WO2008061966A2 - Nouvelle utilisation de la flibansérine - Google Patents

Nouvelle utilisation de la flibansérine Download PDF

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Publication number
WO2008061966A2
WO2008061966A2 PCT/EP2007/062527 EP2007062527W WO2008061966A2 WO 2008061966 A2 WO2008061966 A2 WO 2008061966A2 EP 2007062527 W EP2007062527 W EP 2007062527W WO 2008061966 A2 WO2008061966 A2 WO 2008061966A2
Authority
WO
WIPO (PCT)
Prior art keywords
flibanserin
acid
optionally
use according
pah
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/EP2007/062527
Other languages
English (en)
Other versions
WO2008061966A3 (fr
WO2008061966A8 (fr
Inventor
Angelo Ceci
Marcus Schindler
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.)
Boehringer Ingelheim International GmbH
Boehringer Ingelheim Pharma GmbH and Co KG
Boehringer Ingelheim Pharmaceuticals Inc
Original Assignee
Boehringer Ingelheim International GmbH
Boehringer Ingelheim Pharma GmbH and Co KG
Boehringer Ingelheim Pharmaceuticals 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 Boehringer Ingelheim International GmbH, Boehringer Ingelheim Pharma GmbH and Co KG, Boehringer Ingelheim Pharmaceuticals Inc filed Critical Boehringer Ingelheim International GmbH
Publication of WO2008061966A2 publication Critical patent/WO2008061966A2/fr
Publication of WO2008061966A3 publication Critical patent/WO2008061966A3/fr
Publication of WO2008061966A8 publication Critical patent/WO2008061966A8/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the invention relates to the use of flibanserin for preparing a medicament for treating diseases in which the use of therapeutic effective amounts of compounds displaying affinity for the 5-HT 2B -receptor display a therapeutic benefit.
  • Flibanserin shows affinity for the 5-HT1 A and 5-HT2-receptor. It is therefore a promising therapeutic agent for the treatment or prevention of a variety of diseases, for instance depression, schizophrenia, and anxiety.
  • flibanserin optionally in form the free base
  • the pharmacologically acceptable acid addition salts and/or optionally in form of the hydrates and/or solvates thereof shows affinity for the 5-HT 2B -receptor with antagonistic activity.
  • the instant invention relates to the use of flibanserin, optionally in form the free base, the pharmacologically acceptable acid addition salts and/or optionally in form of the hydrates and/or solvates thereof for the preparation of a medicament for preventing and/or treating diseases in which the use of therapeutic effective amounts of compounds displaying affinity for the 5-HT 2B - receptor display a therapeutic benefit.
  • the instant invention relates to the use of flibanserin, optionally in form the free base, the pharmacologically acceptable acid addition salts and/or optionally in form of the hydrates and/or solvates thereof for the preparation of a medicament for preventing and/or treating diseases in which the use of therapeutic effective amounts of compounds displaying antagonistic activity to the 5- HT 2B -receptor display a therapeutic benefit.
  • Pulmonary arterial hypertension is the clinical term used to describe a condition associated with progressive elevation in pulmonary arterial pressure (by 10-15 mmHg). PAH occurs more commonly secondary to collagen vascular disease, congenital systemic to pulmonary shunt, portal hypertension, human immunodeficiency virus infection, chronic obstructive lung diseases, interstitial fibrosis and high left-sided filling pressures.
  • vasodilators/antiproliferative agents such as prostacyclin and nitric oxide and vasoconstrictors/co-mitogens such as 5-HT (5-Hydroxytryptamin).
  • the invention relates to the use of flibanserin, optionally in form the free base, the pharmacologically acceptable acid addition salts and/or optionally in form of the hydrates and/or solvates thereof for the preparation of a medicament for preventing and/or treating Pulmonary arterial hypertension (PAH).
  • PAH Pulmonary arterial hypertension
  • the invention relates to the use of flibanserin, optionally in form the free base, the pharmacologically acceptable acid addition salts and/or optionally in form of the hydrates and/or solvates thereof for the preparation of a medicament for preventing and/or treating PAH secondary to collagen vascular disease.
  • the invention relates to the use of flibanserin, optionally in form the free base, the pharmacologically acceptable acid addition salts and/or optionally in form of the hydrates and/or solvates thereof for the preparation of a medicament for preventing and/or treating PAH congenital systemic to pulmonary shunt.
  • the invention relates to the use of flibanserin, optionally in form the free base, the pharmacologically acceptable acid addition salts and/or optionally in form of the hydrates and/or solvates thereof for the preparation of a medicament for preventing and/or treating PAH secondary to portal hypertension.
  • the invention relates to the use of flibanserin, optionally in form the free base, the pharmacologically acceptable acid addition salts and/or optionally in form of the hydrates and/or solvates thereof for the preparation of a medicament for preventing and/or treating PAH secondary to human immunodeficiency virus infection.
  • the invention relates to the use of flibanserin, optionally in form the free base, the pharmacologically acceptable acid addition salts and/or optionally in form of the hydrates and/or solvates thereof for the preparation of a medicament for preventing and/or treating PAH secondary to chronic obstructive lung diseases.
  • the invention relates to the use of flibanserin, optionally in form the free base, the pharmacologically acceptable acid addition salts and/or optionally in form of the hydrates and/or solvates thereof for the preparation of a medicament for preventing and/or treating PAH secondary to interstitial fibrosis.
  • the invention relates to the use of flibanserin, optionally in form the free base, the pharmacologically acceptable acid addition salts and/or optionally in form of the hydrates and/or solvates thereof for the preparation of a medicament for preventing and/or treating PAH secondary to high left-sided filling pressures.
  • Another embodiment of the invention relates to a method for preventing and/or treating of any of the aforementioned conditions comprising the administration of a therapeutically effective amount of flibanserin optionally in form the free base, the pharmacologically acceptable acid addition salts and/or optionally in form of the hydrates and/or solvates thereof.
  • Flibanserin can optionally be used in form of its pharmaceutically acceptable acid addition salts.
  • Suitable acid addition salts include for example those of the acids selected from, succinic acid, hydrobromic acid, acetic acid, fumaric acid, maleic acid, methanesulphonic acid, lactic acid, phosphoric acid, hydrochloric acid, sulphuric acid, tartaric acid and citric acid. Mixtures of the abovementioned acid addition salts may also be used. From the aforementioned acid addition salts the hydrochloride and the hydrobromide, particularly the hydrochloride, are preferred. If flibanserin is used in form of the free base, it is preferably used in form of flibanserin polymorph A as disclosed in WO 03/014079.
