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WO2014136717A1 - Composition pharmaceutique absorbable par voie transdermique - Google Patents

Composition pharmaceutique absorbable par voie transdermique Download PDF

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Publication number
WO2014136717A1
WO2014136717A1 PCT/JP2014/055267 JP2014055267W WO2014136717A1 WO 2014136717 A1 WO2014136717 A1 WO 2014136717A1 JP 2014055267 W JP2014055267 W JP 2014055267W WO 2014136717 A1 WO2014136717 A1 WO 2014136717A1
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WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
weight
duloxetine
transdermal absorption
pharmaceutically acceptable
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/JP2014/055267
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English (en)
Japanese (ja)
Inventor
誉子 小幡
高山　幸三
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Nippon Zoki Pharmaceutical Co Ltd
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Nippon Zoki Pharmaceutical Co Ltd
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Filing date
Publication date
Application filed by Nippon Zoki Pharmaceutical Co Ltd filed Critical Nippon Zoki Pharmaceutical Co Ltd
Publication of WO2014136717A1 publication Critical patent/WO2014136717A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • 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
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • 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
    • 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
    • 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
    • A61P25/06—Antimigraine agents
    • 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
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the present invention relates to a pharmaceutical composition for transdermal absorption containing duloxetine or a pharmaceutically acceptable salt thereof as an active ingredient, or a medicine containing this composition.
  • Depression is a type of mood disorder, including depressed mood (anxiety, agitation, etc.), decreased motivation (such as lethargy, hunger, etc.), decreased mental activity (such as lack of thought), and various physical symptoms (such as insomnia, easy sleep) It is a mental illness that causes fatigue, headache / headache, loss of appetite, etc. Depression is a socially important disease because the number of affected people has increased in recent years, and when it becomes severe, it has an impact on daily life and can be life-threatening, such as suicide attempts. Therefore, elucidation of the onset mechanism is desired, but it is thought that psychological factors and neuroscience factors are complicatedly involved in the onset of depression, and it has not been fully elucidated.
  • tricyclic antidepressants first generation
  • imipramine and amitriptyline have been first developed and used.
  • tricyclic antidepressants also block histamine H 1 receptor, acetylcholine muscarinic M 1 receptor, and adrenergic ⁇ 1 receptor at the postsynaptic side, side effects such as constipation and dysuria due to anticholinergic action There were many.
  • SSRI serotonin-selective reuptake inhibitor
  • SNRI noradrenaline reuptake inhibitors
  • Duloxetine [chemical name: (+)-(S) -N-methyl-3- (1-naphthyloxy) -3- (2-thienyl) propylamine] is one of the recently developed SNRIs. It is known to exert an antidepressant action by selectively inhibiting reuptake of serotonin and noradrenaline at the intracerebral nerve junction.
  • the active ingredient in capsule preparations sold in various countries including Japan is duloxetine hydrochloride. In the present application, unless otherwise specified, duloxetine hydrochloride may be simply referred to as duloxetine.
  • Duloxetine does not bind to neurotransmitter receptors like tricyclic or tetracyclic antidepressants, so there are no side effects due to anticholinergic action, and it is not like SSRI, a third-generation antidepressant. There are few side effects of nausea and vomiting by stimulating serotonin receptors in the brain and intestinal tract. Effectively, it inhibits the reuptake of noradrenaline in addition to serotonin, so it does not improve with SSRI that selectively inhibits the reuptake of serotonin. Then it is said. In addition, duloxetine is effective not only for antidepressant action but also for pain.
  • duloxetine is the only antidepressant and has pain associated with diabetic neuropathy as an indication.
  • Duloxetine is unstable under acidic conditions. For this reason, it is marketed in various countries as an oral hard capsule filled with granules of enteric-coated duloxetine hydrochloride. A technique relating to the formulation of duloxetine into a capsule is disclosed in Patent Document 1. However, there has been no report on a pharmaceutical composition for transdermal absorption containing duloxetine as an active ingredient.
  • transdermal agent that is administered by transdermally absorbing the drug to such an oral agent such as a hard capsule is effective in blood compared to the oral agent because the drug is continuously and gradually absorbed from the skin. It is possible to maintain the concentration continuously.
  • gastrointestinal disorders can be avoided, and the maximum blood concentration does not increase at a stretch, which makes it easier to avoid side effects.
  • transdermal administration can avoid the first-pass effect due to drug metabolism in the liver, there is a possibility that an effective dose in blood can be maintained with a smaller amount of drug than oral administration, and duloxetine does not pass through the stomach. It is also possible to avoid being inactivated by.
