EP2178523A2 - Systèmes thérapeutiques transdermiques contenant le principe actif anastrozol - Google Patents

Systèmes thérapeutiques transdermiques contenant le principe actif anastrozol

Info

Publication number
EP2178523A2
EP2178523A2 EP08774817A EP08774817A EP2178523A2 EP 2178523 A2 EP2178523 A2 EP 2178523A2 EP 08774817 A EP08774817 A EP 08774817A EP 08774817 A EP08774817 A EP 08774817A EP 2178523 A2 EP2178523 A2 EP 2178523A2
Authority
EP
European Patent Office
Prior art keywords
group
tts according
tts
adhesive layer
weight
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.)
Withdrawn
Application number
EP08774817A
Other languages
German (de)
English (en)
Inventor
Christian Brätter
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.)
Individual
Original Assignee
Individual
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 Individual filed Critical Individual
Publication of EP2178523A2 publication Critical patent/EP2178523A2/fr
Withdrawn legal-status Critical Current

Links

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
    • A61K9/7061—Polyacrylates
    • 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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4196—1,2,4-Triazoles
    • 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
    • A61K9/7069—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained otherwise than by reactions only involving carbon to carbon unsaturated bonds, e.g. polysiloxane, polyesters, polyurethane, polyethylene oxide

