤よりも相当劣る。
(2)表5及び表7-2から、本発明の実施例の貼付剤は、安定性及び安全性ついても優れていることが示された。比較例1,2,6,及び8では結晶析出が観察された。
(3)その他、表4―1~表7―1に示す結果から、比較例1、2及び6は製剤中での主薬の結晶化の問題があること、比較例3、4及び5は主薬放出性が低く、また比較例7は主薬放出性が低く、かつ粘着性も低いことが判明した。さらに比較例8は、粘着性は高いものの、主薬放出性が低く、製剤中で主薬が結晶化しており、皮膚刺激性も高いことが判明した。
実施例1及び市販品(フェンタニルをエタノールに溶解したリザーバタイプ貼付剤)についてフェンタニルのウサギ血漿中濃度測定試験を行った(投与量各々5mg)。それぞれの貼付剤を除毛したウサギ背部に72時間貼付し、経時的に採血し、液体クロマトグラフ法により血漿中のフェンタニル濃度を測定した。その結果を図1に示す。本実施例の貼付剤は、市販品と比較して、持続性については、ほぼ同等であるが、血中薬物濃度の立ち上がりが早い製剤であることが判明した。
Claims (4)
- 支持体にスチレン・イソプレン・スチレンブロック共重合体を基剤とする粘着剤層が積層された外用貼付剤であって、該粘着剤層に、さらにロジン系樹脂と他の少なくとも1種の粘着付与樹脂からなる粘着付与樹脂;流動パラフィンとポリブテンからなる軟化剤;脂肪酸エステル;およびフェンタニルを配合してなる外用貼付剤において、
(1)該ロジン系樹脂のフェンタニルに対する配合割合が、重量比で1~5倍量であり、
(2)該ロジン系樹脂の全粘着付与樹脂配合量に対する配合割合が、重量比で0.1~0.6倍量であり、さらに
(3)該粘着付与樹脂の粘着剤層全体に対する配合量が30~60重量%である
ことを特徴とするフェンタニル含有外用貼付剤。 - 軟化剤を構成する流動パラフィンとポリブテンの配合比が、0.5:1~3:1である請求項1記載のフェンタニル含有外用貼付剤。
- 脂肪酸エステルがミリスチン酸イソプロピルであり、そして粘着付与樹脂がロジン系樹脂と石油系樹脂からなる請求項1記載のフェンタニル含有外用貼付剤。
- ロジン系樹脂と他の少なくとも1種の粘着付与樹脂からなる粘着付与樹脂は、ロジン系樹脂と石油系樹脂、ポリテルペン樹脂およびフェノール樹脂からなる群から選ばれる少なくとも1種からなる粘着付与樹脂である請求項1記載のフェンタニル含有外用貼付剤。
Priority Applications (10)
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AU2009210075A AU2009210075B2 (en) | 2008-01-28 | 2009-01-26 | Fentanyl-containing patch for external use |
US12/864,932 US9517211B2 (en) | 2008-01-28 | 2009-01-26 | Fentanyl-containing patch for external use |
KR1020167005167A KR20160027258A (ko) | 2008-01-28 | 2009-01-26 | 펜타닐 함유 외용 패치 |
CN2009801033921A CN101925355B (zh) | 2008-01-28 | 2009-01-26 | 含芬太尼的外用贴剂 |
JP2009551507A JP5431969B2 (ja) | 2008-01-28 | 2009-01-26 | フェンタニル含有外用貼付剤 |
CA2711774A CA2711774C (en) | 2008-01-28 | 2009-01-26 | Fentanyl-containing patch for external use |
EP09706430.7A EP2246054B1 (en) | 2008-01-28 | 2009-01-26 | Fentanyl-containing patch for external use |
KR1020107017680A KR101829920B1 (ko) | 2008-01-28 | 2009-01-26 | 펜타닐 함유 외용 패치 |
TW098104053A TWI448309B (zh) | 2009-01-26 | 2009-02-09 | 含吩坦尼(fentanyl)之外用貼附劑 |
US15/345,603 US10376474B2 (en) | 2008-01-28 | 2016-11-08 | Fentanyl-containing patch for external use |
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US12/864,932 A-371-Of-International US9517211B2 (en) | 2008-01-28 | 2009-01-26 | Fentanyl-containing patch for external use |
US15/345,603 Division US10376474B2 (en) | 2008-01-28 | 2016-11-08 | Fentanyl-containing patch for external use |
US15/345,603 Continuation US10376474B2 (en) | 2008-01-28 | 2016-11-08 | Fentanyl-containing patch for external use |
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EP (1) | EP2246054B1 (ja) |
JP (1) | JP5431969B2 (ja) |
KR (2) | KR101829920B1 (ja) |
CN (1) | CN101925355B (ja) |
AU (1) | AU2009210075B2 (ja) |
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WO2011010645A1 (ja) * | 2009-07-24 | 2011-01-27 | 帝國製薬株式会社 | フェンタニル含有外用貼付剤 |
DE102011100619A1 (de) | 2010-05-05 | 2012-01-05 | Amw Gmbh | Transdermales therapeutisches System (TTS) mit einem Gehalt an einem Opiod-Analgetikum |
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EP2462927A1 (en) * | 2010-12-03 | 2012-06-13 | Hexal AG | Transdermal therapeutic system comprising fentanyl |
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DE102011100619A1 (de) | 2010-05-05 | 2012-01-05 | Amw Gmbh | Transdermales therapeutisches System (TTS) mit einem Gehalt an einem Opiod-Analgetikum |
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CA2711774A1 (en) | 2009-08-06 |
US20100322999A1 (en) | 2010-12-23 |
KR101829920B1 (ko) | 2018-02-19 |
KR20160027258A (ko) | 2016-03-09 |
AU2009210075A1 (en) | 2009-08-06 |
CA2711774C (en) | 2016-05-24 |
JPWO2009096354A1 (ja) | 2011-05-26 |
US9517211B2 (en) | 2016-12-13 |
CN101925355B (zh) | 2013-05-29 |
EP2246054A4 (en) | 2014-05-07 |
KR20100116186A (ko) | 2010-10-29 |
CN101925355A (zh) | 2010-12-22 |
EP2246054A1 (en) | 2010-11-03 |
EP2246054B1 (en) | 2018-06-13 |
US20170071872A1 (en) | 2017-03-16 |
JP5431969B2 (ja) | 2014-03-05 |
US10376474B2 (en) | 2019-08-13 |
AU2009210075B2 (en) | 2013-10-24 |
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