WO2000025792A1 - Preparation adhesive contenant de l'oestradiol - Google Patents

Preparation adhesive contenant de l'oestradiol Download PDF

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Publication number
WO2000025792A1
WO2000025792A1 PCT/JP1999/005920 JP9905920W WO0025792A1 WO 2000025792 A1 WO2000025792 A1 WO 2000025792A1 JP 9905920 W JP9905920 W JP 9905920W WO 0025792 A1 WO0025792 A1 WO 0025792A1
Authority
WO
WIPO (PCT)
Prior art keywords
estradiol
patch
hours
weight
polyisobutylene
Prior art date
Application number
PCT/JP1999/005920
Other languages
English (en)
Japanese (ja)
Inventor
Miyuki Shinmura
Yasuhiro Ikeura
Original Assignee
Hisamitsu Pharmaceutical Co., Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Hisamitsu Pharmaceutical Co., Inc. filed Critical Hisamitsu Pharmaceutical Co., Inc.
Priority to AU62307/99A priority Critical patent/AU6230799A/en
Publication of WO2000025792A1 publication Critical patent/WO2000025792A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—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
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/12—Drugs for genital or sexual disorders; Contraceptives for climacteric disorders

Definitions

  • the present invention relates to an estradiol-containing patch having excellent drug release rate and adhesiveness to human skin, which is useful for treatment of menopause or ovarian deficiency.
  • Estrogen replacement therapy Kampo therapy, psychotropic medication, coping therapy, etc. are being used as treatments for women's menopause or menstrual disorders, but recently estrogen replacement therapy has been actively used .
  • This estrogen replacement therapy is a treatment that aims to correct the physical and psychological fluctuations specific to menopause by regulating sudden changes in the hormonal environment during menopause due to estrogen decline. .
  • Estrogen replacement therapy can improve menopausal symptoms based on estrogen deficiency in the short term, and coronary artery disease and osteoporosis due to its effects on lipid metabolism and bone metabolism in the long term. The preventive effect is obtained.
  • estrogen replacement therapy has become a popular disease treatment.
  • the most bioactive is estradiol (17-estradiol), but the first pass through the liver after oral administration of natural estrogen In effect, most are metabolized to estrone and its conjugates. Therefore, it is known that administration of a considerably high dose is necessary to obtain a sufficient therapeutic effect, which increases the burden on the liver and affects protein synthesis and the like.
  • the inventors of the present invention have conducted studies to solve the above problems, and as a result, have determined the release rate of estradiol by using a specific base component and by using a specific proportion of the base component.
  • the present inventors have found that it is possible to obtain a patch which can be controlled within the above range and can maintain the adhesive force for a long time, and completed the present invention.
  • the present invention provides an estradiol-containing patch characterized in that the release rate of estradiol after 3 hours at a water temperature of 32 ⁇ 0.5 ° C. is in the range of 10 to 32%.
  • estradiol-containing patch characterized by containing an estradiol, a thermoplastic elastic body, a tackifier, a softener and / or an absorption promoter,
  • Thermoplastic elastomer is styrene-soprene-styrene block copolymer O 00/25792
  • estradiol-containing patch which is polysobutylene
  • estradiol-containing patch wherein the adhesive strength after 24 hours from the application is 90% or more of the adhesive strength after 12 hours from the application.
  • the estradiol-containing patch of the present invention preferably contains estradiol, a thermoplastic elastomer, a tackifier, a softener and / or an absorption promoter.
  • estradiol used as a medicinal ingredient in the patch of the present invention is a substance commonly called Estra-11,3,5 (10) trien-13,17 / 3 diol.
  • the amount of estradiol is 0.5 to 3 times the total amount of the base including the active ingredient. / 0 is preferable. If the amount is less than 0.5% by weight, a sufficient therapeutic effect cannot be expected, and if it exceeds 3% by weight, the therapeutic effect does not change, leading to a high cost.
  • thermoplastic elastic body used as a base component in the patch of the present invention is not particularly limited, but, for example, styrene-isoprene-styrene block copolymer (hereinafter abbreviated as SIS base) , Polyisobutylene and the like can be suitably used.
  • SIS base styrene-isoprene-styrene block copolymer
  • Polyisobutylene and the like can be suitably used.
  • SIS base examples include SIS base manufactured by Shell Chemical Company (trade name: Kariflex TR-111, Kariflex TR-111), SIS base manufactured by Nippon Synthetic Rubber Co., Ltd. (trade names: JSR500, JSR510), SIS manufactured by Zeon Japan One or more base materials (trade name: Quintac 3421) can be appropriately selected and used.
  • the amount of the SIS base compounded is 15 to 24% by weight based on the total amount of the base including the active ingredient. Re, preferably with / 0 . When the amount is less than 15% by weight, the cohesive strength becomes insufficient, and the weight is 24%. If the ratio exceeds / 0 , the flexibility of the preparation is poor, and there is a problem in adhesion.
  • the SIS base can be used alone, but is preferably used in combination with polyisobutylene.
  • the polyisobutylene is not particularly limited.
