WO2010057594A1 - Système d'administration de médicament - Google Patents

Système d'administration de médicament Download PDF

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Publication number
WO2010057594A1
WO2010057594A1 PCT/EP2009/008080 EP2009008080W WO2010057594A1 WO 2010057594 A1 WO2010057594 A1 WO 2010057594A1 EP 2009008080 W EP2009008080 W EP 2009008080W WO 2010057594 A1 WO2010057594 A1 WO 2010057594A1
Authority
WO
WIPO (PCT)
Prior art keywords
dosage form
triene
estra
diol
vinyl
Prior art date
Application number
PCT/EP2009/008080
Other languages
English (en)
Inventor
Ildiko Terebesi
Adrian Funke
Konstanze Diefenbach
Matthias SCHÄFERS
Sascha General
Original Assignee
Bayer Schering Pharma Aktiengesellschaft
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 Bayer Schering Pharma Aktiengesellschaft filed Critical Bayer Schering Pharma Aktiengesellschaft
Priority to US13/130,326 priority Critical patent/US20120282340A1/en
Priority to EP09753046A priority patent/EP2358351A1/fr
Priority to CA2744127A priority patent/CA2744127A1/fr
Priority to JP2011536762A priority patent/JP2012509286A/ja
Priority to CN2009801462664A priority patent/CN102215818A/zh
Publication of WO2010057594A1 publication Critical patent/WO2010057594A1/fr

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
    • 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
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • 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
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • 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
    • A61K9/7007—Drug-containing films, membranes or sheets
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones

