WO2009104150A1 - Combinaison comprenant du bosentane destinée au traitement du cancer des ovaires - Google Patents

Combinaison comprenant du bosentane destinée au traitement du cancer des ovaires Download PDF

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Publication number
WO2009104150A1
WO2009104150A1 PCT/IB2009/050679 IB2009050679W WO2009104150A1 WO 2009104150 A1 WO2009104150 A1 WO 2009104150A1 IB 2009050679 W IB2009050679 W IB 2009050679W WO 2009104150 A1 WO2009104150 A1 WO 2009104150A1
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WO
WIPO (PCT)
Prior art keywords
pharmaceutically acceptable
acceptable salt
bosentan
paclitaxel
hydrate
Prior art date
Application number
PCT/IB2009/050679
Other languages
English (en)
Inventor
Martine Clozel
Urs Regenass
Original Assignee
Actelion Pharmaceuticals Ltd
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 Actelion Pharmaceuticals Ltd filed Critical Actelion Pharmaceuticals Ltd
Publication of WO2009104150A1 publication Critical patent/WO2009104150A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • 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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention concerns the combination of bosentan with paclitaxel for therapeutic use, simultaneously, separately or over a period of time, in the treatment of ovarian cancer.
  • Ovarian cancer is one of the most common cancers in women. A common complication of ovarian cancer is ascite formation. Today, there is no satisfactory treatment for ovarian cancer or for its complications such as ascite formation.
  • Bosentan is the active principle of Tracleer ® . It is a dual endothelin receptor antagonist compound (i.e. a compound with affinity for both endothelin ET A and ET B receptors) which has the following formula
  • Bosentan and its preparation have been described notably in EP 0 526 708 or US 5,292,740.
  • Paclitaxel (the active principle of a medicament sold under the trademark Taxol ® in the United States) is an anti-microtubule agent extracted from the needles and bark of the Pacific yew tree, Taxus brevifolia. This compound is currently approved in the European Union and the United States for, among others, the treatment of advanced cancer of the ovary.
  • ET A R endothelin receptor A
  • L. Rosano et al ⁇ Cancer Res. (2003), 63, 2447-2453 teach that the selective ET A R antagonist ABT-627 (atrasentan) combined with paclitaxel produced additive antitumor, apoptotic and antiangiogenic effects.
  • L. Rosano et al (MoI. Cancer Ther. (2007), 6(7), 2003-2011) disclosed that ZD4054, a specific ET A R antagonist, inhibits tumor growth and enhances paclitaxel activity in human ovarian carcinoma in vitro and in vivo.
  • bosentan produces surprisingly high effects in an in vivo model of ovarian cancer when combined with paclitaxel. Besides, in the same in vivo model, the applicant found that the use of the combination of bosentan with paclitaxel prevents the formation of ascites. As a result, bosentan in combination with paclitaxel may be used for the preparation of a medicament, and is suitable, for the treatment of ovarian cancer and/or the prevention or treatment of ascite formation associated with ovarian cancer.
  • the invention thus firstly relates to a product containing bosentan or a pharmaceutically acceptable salt or hydrate of this compound, in combination with paclitaxel, or a pharmaceutically acceptable salt thereof, and to said product for therapeutic use, simultaneously, separately or over a period of time, in the treatment of ovarian cancer.
  • pharmaceutically acceptable salt refers to non-toxic, inorganic or organic acid and/or base addition salts. Reference can be made to "Salt selection for basic drugs", Int. J. Pharm. (1986), 33, 201-217.
  • hydrate refers herein to products obtained through incorporation of water molecules into their crystalline structure.
  • bosentan monohydrate will be preferred.
  • Simultaneously or “simultaneous”, when referring to a therapeutic use, means in the present application that the therapeutic use concerned consists in the administration of two or more active ingredients by the same route and at the same time.
  • “Separately” or “separate”, when referring to a therapeutic use, means in the present application that the therapeutic use concerned consists in the administration of two or more active ingredients at approximately the same time by at least two different routes.
  • Therapeutic administration over a period of time” also encompasses situations wherein the ingredients are not given with the same periodicity (e.g. wherein one ingredient is given once a day and another is given once a week).
  • prevention of ascite formation or “prevent(ing) ascite formation” is meant in the present application that, following the administration of the appropriate preventive treatment according to this invention, the formation of ascites is either avoided or that this formation is reduced, or, alternatively, that the ascites nevertheless formed are eliminated or reduced.
  • treatment of ascite formation or “treat(ing) ascite formation” is meant in the present application that, following the administration of the appropriate treatment according to this invention, the ascites present in the patient are eliminated or reduced.
  • the product containing bosentan or a pharmaceutically acceptable salt or hydrate of this compound, in combination with paclitaxel, or a pharmaceutically acceptable salt thereof will be for therapeutic use, simultaneously, separately or over a period of time, in the prevention or treatment of ascite formation in patients having ovarian cancer.