  • Flibanserin optionally used in form the free base, the pharmacologically acceptable acid addition salts and/or optionally in form of the hydrates and/or solvates thereof, may be incorporated into the conventional pharmaceutical preparation in solid, liquid or spray form.
  • the composition may, for example, be presented in a form suitable for oral, rectal, parenteral administration or for nasal inhalation: preferred forms includes for example, capsules, tablets, coated tablets, ampoules, suppositories and nasal spray.
  • the active ingredient may be incorporated in excipients or carriers conventionally used in pharmaceutical compositions such as, for example, talc, arabic gum, lactose, gelatine, magnesium stearate, corn starch, acqueous or non acqueous vehicles, polyvynil pyrrolidone, semisynthetic glicerides of fatty acids, benzalconium chloride, sodium phosphate , EDTA, polysorbate 80.
  • the compositions are advantageously formulated in dosage units, each dosage unit being adapted to supply a single dose of the active ingredient.
  • the dose range applicable per day is between 0.1 to 400, preferably between 1.0 to 300, more preferably between 2 to 200 mg Flibanserin.
  • Each dosage unit may conveniently contain from 0,01 mg to 100 mg Flibanserin, preferably from 0,1 to 50 mg.
  • the dosage units are administered to the patient 1 , 2, 3, or 4 times daily. It is preferred that flibanserin is administered either three or fewer times, more preferably once or twice daily consecutively over a period of time.
  • the dose is administered to a patient in the morning and the evening, more preferably once in the morning and once in the evening, most preferably once in the evening only consecutively over a period of time.
  • Suitable tablets may be obtained, for example, by mixing the active substance(s) with known excipients, for example inert diluents such as calcium carbonate, calcium phosphate or lactose, disintegrants such as corn starch or alginic acid, binders such as starch or gelatine, lubricants such as magnesium stearate or talc and/or agents for delaying release, such as carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate.
  • excipients for example inert diluents such as calcium carbonate, calcium phosphate or lactose, disintegrants such as corn starch or alginic acid, binders such as starch or gelatine, lubricants such as magnesium stearate or talc and/or agents for delaying release, such as carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate.
  • excipients for example inert dilu
  • Coated tablets may be prepared accordingly by coating cores produced analogously to the tablets with substances normally used for tablet coatings, for example collidone or shellac, gum arabic, talc, titanium dioxide or sugar.
  • the core may also consist of a number of layers.
  • the tablet coating may consist of a number or layers to achieve delayed release, possibly using the excipients mentioned above for the tablets.
  • Syrups or elixirs containing the active substances or combinations thereof according to the invention may additionally contain a sweetener such as saccharine, cyclamate, glycerol or sugar and a flavour enhancer, e.g of. a flavouring such as vanilline or orange extract. They may also contain suspension adjuvants or thickeners such as sodium carboxymethyl cellulose, wetting agents such as, for example, condensation products of fatty alcohols with ethylene oxide, or preservatives such as p-hydroxybenzoates.
  • a sweetener such as saccharine, cyclamate, glycerol or sugar
  • a flavour enhancer e.g of. a flavouring such as vanilline or orange extract.
  • suspension adjuvants or thickeners such as sodium carboxymethyl cellulose, wetting agents such as, for example, condensation products of fatty alcohols with ethylene oxide, or preservatives such as p-hydroxybenzoates.
  • Solutions for injection are prepared in the usual way, e.g of. with the addition of preservatives such as p-hydroxybenzoates, or stabilisers such as alkali metal salts of ethylenediamine tetraacetic acid, and transferred into injection vials or ampoules.
  • preservatives such as p-hydroxybenzoates, or stabilisers such as alkali metal salts of ethylenediamine tetraacetic acid
  • Capsules containing one or more active substances or combinations of active substances may for example be prepared by mixing the active substances with inert carriers such as lactose or sorbitol and packing them into gelatine capsules.
  • Suitable suppositories may be made for example by mixing with carriers provided for this purpose, such as neutral fats or polyethyleneglycol or the derivatives thereof.
  • the finely ground active substance, lactose and some of the corn starch are mixed together.
  • the mixture is screened, then moistened with a solution of Polyvinylpyrrolidone in water, kneaded, wet-granulated and dried.
  • the granules, the remaining corn starch and the magnesium stearate are screened and mixed together.
  • the mixture is compressed to produce tablets of suitable shape and size.
  • flibanserin hydrochloride 80 mg corn starch 190 mg lactose 55 mg microcrystalline cellulose 35 mg polyvinylpyrrolidone 15 mg sodium-carboxymethyl starch 23 mg magnesium stearate 2 mg
  • the finely ground active substance, some of the corn starch, lactose, microcrystalline cellulose and polyvinylpyrrolidone are mixed together, the mixture is screened and worked with the remaining corn starch and water to form a granulate which is dried and screened.
  • the sodium-carboxymethyl starch and the magnesium stearate are added and mixed in and the mixture is compressed to form tablets of a suitable size.
  • the active substance, corn starch, lactose and polyvinylpyrrolidone are thoroughly mixed and moistened with water.
  • the moist mass is pushed through a screen with a 1 mm mesh size, dried at about 45°C and the granules are then passed through the same screen.
  • convex tablet cores with a diameter of 6 mm are compressed in a tablet-making machine .
  • the tablet cores thus produced are coated in known manner with a covering consisting essentially of sugar and talc.
  • the finished coated tablets are polished with wax.
  • the substance and corn starch are mixed and moistened with water.
  • the moist mass is screened and dried.
  • the dry granules are screened and mixed with magnesium stearate.
  • the finished mixture is packed into size 1 hard gelatine capsules.
  • the active substance is dissolved in water at its own pH or optionally at pH 5.5 to 6.5 and sodium chloride is added to make it isotonic.
  • the solution obtained is filtered free from pyrogens and the filtrate is transferred under aseptic conditions into ampoules which are then sterilised and sealed by fusion.
  • the hard fat is melted.
  • the ground active substance is homogeneously dispersed. It is cooled to 38°C and poured into slightly chilled suppository moulds.
  • flibanserin is administered in form of specific film coated tablets.
  • these preferred formulations are listed below.
  • the film coated tablets listed below can be manufactured according to procedures known in the art (see hereto WO 03/097058).