Definitions

  • the pharmaceutical industry is constantly aiming at improving delivery systems in order to make a better utilisation of a given drug dose.
  • the drug load can be lowered while, at the same time, still give rise to clinical relevant concentrations of the drug in the blood stream.
  • This is particularly relevant when high-potent drugs, such as steroid hormones, are to be administered.
  • Lowering the dose of, e.g., a steroid hormone while still obtaining clinical relevant concentrations of the steroid hormone in the blood stream not only allows for savings in the pharmaceutical industry, as smaller amounts of drug is needed, but also allows for smaller total amounts of the steroid hormone to be administered to the patients.
  • the patent document WO 03/104253A2 relates to novel 9 alpha -substituted estratrienes of general formula (I) - in which R 9 represents a linear-chain or branched-chain, optionally partially or fully halogenated alkenyl radical comprising between 2 and 6 carbon atoms, or an ethinyl radical or a prop-1-inyl radical - as pharmaceutical active ingredients which have, in vitro, a higher affinity to estrogen receptor preparations of the rat prostate than to estrogen receptor preparation of the rat uterus, and, in vivo, preferably a preferential action on the ovary compared to the uterus.
  • R 9 represents a linear-chain or branched-chain, optionally partially or fully halogenated alkenyl radical comprising between 2 and 6 carbon atoms, or an ethinyl radical or a prop-1-inyl radical - as pharmaceutical active ingredients which have, in vitro, a higher affinity to estrogen receptor preparations of the rat prostate
  • the reporter construct which comprises five copies of the GAL4 binding site upstream of a thymidine kinase promoter, leads to expression of firefly luciferase (Photinus pyralis) after activation and binding of the GAL4-estrogen receptor chimeras by specific agonists.
  • firefly luciferase Photinus pyralis
  • the present invention relates to a unit dosage form comprising a thin water-soluble film matrix, wherein a) said film matrix comprises at least one water-soluble matrix polymer; b) said film matrix comprises 8 ⁇ - or 9 ⁇ -substituted estra-l,3,5(10)-tr ⁇ ene chosen from the group of compounds: 9 ⁇ -Vinyl-estra-l,3,5(10)-triene-3,16 ⁇ -diol, ly ⁇ -Fluoro- ⁇ -vinyl-estra-l ⁇ SClCO-triene ⁇ ie ⁇ -diol, 18a-Homo-9 ⁇ -vinyl-estra-l,3,5(10)-triene-3,16 ⁇ -diol,
  • said film matrix has a thickness of less than 300 ⁇ m.
  • a unit dosage form in the form of a wafer
  • a unit dosage form that contains a low dose of a 8 ⁇ - or 9 ⁇ -substituted estra-l,3,5(10)-triene mentioned as ER- ⁇ selective agonist
  • ER- ⁇ selective agonist can be administered to female mammals via the intra-oral route and still give rise to clinical relevant serum levels in the blood stream.
  • the administered dose and the inter-individual variability with respect to the resulting serum levels of 8 ⁇ - or 9 ⁇ -substituted oestra-l,3,5(10)-triene can be lowered significantly compared to oral administration.
  • the use of a ER- ⁇ selective agonist with reduced inter-individual variability of said active ingredient is particularly beneficial as it allows to avoid opposed treatment.
  • An opposed treatment refers to a continuous or cyclic co-administration of a progestin which is commonly applied in conventional Hormone Replacement Therapy in order to counteract the estrogen-induced Estrogen Receptor alpha (ER- ⁇ ) mediated proliferation of the endometrium.
  • the invention further refers to a unit dosage form to be applied to the oral cavity which is better tolerated with regard to gynaecological effects as compared to standard oral treatment, but which is still effective in treating, alleviating or preventing a physical condition in a female mammal caused by insufficient endogenous levels of estrogen.
  • Additional water-soluble polymers which may be used in accordance with the present invention, include dextrin, dextran and combinations thereof, as well as chitin, chitosin and combinations thereof, polydextrose and fructose oligomers.
  • doses refers in particular to the above specifically named compounds, and more particularly to 17 ⁇ -Fluoro-9 ⁇ -vinyl-estra-l,3,5(10)-triene- 3,16 ⁇ -diol.
  • the unit dosage form of the invention may include a variety of various auxiliary components, such as taste- masking agents; organoleptic agents, such as sweeteners and flavours, anti- and de-foaming agents; plasticizing agents; surfactants; emulsifying agents; thickening agents; binding agents; cooling agents; saliva-stimulating agents, such as menthol; antimicrobial agents; colorants; etc.
  • auxiliary components such as taste- masking agents; organoleptic agents, such as sweeteners and flavours, anti- and de-foaming agents; plasticizing agents; surfactants; emulsifying agents; thickening agents; binding agents; cooling agents; saliva-stimulating agents, such as menthol; antimicrobial agents; colorants; etc.
  • Such various auxiliary components are comprised in the film matrix and is typically dissolved or dispersed in the film matrix.
  • water-soluble sweeteners derived from naturally occurring water-soluble sweeteners, such as a chlorinated derivatives of ordinary sugar (sucrose), known, for example, under the product description of sucralose ® ; and
  • beta citral lemon, lime
  • decanal orange, lemon
  • ethyl vanillin vanilla, cream
  • heliotropine i.e., piperonal (vanilla, cream); vanillin (vanilla, cream); alpha-amyl cinnamaldehyde (spicy fruity flavours); butyraldehyde (butter, cheese); valeraldehyde (butter, cheese); citronellal (modified, many types); decanal (citrus fruits); aldehyde C-8 (citrus fruits); aldehyde C-9 (citrus fruits); aldehyde C-12 (citrus fruits); 2-ethyl butyraldehyde (berry fruits); hexenal, i.e.