  • polyisobutylene manufactured by Nippon Petrochemical Co., Ltd. (trade name: TETRA X3T, 4T, 5T, 6T, HIMOL4H, 5 ⁇ , 5.5 ⁇ , 6 ⁇ ) ), ⁇ ⁇ Polysobutylene manufactured by ASF (trade name: ⁇ ppanol B 10, 12, 12 SF, 15, 15 SF, 30 SF, 50, 50 SF, 80, 100, 120, 1 50, 200), exison polystyrene (VIST AN EX LM—MS, LM—MH, LM—H, MM L—80, MM L—100, MM L—120, MM L—14 0)
  • One or two or more types can be appropriately selected and used from isostatic strength.
  • the compounding amount is 5.:! ⁇ 25 weight. / 0 , preferably 10 to 20 weight. / 0 is more preferable.
  • polyisobutylene means low molecular weight to high molecular weight polyisobutylene of various molecular weights, and the case where two or more kinds of polyisobutylenes having different molecular weights are mixed and used is also included.
  • the tackifier used as a base component in the patch of the present invention is not particularly limited.
  • an alicyclic saturated hydrocarbon resin for example, trade name: Alcon P-100, etc .: manufactured by Arakawa Chemical Co., Ltd.
  • rosin ester for example, trade name: KE-311, KE-100: manufactured by Arakawa Chemical Co., Ltd.
  • hydrogenated rosin ester for example, trade name: Foral 105, etc .: manufactured by Hercules Co., Ltd.
  • hydrogen alicyclic hydrocarbons for example, trade name: Escolets 5300, etc .: manufactured by Exxon
  • polyterpene resin for example, petroleum resin, phenol resin, etc.
  • two or more kinds can be appropriately selected and used.
  • the amount of the tackifier is preferably 26 to 40% by weight based on the total weight of the base containing the medicinal ingredient, in consideration of the balance between adhesive force, skin damage and skin irritation. If the amount is less than 26% by weight, sufficient adhesive strength cannot be maintained, and the weight is 40% by weight. If the ratio exceeds / 0 , the adhesive strength becomes too strong, and skin damage and skin irritation tend to occur.
  • the softening agent used as a base component of the patch of the present invention is not particularly limited, and one or more of liquid paraffin, polybutene, liquid polyisobutylene, animal and vegetable oils and the like can be appropriately selected and used. . Among them, liquid paraffin is particularly preferred because of its good compatibility with the SIS base.
  • the compounding amount of the softener is 15 to 30% by weight based on the total amount of the base including the active ingredient. / 0 is preferable. 15 weight. If the ratio is less than / 0 , the flexibility of the pressure-sensitive adhesive becomes poor, and the pressure-sensitive adhesiveness also decreases. Also 30 weight. If the ratio exceeds / 0 , the pressure-sensitive adhesive becomes soft and generates cohesive force, which is not preferable.
  • the absorption enhancer used as a base component in the patch of the present invention is not particularly limited, and one or more of clotamiton, L-menthol, heart oil, pyrothiodecane and the like are used. Can be selected and used at appropriate times. Among these, crotamiton and pyrothiodecane are preferred.
  • the absorption enhancer When the absorption enhancer is used, its compounding amount is 0.5 to 8% by weight based on the total amount of the base including the active ingredient. / 0 is preferable. 0.5 sufficient absorption promoting effect of weight 0/0 less than when it comes to E be sampled radio Ichiru can not be obtained. Also, more than 8% by weight However, no further absorption promoting effect can be expected, and it is not preferable because it has an effect on a decrease in the adhesive strength of the base or a dripping of the plaster.
  • either one of the above-mentioned softener and absorption enhancer may be used, or both may be used in combination.
  • an antioxidant to the patch containing the radioactive ingredient of the present invention in addition to the above essential components in order to improve the stability of the preparation.
  • the antioxidant butylhydroxytoluene and the like are preferable, and the compounding amount is 2% by weight in the total base containing the active ingredient. / 0 or less is preferable.
  • a known filler or other usable additives, or a medicinal ingredient other than estradiol, and the like can be appropriately compounded in an appropriate amount.
  • the support in the patch of the present invention is desirably one that does not affect the release of the drug and has excellent flexibility, and is a non-stretchable or stretchable polyester, polypropylene, polyethylene, polyethylene terephthalate, or vinyl acetate. Films or woven fabrics and composites thereof can be used. Among them, a polyethylene terephthalate film having a breaking strength (longitudinal direction) of ZSSS kgf Z mm 2 and a modulus of 2 ⁇ 1 ⁇ 2 (longitudinal direction) of 7.5 to 9.5 kg ⁇ Zm m 2 alone is used. It is preferable to use a force to be used or a force obtained by combining the force with a flexible film.
  • the method for producing the estradiol-containing patch of the present invention is not particularly limited, and it can be produced by any known production method.
  • a preferred production example of 1 will be described.
  • the base components consisting of SIS base and / or polyisobutylene, tackifier and softener, or dissolving these base components in inexpensive dissolving agents such as toluene and hexane, estradiol, Add oxidizing agent and mix evenly.
  • this is applied to a support, covered with a liner and cut into a desired shape to obtain a product, or applied to a film that has been subjected to a peeling treatment, and then transferred to a suitable support by pressure bonding. , Good as a product.