Definitions

  • the invention relates to a transdermal therapeutic system (TTS) containing the aromatase inhibitor anastrozole.
  • TTS transdermal therapeutic system
  • This TTS allows delivery of anastrozole in therapeutically effective amounts over a period of at least 12 hours.
  • the invention also encompasses the use of a TTS 'according to the invention alone or in combination therapy for the therapy of breast cancer or related tumors.
  • Anastrozole like other aromatase inhibitors of the 1 / - / - 1, 2,4-triazole group (eg letrozole, fadrozole and vorozole), is already approved for oral use in the pharmaceutical market. This currently available oral therapy with aromatase inhibitors is associated with significant pharmacokinetic problems and / or compliance issues. Gastrointestinal side effects have also been described. In particular, a lack of compliance can jeopardize the therapeutic success in the treatment of cancer.
  • WO 93/19746 A1 mentions topical preparations for the estrogen receptor antagonist toremifene and its salts. Toremifen does not interfere with the denovo-Estrogensynthese, but blocks rather the estrogen receptor.
  • the excipients of WO 97/019746 are dosage forms for topical application.
  • the site of action is therefore local, i. limited to the site of application and surrounding tissue.
  • the application is in a topical application, for example in the form of ointments, creams, powders, suspensions, emulsions or solutions.
  • EP 0 943 333 likewise describes systems which are to be used for topical application.
  • the focus here is on the active substance formestane, which is structurally and thus in its physicochemical as well as in its pharmacodynamic see characteristics significantly different from anastrozole. A systemic effect is undesirable here.
  • WO 97/29735 mentions transdermal therapeutic systems for the administration of the aromatase inhibitor exemestane.
  • Exemestane has a steroid backbone and thus differs significantly in the physicochemical properties of the triazole derivative anastrozole, requiring a different approach and formulation strategy.
  • exemestane unlike anastrozole, acts as an irreversible enzyme inhibitor.
  • the document WO 97/06788 comprises a transdermal therapeutic system with a reservoir for administering the active substance vorozole.
  • Vorozole is significantly different from the active substance anastrozole.
  • the triazole backbone is condensed to a bicyclic benzotriazole, while anastrozole has only a simple 1 / - / - 1, 2,4-triazole skeleton.
  • the physico-chemical properties, which significantly influence the skin permeability of the drug thus differ in particular in solubility parameters, which requires different development strategies.
  • TTS transdermal therapeutic system
  • TTS dosage forms which, when applied to the skin, release the active ingredient continuously at a predetermined rate over a defined time interval.
  • Such TTSs consist of a drug-impermeable backing layer, a drug-containing layer, an adhesive layer which may be identical to the drug-containing layer, and a release liner which is removed prior to application of the system.
  • a control membrane for defining the rate of release may be incorporated into the system.
  • TTS transdermal therapeutic system
  • TTS transdermal therapeutic system
  • a transdermal therapeutic system for transdermal administration, which comprises a drug-impermeable backing layer, an adhesive layer containing an adhesive component and the active substance anastrozole or its physiologically compatible hydrate, solvate or salt dissolved in a concentration of 0, 1% (m / m) to 30% (m / m), based on the weight of the adhesive layer, comprises (active substance-containing layer) and a skin-side peel-off layer which is removed before the application of the TTS.
  • other ingredients may be included.
  • Anastrozole itself is particularly preferably used as active ingredient.
  • TTS for the active ingredient anastrozole should release the drug in therapeutic doses so that it can achieve its desired pharmacological effects.
  • the TTS according to the invention makes it possible to release the active ingredient over a time interval of at least 12 hours, preferably 24 hours and most preferably 48 hours or longer. This can be expected a significant improvement for a corresponding therapy. Also, by transdermal application of the drug, a nearly constant concentration level of the drug in the plasma can be achieved. Thus, the plasma concentration spikes that occur as a result of oral therapy and are responsible for typical drug-specific side effects are avoided. Likewise, the gastrointestinal side effects are reduced. Overall, improved therapy with anastrozole is therefore to be expected.
  • the adhesive component of the TTS according to the invention comprises at least one polymer as a pressure-sensitive adhesive, which is selected from the group of acrylates, methacrylates or the acrylate methacrylates or their copolymers, the group of silicones, the group of polystyrenes, the group of polyisobutylenes or the group of celluloses and cellulose derivatives, optionally containing functional groups in the polymer chains. These functional groups can be selected from the group of amino and hydroxy groups and their amides and esters.
  • the at least one polymer of the adhesive component is preferably a copolymer of an acrylate, methacrylate or acrylate methacylate with vinyl acetate, with an acrylate-vinyl acetate copolymer being particularly preferred
  • Preferred acrylates are the DuroTak adhesives (National Starch, USA).
  • Eudragite from Rohm Pharma Polymers, Germany
  • Preferred acrylate copolymers such as acrylate vinyl acetates
  • Gelva adhesives Solutia, USA
  • a preferred example of adhesives with functional groups is the Eudragit E 100, which contains amino functions in the side chains.
  • the active ingredient may be contained in dissolved and / or suspended (dispersed) form in the TTS according to the invention, the dissolved form being preferred.