  • the unit dosage form may be prepared and adhered to a second layer, i.e. a support or backing layer (liner) from which it is removed prior to use, i.e. before being introduced into the oral cavity.
  • a second layer i.e. a support or backing layer (liner) from which it is removed prior to use, i.e. before being introduced into the oral cavity.
  • the support or backing material is not water-soluble and may preferably consist of polyethylene-terephthalate, or other suitable materials well known to the skilled person.
  • an adhesive it should preferably be a food grade adhesive that is not ingestible and does not alter the properties of the active ingredient(s).
  • the unit dosage form of the invention further comprises another active drug substance, such as a progestin.
  • the active drug substance is typically comprised in the film matrix.
  • the coating solution may be prepared directly by adding the ER- ⁇ selective agonist, or a derivatives thereof, to an appropriate solvent, preferably an alcohol, in particular ethanol, followed by addition of water and subsequent addition of the matrix polymer.
  • an appropriate solvent preferably an alcohol, in particular ethanol
  • the mixture is then processed as described above until a solution is obtained.
  • the resulting solution (coating solution) can be used for coating immediately or within a few days, commonly within one day.
  • the various amounts of solvent, matrix polymer, etc. are adjusted to reach a solid content of the coating solution of about 5-50% by weight, preferably 10-40% by weight, in particular 20-35% by weight.
  • the coating solution may be prepared by directly adding the ER- ⁇ selective agonist, or a derivative thereof, to an appropriate polymer solution and dissolving the drug in said polymer solution.
  • the polymer solution is prepared beforehand by dissolving the polymer in the solvent/water mixture according the above described process.
  • the resulting solution can be used for coating immediately or within a few days, commonly within one day.
  • the various amounts of solvent, matrix polymer, etc. are adjusted to reach a solid content of the coating solution of about 5-50% by weight, preferably 10-40% by weight, in particular 20-35% by weight.
  • the coating solution is degassed before being spread out on a suitable support or backing layer (liner).
  • suitable liners include, but are not limited to polyethylene-terephthalate (PET) liners, such as Perlasic ® LF75 (available from Perlen Converting), Loparex ® LF2000 (available from Loparex BV) and Scotchpack ® 9742 (available from 3M Drug delivery Systems).
  • PET polyethylene-terephthalate
  • the coating solution is spread out with the aid of a spreading box onto a suitable liner and dried for 12-24 hours at room temperature. A thin film of 30-100 ⁇ m thickness, preferably 40-80 ⁇ m thickness is then produced, which is subsequently cut into pieces of the desired size and shape.
  • Urogenital atrophy, and conditions associated with it such as vaginal dryness, increase in vaginal pH and subsequent changes in flora, or events which lead to such atrophy, such as decreases in vascularity, fragmentation of elastic fibres, fusion of collagen fibres, or decreases in cell volume, are symptoms thought to be particularly relevant to be treated or alleviated with the unit dosage forms described herein.
  • the unit dosage forms described herein are thought to be relevant to other urogenital changes associated with estrogen deficiency, decreases in mucus production, changes in cell population, decreases in glycogen production, decreases in growth of lactobacilli or increases in growth of streptococci, staphylococci, or coliform bacilli.
  • ER- ⁇ selective agonist wafer 1000 ⁇ g (with Hydroxypropyl cellulose Matrix), 5 cm 2
  • the film thickness was measured by a MiniTest 600, Erichsen, Hemer, Germany
  • the mechanical properties were quantified by measurement of the tensile strength and elongation (Zwick Material Testing, UIm, Germany) and calculation of the modulus of elasticity, E, by following equation:
  • Disintegration time of placebo wafer formulation after administration (normalized to a wafer thickness of 50 ⁇ m)
  • the taste of the formulation was related to the polymer matrix. Most additives altered the taste of the formulations significantly such that the taste turned bad, or even inacceptable (e.g. Triethylcitrate (TEC), gamma-Cyclodextrin (gamma CD)).
  • TEC Triethylcitrate
  • gamma-Cyclodextrin gamma CD
  • the present wafer demostrates improved mouthfeel and taste, by defining favourable thickness and elasticity, able to confer improved patient acceptability, this particularly the case with the film matrix having a modulus of elasticity ⁇ 200 MPas or particularly ⁇ 150 MPas or more particularly ⁇ 100 MPas and a %-elongation > 15%, or particularly> 20%.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Endocrinology (AREA)
  • Nutrition Science (AREA)
  • Physiology (AREA)
  • Diabetes (AREA)
  • Reproductive Health (AREA)
  • Inorganic Chemistry (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention porte sur des systèmes d'administration de médicament sous la forme de films minces solubles dans l'eau (cachets), contenant un agoniste sélectif du récepteur bêta de l'oestrogène (ER-ß). Les cachets de la présente invention sont appropriés pour traiter, soulager ou prévenir un état physique chez une femme souffrant de taux endogènes d'oestrogène insuffisants.
PCT/EP2009/008080 2008-11-21 2009-11-13 Système d'administration de médicament WO2010057594A1 (fr)