  • the patch of the present invention has a release rate after 3 hours at a water temperature of 32 soils and 0.5 ° C in the range of 10 to 32% of the total content of the drug. The range of 8 to 30% is more preferable. 10 hours after 3 hours. If it is less than / 0 , stable pharmacological effects cannot be expected, and if it exceeds 32%, it will be released in a short period of time, making it impossible to expect a constant drug supply for a long time. Further, the patch of the present invention can be stuck to human skin for a long period of time and is not easily peeled off, so that a certain amount of drug can be reliably supplied.
  • SIS base and the base components consisting of "or polyisobutylene, a tackifier and a softener, or dissolving these base components in a dissolving agent such as toluene or hexane
  • a dissolving agent such as toluene or hexane
  • Add the absorption enhancer crotamitone
  • the contents of polyisobutylene (thermoplastic elastomer), rosin ester (tackifier) and liquid paraffin (softener) in this comparative example were outside the above-mentioned preferred ranges, and the water temperature was 32 ° C and 0.5 ° C.
  • the estradiol release rate after 3 hours was less than 10% (Test Example 1 below).
  • the adhesive strength 24 hours after application relative to the adhesive force 12 hours after application was less than 90% (Test Example 2 below).
  • the polyisobutylene (thermoplastic elastomer) and the fluid The contents of raffin (softener) and rosin ester (tackifier) are out of the preferred ranges described above, and the release rate of Estradiol after 3 hours at a water temperature of 32 ⁇ 0.5 ° C is 10%. % (Test Example 1 below). In addition, the adhesive strength 24 hours after application relative to the adhesive force 12 hours after application was less than 90% (Test Example 2 below).
  • Each of the patches containing the estradiol obtained in Examples 4, 5, 7 to 9 and Comparative Examples 1 to 2 was adjusted to have a release area of 10 cm2 and used as a sample. A release test was performed.
  • test solution Three hours after the start of the test, take 10 mm of the test solution from a position at least 10 mm away from the container wall in the middle of the cylinder and use it as the sample solution. After collection, immediately add 10 ml of water heated to 0.5 ° C to the test solution. Separately, accurately weigh about 0.02 g of the estradiol standard, add ethanol (99.5) to dissolve it to make 50 ml, and add water to 5 ml of this liquid to make 100 ml. . Water is added to 2 ml of this solution to make 50 ml, and used as a standard solution. Perform a test with 50 ⁇ L of the sample solution and standard solution by liquid chromatography under the following conditions.
  • Liquid volume Adjust so that the retention time of estradiol is about 1 minute. Column selection: Weigh about 0.02 g of estradiol and dissolve in ethanol (99.5) to make 50 ml. Add water to 5 ml of the solution to make 100 ml. Also, about 0.028 g of naphthalene is dissolved in ethanol (99. 5) to make 50 ml, and water is added to 10 ml of this solution to make 100 ml. Water is added to 2 ml each of these solutions to bring the total volume to 50 ml. When this liquid 50 / L is operated under the above conditions, estradiol and naphthalene are dissolved in this order.
  • the estradiol release rate (./.) After 3 hours is calculated by the following formula.
  • H T 3 represents the peak height of the sample solution after 3 hours
  • H s represents the height of the standard solution peak.
  • Comparative Example 1 8.2% Comparative Example 2 9.1%
  • the release rate of the patches of the present invention (Examples 4, 5, 7 to 9) was much higher than that of Comparative Examples 1 and 2. High, 10 ⁇ 32. /. It was within the range.
  • Each of the patches obtained in Examples 6 to 9 and Comparative Examples 1 and 2 was applied to human skin for 12 hours and 24 hours, and then tested for adhesive strength with respect to each application time.
  • the adhesive strength after 12 hours is 100%, and the adhesive strength after 24 hours is shown. /. Indicated by The adhesive strength test was performed according to the method described below.
  • the experiment was performed using a digital panel only (digital force gauge). Each patch was cut into small pieces of 2 cm ⁇ 2 cm and attached to human forearm skin. At 12 hours and 24 hours after application, the edge of the patch was sandwiched between digitally connected clips and fixed. The digital panel alone was raised at a constant speed, and the patch was kept at 90 ° against human skin so as not to be peeled off for a certain period of time, then peeled off, and the force at that time was measured. The results are shown in Table 2 below.
  • Example 9 1 6 8 (1 0 0) 1 6 3 (97) Comparative Example 1 1 20 (100) 78 (65)
  • Comparative Example 2 1 1 2 (100) 6 2 (55)
  • the adhesive preparations of the present invention had an adhesive force after 24 hours, It was 90% or more of the adhesive strength after 12 hours, and the adhesive strength was extremely high as compared with the patches of Comparative Examples 1 and 2.
  • the patch containing the estradiol of the present invention can maintain a sufficient adhesive force even after pasting for a long time, and is excellent in controlling the release of a drug from a base.
  • the patch containing the estradiol of the present invention is used, the estradiol is surely transdermally absorbed from the skin and a constant drug concentration in serum can be maintained for a certain time. Therefore, the patch containing the estradiol of the present invention is expected to be used as a patch for medical use for treatment of climacteric disorders in women.