  • concentration data based on the mass or the weight of the adhesive layer are understood to refer to the adhesive layer after the necessary drying (for removal of process solvent) i. on the dry adhesive layer.
  • the active ingredient itself is in the TTS invention in a concentration between 0.1% and 30% (m / m, based on the mass of the adhesive layer), preferably in concentrations between 0.5% and 20% (m / m, based on the Mass of the adhesive layer) and most preferably a concentration of between 1% and 10% (m / m, based on the mass of the adhesive layer).
  • the adhesive layer may also contain further ingredients, for example for stabilizing the system or for improving the release of active ingredient.
  • the further ingredients may be present in the TTS according to the invention in concentrations between 0.01% (m / m) and 50% (m / m), based on the weight of the adhesive layer.
  • the further ingredients include, for example, at least one aliphatic alcohol.
  • the at least one aliphatic alcohol is preferably selected from the group of linear aliphatic alcohols having a terminal OH function, preferably having a chain length of from 2 to 14 carbon atoms, such as ethanol or dodecanol. Most preferably these are ethanol or / and dodecanol.
  • the at least one aliphatic alcohol may also contain more than one OH function and is then preferably propylene glycol, 1, 3-butanediol or / and glycerol, and most preferably propylene glycol.
  • the at least one aliphatic alcohol is selected from the group of propylene glycol, 1,2-butanediol and / or dodecanol.
  • the at least one alcohol is present in a concentration of 0.5% (m / m) to 50% (m / m), based on the weight of the adhesive layer, with a concentration of 0.5% (m / m). to 20% (m / m), based on the weight of the adhesive layer, and a concentration of 1% (m / m) to 10% (m / m), based on the weight of the adhesive layer, is most preferable.
  • the TTS can be used as further ingredients in addition to the adhesive component which comprises at least one polymer selected from the group of acrylates, methacrylates or acrylate methacrylates or their copolymers, the group of polystyrenes, the group of polyisobutylenes or the group of Celluloses and cellulose derivatives is selected to contain at least one chemical permeation enhancer.
  • the adhesive component which comprises at least one polymer selected from the group of acrylates, methacrylates or acrylate methacrylates or their copolymers, the group of polystyrenes, the group of polyisobutylenes or the group of Celluloses and cellulose derivatives is selected to contain at least one chemical permeation enhancer.
  • the adhesive component which comprises at least one polymer selected from the group of acrylates, methacrylates or acrylate methacrylates or their copolymers, the group of polystyrenes, the group of polyisobutylenes or the group of Celluloses and
  • the at least one chemical permeation enhancer is preferably selected from the group of the alcohols, the N-alkylpyrrolidones, the 2-alkylpyrrolidones, the N-alkylazacycloheptanones, the polyoxyethylene sorbitan esters or the sorbitan esters. addiction is.
  • N-methylpyrrolidone N-dodecylpyrrolidone
  • 2-methylpyrrolidone 2-ethylpyrrolidone
  • 2-dodecylpyrrolidone N-dodecylazacycloheptanone
  • polyoxyethylene sorbitan esters with fatty acids or the sorbitan esters with fatty acids.
  • Suitable polyoxyethylene sorbitan esters with fatty acids are, in particular, the compounds known briefly as polysorbates or under the trade name Tween.
  • Tween 20 polyoxyethylene (20) sorbitan monolaurate
  • 40 polyoxyethylene (20) sorbitan monopalmitate
  • 60 polyoxyethylene (20) sorbitan monostearate
  • 80 polyoxyethylene (20) sorbitan monooleate
  • Tween 80 The sorbitan esters with fatty acids are known by the name Span.
  • Span 20 sorbitan monolaurate
  • 40 sorbitan monopalmitate
  • 60 sorbitan monostearate
  • 80 sorbitan monooletate
  • the at least one chemical permeation enhancer can be a straight-chain hydrocarbon radical having 10 to 18 carbons, preferably 12 carbon atoms, and a polar head group selected from the group consisting of hydroxyl and carbonyl groups and also ⁇ -, ⁇ - or ⁇ -lactones.
  • cosolvents may be included to increase the solubility of the active ingredient. These cosolvents improve the solubility parameters for the active substance anastrozole in the patch or - after release - in the skin.
  • At least one crystallization inhibitor to avoid the crystallization or precipitation of dissolved active ingredient may be included. It is preferred that the at least one crystallization inhibitor belongs to the group of polymers, in particular vinylpyrrolidones and acrylates. In particular, it is preferred that the at least one crystallization inhibitor belongs to the group of polyvinyl nylpyrrolidone having a molecular weight in the range of 2,500 to 750,000 daltons.
  • the active ingredient may be included as additional ingredients in addition adjuvants for stabilizing the active ingredient, i. to protect it from decomposition. Accordingly, it is preferred that at least one antioxidant is included.
  • the at least one antioxidant preferably belongs to the group of PHB esters, p-hydroxytoluene derivatives, ubiquinones, vitamins or vitamins.
  • the TTSs of the invention are individually packaged in a sealed bag to protect the system from external influences such as moisture and light.
  • These pouches are preferably made of a sealable multilaminate film containing inside a sealable polymer layer and then an aluminum layer. To the outside, a further polymer or paper layer can be applied, which is preferably printable.
  • the TTS according to the invention which comprises an active-substance-impermeable backing layer, an adhesive layer which comprises an adhesive component and the active substance Ana strozo I or its physiologically tolerated hydrate, solvate or salt dissolved in a concentration of 0.1% (m / m) to 30% (m / m), based on the weight of the adhesive layer, comprises (drug-containing layer) and a skin-side release layer, which is removed before the application of the TTS, is used for the therapy of breast cancer or related tumors, alone or in combination therapy.