  • bosentan or its pharmaceutically acceptable salt or hydrate will be intended to be administered by intravenous or intraperitoneal route.
  • bosentan or its pharmaceutically acceptable salt or hydrate will be intended to be administered by oral route.
  • Paclitaxel or its pharmaceutically acceptable salt will preferably be administered by intravenous or intraperitoneal route.
  • a dose of 0.05 to 30 mg (and preferably 0.1 to 10 mg and more preferably 0.5 to 5 mg) of bosentan per kg of patient body weight per day combined with a dose of 0.1 to 10 mg (and preferably 1 to 3 mg) of paclitaxel per kg of patient body weight per day, will be appropriate.
  • the invention also relates to a pharmaceutical composition containing, as active principles, bosentan or a pharmaceutically acceptable salt or hydrate of this compound, in combination with paclitaxel, or a pharmaceutically acceptable salt thereof, as well as at least one non-toxic excipient.
  • such a pharmaceutical composition will be in a liquid form suitable for intravenous or intraperitoneal administration.
  • said pharmaceutical composition may contain bosentan or a pharmaceutically acceptable salt or hydrate of this compound and paclitaxel or a pharmaceutically acceptable salt thereof, in solution in a mixture of polyoxyethylated castor oil (e.g. Cremophor ® EL) and ethanol (said mixture containing for example from 40 to 60% in volume of polyoxyethylated castor oil in ethanol).
  • polyoxyethylated castor oil e.g. Cremophor ® EL
  • ethanol e.g. Cremophor ® EL
  • bosentan or its pharmaceutically acceptable salt or hydrate of this compound may be formulated as a tablet as for commercial Tracleer ®
  • paclitaxel may be formulated as a solution in a mixture of polyoxyethylated castor oil (e.g. Cremophor ® EL) and ethanol.
  • compositions can be effected in a manner which will be familiar to any person skilled in the art (see for example Remington, The Science and Practice of Pharmacy, 21st Edition (2005), Part 5, "Pharmaceutical Manufacturing” [published by Lippincott Williams & Wilkins]) by bringing the described compounds or their pharmaceutically acceptable salts or hydrates, optionally in combination with other therapeutically valuable substances, into a galenical administration form together with suitable, non-toxic, inert, therapeutically compatible solid or liquid carrier materials and, if desired, usual pharmaceutical adjuvants.
  • the invention further relates to the use of bosentan or a pharmaceutically acceptable salt or hydrate of this compound, in combination with paclitaxel, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament intended to treat ovarian cancer. It also relates to the use of bosentan or a pharmaceutically acceptable salt or hydrate of this compound, in combination with paclitaxel, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament intended to prevent or treat ascite formation in patients having ovarian cancer.
  • the invention further relates to a method of treating a patient having an ovarian cancer by administering to said patient a combination of bosentan or a pharmaceutically acceptable salt or hydrate of this compound, with paclitaxel or a pharmaceutically acceptable salt thereof. It also relates to a method of preventing or treating the formation of ascites in a patient having an ovarian cancer by administering to said patient a combination of bosentan or a pharmaceutically acceptable salt or hydrate of this compound, with paclitaxel or a pharmaceutically acceptable salt thereof.
  • Vehicle solution An aqueous 0.5% (by weight) solution of methylcellulose is prepared by stirring the appropriate quantity of methylcellulose in the appropriate quantity of water for 4 hours. This solution can be prepared up to 3 days in advance. On the day of the experiment, 0.05% (by volume) of Tween 80 is dissolved in the methylcellulose solution previously obtained to yield the vehicle solution.
  • mice 43 mice are injected i.p. with 10 6 SKOV3ipl cells. Ten days later, the tumor weight is evaluated in three of the mice and treatment with a suspension of bosentan in the vehicle solution (10 mice), paclitaxel diluted 1 :6 in phosphate buffered saline (PBS) for i.p. injections (10 mice), a suspension of bosentan in the vehicle solution as well as paclitaxel diluted 1 :6 in PBS for i.p.
  • PBS phosphate buffered saline
  • mice injections (10 mice), or the vehicle solution only (10 mice), is administered to the mice using the following doses, frequencies and routes: ⁇ paclitaxel: 5 mg/kg (125 ⁇ g paclitaxel in 200 ⁇ L PBS per mouse), once a week, i.p. route; ⁇ ⁇ bosentan: 300 mg/kg (as suspension in the vehicle solution at a concentration of up to 25 mg/mL), once a day, oral route.
  • ⁇ paclitaxel 5 mg/kg (125 ⁇ g paclitaxel in 200 ⁇ L PBS per mouse), once a week, i.p. route
  • ⁇ ⁇ bosentan 300 mg/kg (as suspension in the vehicle solution at a concentration of up to 25 mg/mL), once a day, oral route.
  • the combination of bosentan with paclitaxel markedly increased the response to the paclitaxel treatment alone: six out of ten mice were tumor- free after the combination treatment while all mice still had tumors in the paclitaxel-treated group; the average tumor weight in the combination treatment group was close to zero, although in the mice treated with bosentan alone, the tumor weight was on average the same as in the control group and in the mice treated with paclitaxel alone the average tumor weight was still about a third of that in the mice of the control group; and no mouse treated with the combination developed ascites even though 4 out of 10 still had tumors, whereas ascites were present in 4 out of 9 mice treated with paclitaxel alone and in 5 out of 10 mice treated with bosentan alone.