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  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Dermatology (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Reproductive Health (AREA)
  • Organic Chemistry (AREA)
  • Endocrinology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Epidemiology (AREA)
  • Botany (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention se rapporte à une préparation adhésive contenant de l'oestradiol, qui se caractérise en ce que 10 à 32 % de l'oestradiol est libéré en trois heures après immersion dans de l'eau à une température de 32±0,5 °C. De préférence, la préparation contient un élastomère thermoplastique, un agent donnant du collant et un plastifiant et/ou un accélérateur d'absorption. Ledit élastomère comporte de préférence un copolymère séquencé styrène/isoprène/styrène et du polyisobutylène. La préparation comporte de préférence 0,5 à 3 % en poids d'oestradiol, 15 à 24 % en poids du copolymère séquencé styrène/isoprène/styrène, 5,1 à 25 % en poids du polyisobutylène, 26 à 40 % en poids de l'agent donnant du collant et 15 à 30 % en poids du plastifiant et/ou 0,5 à 8 % en poids de l'accélérateur d'absorption.
PCT/JP1999/005920 1998-10-29 1999-10-26 Preparation adhesive contenant de l'oestradiol WO2000025792A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU62307/99A AU6230799A (en) 1998-10-29 1999-10-26 Estradiol-containing adhesive preparation