  • other ingredients may be included.
  • Preferred is the use for the treatment of anti-estrogen-sensitive tumors.
  • the TTS according to the invention can be used for the treatment of the prostate adenoma, alone or in combination therapy.
  • a further use according to the invention is the stimulation of foil proliferation as a measure of in vitro fertilization or as a measure of in vivo fertilization.
  • the TTS according to the invention likewise finds application in the treatment of hypogonadism and its consequences, in particular lack of libido and erectile dysfunction.
  • Another use of the invention is in the treatment of gynecomastia.
  • the TTS according to the invention is used for the treatment of Benign Prostatic Hyperplasia, which are associated with increased estrogen action, alone or in combination therapy.
  • the TTS according to the invention is used for the prevention of tumor formation.
  • the application is made by sticking to the skin of the human body, preferably by sticking to the abdomen, the chest, the lateral trunk, the back, the shoulders, the upper arms or the thighs.
  • a saturated aqueous solution of anastrozole was prepared.
  • An HPLC analytical assay provided a solubility of 32 mg anastrozole per 100 mL. Due to the saturation, the thermodynamic activity, which is the driving force for the permeation process, is maximal.
  • the excised skin was carefully freed of adherent fatty tissue, divided into segments of sufficient size and then placed skin-side up in static Franz diffusion cells filled with the skin permeation medium so that it was in contact with the underside of the skin.
  • the skin permeation medium consisted of a pH 7.4 phosphate buffered solution with additions of polyethylene glycol 400 and 2-hydroxypropyl-beta-cyclodextrin to ensure sink conditions for the drug.
  • the water-jacketed cells were tempered with water of 38 0 C, so that a temperature of 32 0 C at the permeation surface of the skin resulted.
  • the medium was stirred continuously with a magnetic stirrer at 500 rpm.
  • 150 ⁇ L of the saturated anastrozole solution was applied to the skin.
  • Samples were taken at defined times and collected in HPLC vials. The removed sample volume was replaced by fresh and tempered skin permeation medium. This dilution was taken into account in the calculation of cumulatively permeated amounts of anastrozole.
  • the samples were analyzed for anastrozole content by a selective HPLC analytical method with UV detection.
  • the cumulated permeated amounts were plotted against time in a Cartesian coordinate system.
  • the slope of the linear part of the profile was defined as a steady state flow, the x-intercept as lag time.
  • average flows were calculated based on 24 and 48 hours.
  • the permeation profile of anastrozole is shown in Figure 1.
  • anastrozole permeates the skin tissue in clearly measurable quantities.
  • a constant release of the drug (steady state) could be maintained for at least 24 hours.
  • the drug flux in the steady state was calculated to be 2.30 (0.47) ⁇ g / cm 2 / h.
  • TTS on the basis of a silicone adhesive (Bio PSA ® 7-4301, Dow Corning, USA) were prepared by the solvent casting method.
  • Anastrozole was dissolved in ethyl acetate, optionally together with potential permeation enhancers, and then added to the silicone polymer dissolved in n-heptane.
  • the mass ratio of the solid components was as follows: anastrozole to silicone 1; 99, or in the case of using permeation enhancers anastrozole: permeation enhancer: silicone 1: 10: 89.
  • the adhesive solution was applied to a fluoropolymerized PET film by means of a doctor blade and the film subjected to a controlled drying program to remove the process solvents To remove ethyl acetate and n-heptane. Subsequently, the dried film was laminated with a PE membrane. The average weight of the adhesive layer containing anastrozole was determined to be about 55 mg per 10 cm 2 .
  • the TTS were examined by polarization microscopy immediately after production and immediately before a permeation experiment. All TTS had a homogeneous and crystal-free appearance.
  • the test series shows that anastrozole from a non-optimized TTS without the addition of a permeation enhancer already permeates the model skin in vitro to a significant extent.
  • continuous permeation of anastrozole begins without any appreciable delay (lag time) and persists for a time interval of about 32 hours.
  • the steady state flux could be determined to be 2.07 (0.13) ⁇ g / cm 2 / h and thus surprisingly only slightly below that of a saturated solution with maximum thermodynamic activity (see Example 1).
  • Table 1 Permeation parameters for the silicone TTS, calculated from the respective permeation profiles.
  • Example 2 Analogous to the silicone TTS described in Example 2, a TTS based on an acrylate-vinyl acetate (Gelva® 7883, Solutia Inc., USA) was likewise produced.
  • the composition of the adhesive layer was determined as follows: anastrozole 2.5%, dodecanol 10%, polymer 87.5% (data in% by weight (m / m).)
  • Anastrozole and dodecanol were dissolved in a mixture of 2-propanol and After a homogenization phase, the TTSs were prepared analogously to Example 2. The absence of crystals and the homogeneity of the TTSs were demonstrated by polarization microscopic investigations The profile determined from the permeation test is in Figure 6 shown.
  • anastrozole permeates the excised skin of the hairless mouse.
  • the steady-state transdermal flux of anastrozole was determined to be 1.72 (0.41) ⁇ g / cm 2 / h, permitting skin penetration up to 42 ⁇ g / cm 2 within one day.
  • the average flow in relation to the first 24-hour interval was 1.75 ⁇ g / cm 2 / h.