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

Abstract

La présente invention concerne l'utilisation de la flibansérine dans la préparation d'un médicament pour traiter des maladies pour lesquelles l'utilisation de doses thérapeutiques efficaces de composés possédant une affinité avec le récepteur 5-HT2B présente un avantage thérapeutique.
PCT/EP2007/062527 2006-11-22 2007-11-20 Nouvelle utilisation de la flibansérine Ceased WO2008061966A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP06124575.9 2006-11-22
EP06124575 2006-11-22

Publications (3)

Publication Number Publication Date
WO2008061966A2 true WO2008061966A2 (fr) 2008-05-29
WO2008061966A3 WO2008061966A3 (fr) 2008-07-10
WO2008061966A8 WO2008061966A8 (fr) 2008-09-04

Family

ID=39201544

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2007/062527 Ceased WO2008061966A2 (fr) 2006-11-22 2007-11-20 Nouvelle utilisation de la flibansérine

Country Status (1)

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WO (1) WO2008061966A2 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010047999A3 (fr) * 2008-10-22 2010-07-15 Sam Amer & Co., Inc. Procédé pour traiter l’hypertension artérielle pulmonaire
CN103467596A (zh) * 2012-06-06 2013-12-25 北京大学 一个治疗肺动脉高压的新靶点

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
UA76767C2 (uk) * 2001-08-02 2006-09-15 Бідакем С.П.А. Стабільна поліморфна модифікація флібансерину, спосіб її промислового одержання та її застосування для одержання лікарських засобів
US7612078B2 (en) * 2003-03-31 2009-11-03 Epix Delaware, Inc. Piperidinylamino-thieno[2,3-D] pyrimidine compounds
US20060120972A1 (en) * 2004-11-09 2006-06-08 Peter Engels 9-(N-methyl-piperidyliden-4)-thioxanthene for treatment of pulmonary hypertension

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010047999A3 (fr) * 2008-10-22 2010-07-15 Sam Amer & Co., Inc. Procédé pour traiter l’hypertension artérielle pulmonaire
US8324247B2 (en) 2008-10-22 2012-12-04 Ventrus Biosciences, Inc. Method for treating pulmonary arterial hypertension
CN103467596A (zh) * 2012-06-06 2013-12-25 北京大学 一个治疗肺动脉高压的新靶点

Also Published As

Publication number Publication date
WO2008061966A3 (fr) 2008-07-10
WO2008061966A8 (fr) 2008-09-04

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