  • transdermal agents are very useful from the viewpoints of patient compliance, quality of life (QOL) improvement, safety, and the like.
  • QOL quality of life
  • some drugs are difficult to be transdermally absorbed, and it is often difficult to find a formulation that can be an appropriate transdermally absorbable preparation.
  • An object of the present invention is to provide a novel pharmaceutical composition for percutaneous absorption, which is characterized by excellent skin permeability and low skin irritation of duloxetine, which is an active ingredient, or a pharmaceutically acceptable salt thereof. To provide medicine.
  • the pharmaceutical composition of the present invention can exert its effect safely by transdermal absorption of duloxetine or a pharmaceutically acceptable salt thereof. Therefore, the medicine containing the pharmaceutical composition of the present invention is useful as an external preparation. In particular, when used as a patch, it is extremely useful as a transdermal antidepressant or analgesic that can be used for a long time with good compliance.
  • FIG. 1 is a graph showing the skin permeation rate of duloxetine of each formulation in the in vitro skin permeability test of Example 1.
  • FIG. 2 is a graph showing the delay time of duloxetine for each formulation in the in vitro skin permeability test of Example 1.
  • FIG. 3 is a graph showing the viable cell ratio of each formulation in the in vitro skin irritation test of Example 1.
  • the present invention relates to a novel pharmaceutical composition for transdermal absorption containing duloxetine or a pharmaceutically acceptable salt thereof as an active ingredient and menthol, isopropyl alcohol and isopropyl myristate as additives, or a medicine containing the same.
  • the active ingredient of the pharmaceutical composition or medicine of the present invention is duloxetine or a pharmaceutically acceptable salt thereof.
  • the salt can be used without particular limitation as long as it is a pharmaceutically acceptable acid addition salt.
  • inorganic salts such as hydrochloride, sulfate, nitrate, phosphate, hydrofluoride, hydrobromide, etc.
  • Acid salt acetic acid, tartrate, lactate, citrate, fumarate, maleate, mesylate, succinate, methanesulfonate, benzenesulfonate, toluenesulfonate, naphthalenesulfonate
  • organic acid salts such as camphor sulfonate.
  • duloxetine hydrochloride which is commercially available and widely used clinically.
  • the hydrate and solvate of duloxetine are also included in the duloxetine which is an active ingredient of this invention.
  • the amount of duloxetine or a pharmaceutically acceptable salt thereof contained as an active ingredient in the pharmaceutical composition or medicine of the present invention is 0.5 to 10% by weight, preferably 1 to 5% by weight, more preferably 2 to 4%. % By weight.
  • the menthol used in the pharmaceutical composition of the present invention includes 1-menthol and dl-menthol which are optical isomers thereof. Mentha oil and mint water mainly composed of menthol are also included in the menthol of the present invention. As menthol, l-menthol is particularly preferable.
  • the amount of menthol used varies depending on the dosage form, etc. described later, but is 1 to 5% by weight, preferably 2.3 to 2.9% by weight, more preferably 2.5 to 2.7% by weight. Can do.
  • the amount of isopropyl alcohol used in the pharmaceutical composition or medicine of the present invention is 10 to 20% by weight, preferably 13.5 to 16.5% by weight, more preferably 14.5 to 15.5% by weight. Can do.
  • the amount of isopropyl myristate used in the pharmaceutical composition or medicine of the present invention is 5 to 15% by weight, preferably 9.0 to 11.0% by weight, more preferably 9.5 to 10.5% by weight. be able to.
  • the ratio by weight of isopropyl alcohol to isopropyl myristate is 1: 1 to 4: 1, preferably 1: 1 to 2: 1, more preferably 1.2: 1 to 1.8: 1. it can.
  • the present invention relates to a pharmaceutical composition for transdermal absorption containing duloxetine or a pharmaceutically acceptable salt thereof as an active ingredient, wherein duloxetine or a pharmaceutically acceptable salt thereof is used with respect to 100% by weight of the pharmaceutical composition.
  • a transdermal pharmaceutical composition containing 0.5 to 10% by weight of the resulting salt, 1 to 5% by weight of menthol, 10 to 20% by weight of isopropyl alcohol, and 5 to 15% by weight of isopropyl myristate.
  • the present invention is a pharmaceutical composition for transdermal absorption containing duloxetine or a pharmaceutically acceptable salt thereof as an active ingredient, wherein duloxetine or a pharmaceutical composition thereof is used with respect to 100% by weight of the pharmaceutical composition.
  • duloxetine or a pharmaceutical composition thereof is used with respect to 100% by weight of the pharmaceutical composition.
  • 1 to 5% by weight of pharmaceutically acceptable salt, 2.3 to 2.9% by weight of menthol, 13.5 to 16.5% by weight of isopropyl alcohol, and 9.0 to 11.0% by weight of isopropyl myristate % Is a pharmaceutical composition for transdermal absorption.
  • the present invention relates to a pharmaceutical composition for transdermal absorption containing duloxetine or a pharmaceutically acceptable salt thereof as an active ingredient, wherein duloxetine or a pharmaceutical composition thereof is used with respect to 100% by weight of the pharmaceutical composition.