Priority Applications (5)

Application Number Priority Date Filing Date Title
US13/130,326 US20120282340A1 (en) 2008-11-21 2009-11-13 Drug delivery system
EP09753046A EP2358351A1 (fr) 2008-11-21 2009-11-13 Système d'administration de médicament
CA2744127A CA2744127A1 (fr) 2008-11-21 2009-11-13 Systeme d'administration de medicament
JP2011536762A JP2012509286A (ja) 2008-11-21 2009-11-13 薬物送達システム
CN2009801462664A CN102215818A (zh) 2008-11-21 2009-11-13 药物递送系统

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
EP08105842.2 2008-11-21
EP08105842 2008-11-21
EP09075321 2009-07-17
EP09075321.1 2009-07-17

Publications (1)

Publication Number Publication Date
WO2010057594A1 true WO2010057594A1 (fr) 2010-05-27

Family

ID=41396206

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2009/008080 WO2010057594A1 (fr) 2008-11-21 2009-11-13 Système d'administration de médicament

Country Status (7)

Country Link
US (1) US20120282340A1 (fr)
EP (1) EP2358351A1 (fr)
JP (1) JP2012509286A (fr)
KR (1) KR20110097779A (fr)
CN (1) CN102215818A (fr)
CA (1) CA2744127A1 (fr)
WO (1) WO2010057594A1 (fr)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114044764B (zh) * 2021-10-21 2023-07-21 香港中文大学（深圳） 中草药小分子化合物及其应用、药物组合物
CN114044765B (zh) * 2021-11-05 2023-03-14 中国人民解放军海军特色医学中心 Eudesmanolide倍半萜类化合物及其制备方法与应用

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0232877A2 (fr) * 1986-02-10 1987-08-19 Zetachron, Inc. Forme de dosage d'un médicament pour la cavité buccale
WO2001077139A1 (fr) * 2000-04-12 2001-10-18 Schering Aktiengesellschaft Estratrienes a substitution 8.beta-hydrocarbyle utilises comme oestrogenes a action selective
WO2003104253A2 (fr) * 2002-06-11 2003-12-18 Schering Aktiengesellschaft Estratrienes 9-alpha substitues servant d'oestrogenes selectivement actifs
DE102006003512A1 (de) * 2006-01-24 2007-08-02 Bayer Schering Pharma Ag Plättchenförmige Arzneimittel zur transbukkalen Applikation von Arzneistoffen
WO2009100871A2 (fr) * 2008-02-13 2009-08-20 Bayer Schering Pharma Aktiengesellschaft Système d'administration de médicament présentant un effet stabilisateur

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE10019167A1 (de) * 2000-04-12 2001-10-18 Schering Ag Substituierte Estratriene als selektiv wirksame Estrogene
DE102005015128B4 (de) * 2005-03-31 2008-12-11 Bayer Schering Pharma Aktiengesellschaft Wafer enthaltend Steroidhormone

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0232877A2 (fr) * 1986-02-10 1987-08-19 Zetachron, Inc. Forme de dosage d'un médicament pour la cavité buccale
WO2001077139A1 (fr) * 2000-04-12 2001-10-18 Schering Aktiengesellschaft Estratrienes a substitution 8.beta-hydrocarbyle utilises comme oestrogenes a action selective
WO2003104253A2 (fr) * 2002-06-11 2003-12-18 Schering Aktiengesellschaft Estratrienes 9-alpha substitues servant d'oestrogenes selectivement actifs
DE102006003512A1 (de) * 2006-01-24 2007-08-02 Bayer Schering Pharma Ag Plättchenförmige Arzneimittel zur transbukkalen Applikation von Arzneistoffen
WO2009100871A2 (fr) * 2008-02-13 2009-08-20 Bayer Schering Pharma Aktiengesellschaft Système d'administration de médicament présentant un effet stabilisateur

Also Published As

Publication number Publication date
EP2358351A1 (fr) 2011-08-24
JP2012509286A (ja) 2012-04-19
CA2744127A1 (fr) 2010-05-27
KR20110097779A (ko) 2011-08-31
US20120282340A1 (en) 2012-11-08
CN102215818A (zh) 2011-10-12

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