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP10308119A JP2000136128A (ja) 1998-10-29 1998-10-29 エストラジオール含有貼付剤
JP10/308119 1998-10-29

Publications (1)

Publication Number Publication Date
WO2000025792A1 true WO2000025792A1 (fr) 2000-05-11

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1999/005920 WO2000025792A1 (fr) 1998-10-29 1999-10-26 Preparation adhesive contenant de l'oestradiol

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JP (1) JP2000136128A (fr)
AU (1) AU6230799A (fr)
WO (1) WO2000025792A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002096434A1 (fr) * 2001-05-29 2002-12-05 Tokuhon Corporation Composition de platre
WO2004014395A1 (fr) * 2002-08-09 2004-02-19 Teikoku Seiyaku Co.,Ltd. Timbre adhesif contenant une hormone femelle
JP2004075537A (ja) * 2002-08-09 2004-03-11 Teikoku Seiyaku Co Ltd エストラジオール含有貼付剤
WO2004024155A1 (fr) * 2002-09-13 2004-03-25 Hisamitsu Pharmaceutical Co., Inc. Pastille adhesive

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050186262A1 (en) * 2004-01-14 2005-08-25 James Osborne Transdermal delivery device for dihydropyridine type calcium antagonists
DE102006050558B4 (de) 2006-10-26 2009-03-26 Lts Lohmann Therapie-Systeme Ag Transdermales therapeutisches System enthaltend Norelgestromin zur Kontrazeption und Hormonsubstitution

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH05271056A (ja) * 1992-03-27 1993-10-19 Hisamitsu Pharmaceut Co Inc 微粉体制御型経皮投与製剤
JPH08113532A (ja) * 1994-10-17 1996-05-07 Daikyo Yakuhin Kogyo Kk 硬膏剤及びその製造法
WO1996015776A1 (fr) * 1994-11-18 1996-05-30 Hisamitsu Pharmaceutical Co., Inc. Timbre absorbable par voie percutanee
JPH09315957A (ja) * 1996-05-28 1997-12-09 Hisamitsu Pharmaceut Co Inc 経皮治療用装置

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH05271056A (ja) * 1992-03-27 1993-10-19 Hisamitsu Pharmaceut Co Inc 微粉体制御型経皮投与製剤
JPH08113532A (ja) * 1994-10-17 1996-05-07 Daikyo Yakuhin Kogyo Kk 硬膏剤及びその製造法
WO1996015776A1 (fr) * 1994-11-18 1996-05-30 Hisamitsu Pharmaceutical Co., Inc. Timbre absorbable par voie percutanee
JPH09315957A (ja) * 1996-05-28 1997-12-09 Hisamitsu Pharmaceut Co Inc 経皮治療用装置

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002096434A1 (fr) * 2001-05-29 2002-12-05 Tokuhon Corporation Composition de platre
WO2004014395A1 (fr) * 2002-08-09 2004-02-19 Teikoku Seiyaku Co.,Ltd. Timbre adhesif contenant une hormone femelle
JP2004075537A (ja) * 2002-08-09 2004-03-11 Teikoku Seiyaku Co Ltd エストラジオール含有貼付剤
US8124122B2 (en) 2002-08-09 2012-02-28 Teikoku Seiyaku Co., Ltd. Female hormone-containing patch
WO2004024155A1 (fr) * 2002-09-13 2004-03-25 Hisamitsu Pharmaceutical Co., Inc. Pastille adhesive
US7785622B2 (en) 2002-09-13 2010-08-31 Hisamitsu Pharmaceutical Co., Inc. Adhesive patch for fentanyl administration

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Publication number Publication date
AU6230799A (en) 2000-05-22
JP2000136128A (ja) 2000-05-16

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