Abstract

L'invention se rapporte à un système thérapeutique transdermique (STT) comprenant une couche de support imperméable au principe actif, une couche adhésive (couche contenant le principe actif) contenant un composant adhésif et le principe actif anastrozol ou son hydrate, solvate ou sel physiologiquement acceptable dissous à une concentration de 0,1 % (m/m) à 30 % (m/m), sur la base du poids de la couche adhésive, et une couche pelliculable côté peau qui se retire du STT avant application. L'invention se rapporte aussi à l'utilisation de ce STT.
EP08774817A 2007-07-10 2008-07-07 Systèmes thérapeutiques transdermiques contenant le principe actif anastrozol Withdrawn EP2178523A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE200710032468 DE102007032468A1 (de) 2007-07-10 2007-07-10 Transdermale Therapeutische Systeme, welche den Wirkstoff Anastrozol enthalten
PCT/EP2008/058743 WO2009007334A2 (fr) 2007-07-10 2008-07-07 Systèmes thérapeutiques transdermiques contenant le principe actif anastrozol

Publications (1)

Publication Number Publication Date
EP2178523A2 true EP2178523A2 (fr) 2010-04-28

Family

ID=40121449

Family Applications (1)

Application Number Title Priority Date Filing Date
EP08774817A Withdrawn EP2178523A2 (fr) 2007-07-10 2008-07-07 Systèmes thérapeutiques transdermiques contenant le principe actif anastrozol

Country Status (3)

Country Link
EP (1) EP2178523A2 (fr)
DE (1) DE102007032468A1 (fr)
WO (1) WO2009007334A2 (fr)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102010046464A1 (de) 2009-03-19 2011-04-21 Amw Gmbh Transdermales System mit Aromatasehemmer
DE102010026883A1 (de) 2010-03-11 2011-12-15 Amw Gmbh Transdermales System mit Aromatasehemmer
WO2017054151A1 (fr) * 2015-09-30 2017-04-06 徐静 Timbre pour application externe contenant de l'anastrozole et utilisation de celui-ci
DE102019110397A1 (de) * 2019-04-18 2020-10-22 Amw Gmbh Transdermales Darreichungssystem mit Aromatasehemmer in übersättigter Matrix
DE102019110398A1 (de) * 2019-04-18 2020-10-22 Amw Gmbh Transdermales Darreichungssystem mit Aromatasehemmer

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Publication number Priority date Publication date Assignee Title
WO1997006788A1 (fr) 1995-08-14 1997-02-27 Janssen Pharmaceutica N.V. Administration trans-cutanee de vorozole
SE505635C2 (sv) 1995-11-28 1997-09-22 Aga Ab Sätt och anordning för att tillsätta ett luktämne till ett ledningssystem för gas
AUPN814496A0 (en) 1996-02-19 1996-03-14 Monash University Dermal penetration enhancer
EP0943333A1 (fr) 1998-03-18 1999-09-22 S.W. Patentverwertungs GmbH Médicament pour la prévention et/ou le traitement du cancer du sein contenant un inhibiteur de la synthèse d'estrogènes
US6476079B1 (en) * 1999-12-23 2002-11-05 Leiras Oy Devices for the delivery of drugs having antiprogestinic properties
AU2001262378A1 (en) * 2000-07-10 2002-02-13 Hormos Medical Corporation Method for treating cryptorchidism
DE10042411A1 (de) * 2000-08-30 2002-03-28 Lohmann Therapie Syst Lts Transdermales therapeutisches System zur Abgabe von Exemestan
CA2492287C (fr) * 2002-07-12 2011-12-13 Pantarhei Bioscience B.V. Composition pharmaceutique comprenant des derives d'estetrol utilises dans la therapie anticancereuse
US20060189670A1 (en) * 2005-02-22 2006-08-24 Glenmark Pharmaceuticals Limited Process for the preparation of anastrozole and intermediates thereof
JP5449775B2 (ja) * 2005-10-19 2014-03-19 チャバフ ピーティーワイ エルティーディー 乳癌の治療に使用されるアロマターゼ阻害薬による副作用の低減
CN1927190A (zh) * 2006-09-28 2007-03-14 哈尔滨健迪医药技术有限公司 来曲唑透皮给药贴剂及其贴剂的制备方法

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Also Published As

Publication number Publication date
WO2009007334A3 (fr) 2009-03-12
WO2009007334A2 (fr) 2009-01-15
DE102007032468A1 (de) 2009-01-15

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