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  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (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

L'invention concerne une combinaison de bosentane avec du paclitaxel, et plus particulièrement, cette combinaison à usage thérapeutique, simultanément, séparement ou durant une certaine période, dans le traitement du cancer des ovaires.
PCT/IB2009/050679 2008-02-20 2009-02-19 Combinaison comprenant du bosentane destinée au traitement du cancer des ovaires WO2009104150A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IBPCT/IB2008/050608 2008-02-20
IB2008050608 2008-02-20

Publications (1)

Publication Number Publication Date
WO2009104150A1 true WO2009104150A1 (fr) 2009-08-27

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Family Applications (1)

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PCT/IB2009/050679 WO2009104150A1 (fr) 2008-02-20 2009-02-19 Combinaison comprenant du bosentane destinée au traitement du cancer des ovaires

Country Status (3)

Country Link
AR (1) AR070457A1 (fr)
TW (1) TW200940061A (fr)
WO (1) WO2009104150A1 (fr)

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
GODARA GEETA ET AL: "Role of endothelin axis in progression to aggressive phenotype of prostate adenocarcinoma", PROSTATE, vol. 65, no. 1, September 2005 (2005-09-01), pages 27 - 34, XP002527398, ISSN: 0270-4137 *
MIKI ADACHI ET AL: "Identification of a region of the human endothelin ETA receptor required for interaction with bosentan", EUROPEAN JOURNAL OF PHARMACOLOGY. MOLECULAR PHARMACOLOGY SECTION, ELSEVIER SCIENCE BV, AMSTERDAM, NL, vol. 269, no. 2, 14 October 1994 (1994-10-14), pages 225 - 234, XP023817030, ISSN: 0922-4106, [retrieved on 19941014] *
ROSANO LAURA ET AL: "ZD4054, a potent endothelin receptor A antagonist, inhibits ovarian carcinoma cell proliferation", EXPERIMENTAL BIOLOGY AND MEDICINE (MAYWOOD), vol. 231, no. 6, June 2006 (2006-06-01), pages 1132 - 1135, XP002527397, ISSN: 1535-3702 *

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AR070457A1 (es) 2010-04-07
TW200940061A (en) 2009-10-01

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