  • a pharmaceutical composition for transdermal absorption containing% by weight 2 to 4% by weight of a pharmaceutically acceptable salt, 2.5 to 2.7% by weight of menthol, 14.5 to 15.5% by weight of isopropyl alcohol, 9.5 to 10.5 of isopropyl myristate It is a pharmaceutical composition for transdermal absorption containing% by weight.
  • the specific dosage form of the pharmaceutical containing the pharmaceutical composition for transdermal absorption according to the present invention is not particularly limited, and examples thereof include solutions, creams, ointments, gels, lotions, sprays, patches, It can be formulated as an external preparation such as a tape.
  • additives and bases suitable for each dosage form are used as appropriate, and they can be produced according to the usual methods described in the general rules of formulation of the Japanese Pharmacopoeia. In prescription, it is good also as a compounding agent with another pharmaceutical active ingredient with a duloxetine.
  • a patch is that it is formulated into a patch (patch) in the form of a hydrogel.
  • the hydrogel can be produced by using a conventional method of using a viscous agent such as hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxyvinyl polymer, etc. and swollen with water as a base.
  • a viscous agent such as hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxyvinyl polymer, etc.
  • an appropriate solvent such as isopropanol or ethanol.
  • the pharmaceutical composition and medicine for percutaneous absorption according to the present invention can be used for patients who have conventionally been administered oral duloxetine for depression or chronic pain.
  • analgesics in addition to or included in chronic pain such as chronic low back pain, neuropathic pain such as pain associated with diabetic neuropathy, headache, migraine, tension headache, chronic pelvic pain, muscle It can be used to treat various pains such as pain, joint pain, low back pain, fibromyalgia.
  • it can be used for treatment of diseases such as generalized anxiety disorder and stress urinary incontinence for which the effect of duloxetine is reported.
  • Example 1 Examination of optimal formulation (1) Preparation of duloxetine-containing hydrogel Based on the Box-Benken Design, 27 types of formulations were assigned by assigning concentrations of l-menthol, isopropyl alcohol and isopropyl myristate as shown in Table 1. The designed and duloxetine-containing hydrogel was prepared by the following method. In the following examples, duloxetine hydrochloride is used, and the indicated weight% of each composition component is based on the final total amount (100 weight%). Hydroxyethyl cellulose and hydroxypropyl cellulose were each added to water so as to be 1% by weight, and allowed to stand for 12 hours to swell the base.
  • duloxetine, l-menthol, isopropyl alcohol and isopropyl myristate were added in the proportions shown in Table 1, and the mixture was stirred with a magnetic stirrer for 12 hours to obtain a uniform hydrogel.
  • the amount of water to be used was adjusted in accordance with the increase / decrease in the amount of the components so that the total amount became 100% by weight.
  • HPLC high performance liquid chromatography
  • FIG. 1 shows the results of calculating the slope of the regression line obtained by linear regression of the transmission amount-time curve plot. Furthermore, the delay time obtained from this regression line [time until the skin permeation rate reaches a steady state] is shown in FIG.
  • FIG. 2 shows the results of evaluating the skin irritation by calculating the viable cell ratio by applying the hydrogel to human three-dimensional cultured skin.
  • the human three-dimensional cultured skin uses a human three-dimensional cultured epidermis kit (registered trademark: LabCyte EPI-MODEL24) manufactured by Japan Tissue Engineering Co., Ltd., according to the instruction manual attached to the kit. Irritation was evaluated.
  • the optimal prescription was analyzed using analysis software (registered trademark: dataNESIA) manufactured by Azbil Corporation.
  • This analysis software can create a response phase from experimental data by double harmonic spline interpolation and search for the optimum value (Savemation Review 2003 Vol. 21 32-39: http://www.azbil.com/ jp / library / review / pdf / 2003_8_05.pdf).
  • the response phase was created by this analysis software with the characteristic value.
  • the size of the preparation is 25 cm 2
  • the maximum blood concentration described in the interview form of the existing duloxetine preparation is set as the target value
  • the number of living cells is set as 80%
  • the skin permeation from the above response phase is set.
  • l-menthol was about 2.6% by weight (optimal solution 2.5667%)
  • isopropyl alcohol was about 15% by weight (idle 14.764%)
  • isopropyl myristate was about 10% by weight (same as 10.049%).
  • the absorption rate was calculated to be about 3000 ⁇ g / cm 2 / hour
  • the delay time was about 4 hours
  • the cell viability was about 80%.
  • the range of the +/- 10% is accept
  • the medicament containing the pharmaceutical composition of the present invention comprises duloxetine, which is widely used clinically as a therapeutic drug for depression and has been recognized as useful as an analgesic, and has excellent transdermal absorbability. It is very useful as a transdermal antidepressant and analgesic that can be used for a long time with good compliance.

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

Abstract

L'invention concerne : une nouvelle composition pharmaceutique absorbable par voie transdermique qui a des propriétés caractéristiques telles que la perméabilité de la peau à la duloxétine ou un sel pharmaceutiquement acceptable de celle-ci contenu dans la composition pharmaceutique peut être augmentée pour présenter un effet excellent pharmacologique de duloxétine ou du sel pharmaceutiquement acceptable de celle-ci et la propriété irritante de la peau de la composition pharmaceutique est faible ; et un médicament comprenant la composition pharmaceutique. La présente invention concerne : une nouvelle composition pharmaceutique absorbable par voie transdermique qui contient de la duloxétine ou un sel pharmaceutiquement acceptable de celle-ci comme ingrédient actif et contient également du menthol, de l'alcool isopropylique et du myristate d'isopropyle ; et un médicament comprenant la composition pharmaceutique. Chacun de la composition et du médicament selon la présente invention contient de la duloxétine, qui a été largement utilisée dans la pratique clinique comme agent thérapeutique pour la dépression et est connue être utile comme agent analgésique pour une douleur chronique et similaire, comme ingrédient actif. En conséquence, chacun de la composition et du médicament a une excellente efficacité et une excellente innocuité et a une utilité extrêmement élevée comme agent antidépresseur absorbable par voie transdermique et agent analgésique absorbable par voie transdermique qui peuvent être utilisés pendant une longue période avec une bonne observance.
PCT/JP2014/055267 2013-03-04 2014-03-03 Composition pharmaceutique absorbable par voie transdermique Ceased WO2014136717A1 (fr)

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JP2013042068A JP5376481B1 (ja) 2013-03-04 2013-03-04 経皮吸収用医薬組成物
JP2013-042068 2013-03-04

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JP2016524609A (ja) * 2013-05-24 2016-08-18 ネステク ソシエテ アノニム メントール及び／又はイシリンを用いるうつ病の処置又は予防

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000029021A1 (fr) * 1998-11-17 2000-05-25 Shionogi & Co., Ltd. Preparations administrables par voie percutanee d'activateurs des fonctions cerebrales
JP2007522249A (ja) * 2004-02-13 2007-08-09 ニューロモレキュラー・インコーポレイテッド 精神医学的状態の処置のための、ｎｍｄａレセプターアンタゴニストと、抗うつ薬であるｍａｏインヒビターまたはｇａｄｐｈインヒビターとの併用
WO2010016219A1 (fr) * 2008-08-05 2010-02-11 株式会社メドレックス Préparation externe comprenant un sel d'acide gras ou un sel d'acide benzoïque d'un composant basique pharmacologiquement actif, et procédé de production de celui-ci
WO2012077651A1 (fr) * 2010-12-07 2012-06-14 祐徳薬品工業株式会社 Timbre transdermique contenant un antidépresseur noradrénergique et sérotoninergique spécifique
JP2012193176A (ja) * 2011-03-03 2012-10-11 Nippon Zoki Pharmaceut Co Ltd ミルナシプラン含有経皮吸収用医薬組成物

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000029021A1 (fr) * 1998-11-17 2000-05-25 Shionogi & Co., Ltd. Preparations administrables par voie percutanee d'activateurs des fonctions cerebrales
JP2007522249A (ja) * 2004-02-13 2007-08-09 ニューロモレキュラー・インコーポレイテッド 精神医学的状態の処置のための、ｎｍｄａレセプターアンタゴニストと、抗うつ薬であるｍａｏインヒビターまたはｇａｄｐｈインヒビターとの併用
WO2010016219A1 (fr) * 2008-08-05 2010-02-11 株式会社メドレックス Préparation externe comprenant un sel d'acide gras ou un sel d'acide benzoïque d'un composant basique pharmacologiquement actif, et procédé de production de celui-ci
WO2012077651A1 (fr) * 2010-12-07 2012-06-14 祐徳薬品工業株式会社 Timbre transdermique contenant un antidépresseur noradrénergique et sérotoninergique spécifique
JP2012193176A (ja) * 2011-03-03 2012-10-11 Nippon Zoki Pharmaceut Co Ltd ミルナシプラン含有経皮吸収用医薬組成物

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
KAZUO HANAOKA ET AL.: "Duloxetine Ensan'en", PAIN CLINIC, vol. 33, no. 1, January 2012 (2012-01-01), pages 99 - 102 *

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