US20130317048A1 - Combination comprising paclitaxel for treating ovarian cancer - Google Patents
Combination comprising paclitaxel for treating ovarian cancer Download PDFInfo
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- US20130317048A1 US20130317048A1 US13/957,126 US201313957126A US2013317048A1 US 20130317048 A1 US20130317048 A1 US 20130317048A1 US 201313957126 A US201313957126 A US 201313957126A US 2013317048 A1 US2013317048 A1 US 2013317048A1
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- paclitaxel
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- pharmaceutically acceptable
- acceptable salt
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- JGCMEBMXRHSZKX-UHFFFAOYSA-N CCCNS(=O)(=O)NC1=C(C2=CC=C(Br)C=C2)C(OCCOC2=NC=C(Br)C=N2)=NC=N1 Chemical compound CCCNS(=O)(=O)NC1=C(C2=CC=C(Br)C=C2)C(OCCOC2=NC=C(Br)C=N2)=NC=N1 JGCMEBMXRHSZKX-UHFFFAOYSA-N 0.000 description 5
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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
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
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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
- A61K31/395—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
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/10—Antioedematous agents; Diuretics
Definitions
- the present invention concerns the combination of an endothelin receptor antagonist of formula (I)
- 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.
- endothelin receptor antagonists including the compound of formula (I) (the International Nonproprietary Name of which is macitentan) and the use of said endothelin receptor antagonists in the treatment of various diseases, including cancer in general.
- 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.
- ZD4054 a specific ET A R antagonist, inhibits tumor growth and enhances paclitaxel activity in human ovarian carcinoma in vitro and in vivo.
- the compound of formula (I) which is both an ET A R and an ET B R antagonist, produces surprisingly high effects in several in vivo models of ovarian cancer when combined with paclitaxel. Besides, in one of these in vivo models, the applicant found that the use of the combination of the compound of formula (I) with paclitaxel prevents or treats the formation of ascites. As a result, the compound of formula (I) 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 the compound of formula (I) below
- 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.
- “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” is meant in the present application the administration of two or more ingredients at different times, and in particular an administration method according to which the entire administration of one of the active ingredients is completed before the administration of the other or others begins. In this way it is possible to administer one of the active ingredients for several months before administering the other active ingredient or ingredients. In this case, no simultaneous administration occurs.
- 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 “preventing 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 “treating 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 the abovementioned compound of formula (I) or a pharmaceutically acceptable salt 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.
- the compound of formula (I) or its pharmaceutically acceptable salt will be intended to be administered by intravenous or intraperitoneal route.
- the compound of formula (I) or its pharmaceutically acceptable salt 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 0.01 to 10 mg (and preferably 0.1 to 5 mg and more preferably 0.1 to 1 mg) of compound of formula (I) 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, the compound of formula (I) as defined previously, or a pharmaceutically acceptable salt 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 the compound of formula (I) or a pharmaceutically acceptable salt 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 said mixture containing for example from 40 to 60% in volume of polyoxyethylated castor oil in ethanol.
- the compound of formula (I) may be formulated as a tablet as described in WO 2007/031933, whereas paclitaxel may be formulated as a solution in a mixture of polyoxyethylated castor oil (e.g. Cremophor® EL) and ethanol.
- polyoxyethylated castor oil e.g. Cremophor® EL
- 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, 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 the compound of formula (I) as defined previously, or a pharmaceutically acceptable salt 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 the compound of formula (I) as defined previously, or a pharmaceutically acceptable salt 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 the compound of formula (I) as defined previously or a pharmaceutically acceptable salt 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 the compound of formula (I) as defined previously or a pharmaceutically acceptable salt of this compound, with paclitaxel or a pharmaceutically acceptable salt thereof.
- aqueous 0.5% (by weight) solution of methylcellulose is prepared by stiffing 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 SKOV3ip1 cells. Ten days later, the tumor weight is evaluated in three of the mice.
- the tumor incidence and weight are determined in each of the mice.
- the ascite incidence and volume are also determined.
- Tumor Treatment Body weight g
- Tumor weight g
- group Mean ⁇ S.D. incidence Median range
- p Control 23.1 ⁇ 2.5 8/10 1.1 (0-1.8)
- 0.1-0.5 0.01
- CF(I) 25.5 ⁇ 2.6 7/10 2.3 (0-4.6)
- S.D. standard deviation
- CF(I) compound of formula (I)
- the vehicle solution is the same as that described for the “Human SKOV3ip1 tumor growth inhibition assay in mice” (see above).
- mice 43 female nude mice are injected i.p. with 10 6 IGROV cells into the peritoneal cavity. Ten days later, the tumor weight is evaluated in three of the mice.
- the tumor incidence and weight are determined in each of the mice.
- Body Treatment weight g
- Tumor Tumor weight g
- group Mean ⁇ S.D. incidence Median range
- p Control 28.0 ⁇ 3.2 10/10 1.1
- Paclitaxel 28.5 ⁇ 2.4 9/10 0.5
- 0.057 CF(I) 31.0 ⁇ 4.4 10/10 0.7 (0.4-1.3) 0.195
- Paclitaxel + CF(I) 29.4 ⁇ 6.1 9/10 0.3 (0-0.6)
- S.D. standard deviation
- CF(I) compound of formula (I)
- the maximal tumor size reduction was achieved in the human IGROV tumor model in mice using the combination of the compound of formula (I) with paclitaxel.
- the vehicle solution is the same as that described for the “Human SKOV3ip1 tumor growth inhibition assay in mice” (see above).
- mice 43 female nude mice are injected i.p. with 10 6 HeyA8-MDR cells into the peritoneal cavity. Ten days later, the tumor weight is evaluated in three of the mice. Mice groups and treatments (doses, frequencies and routes) for the mice groups are the same as those described in the experimental procedure for the “Human IGROV tumor growth inhibition assay in mice” (see above). After 4 weeks of treatment, the tumor incidence and weight are determined in each of the mice.
- Body Treatment weight g
- Tumor Tumor weight g
- group Mean ⁇ S.D. incidence Median range
- p Control 28.5 ⁇ 2.8 10/10 1.1
- Paclitaxel 27.7 ⁇ 3.7 10/10 1.0 (0.5-2.3) 0.52 CF(I) 27.0 ⁇ 2.2 6/10 0.1 (0-0.3) 0.004
- Paclitaxel + CF(I) 27.0 ⁇ 3.0 5/10 0.025 (0-0.7) 0.0005 S.D. standard deviation
- CF(I) compound of formula (I)
- the maximal tumor size reduction was achieved in the multi-drug resistant human ovarian HeyA8-MDR tumor model in mice using the combination of the compound of formula (I) with paclitaxel. Using this combination, half of the mice treated were tumor-free at the end of the treatment.
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Abstract
Description
- This application is a continuation of U.S. application Ser. No. 12/867,939, which application was filed on Aug. 17, 2010 under 35 U.S.C. §371 claiming benefit of PCT Application No. PCT/IB2009/050677, filed on Feb. 19, 2009, which claims the benefit of PCT Application No. PCT/IB2008/050607, filed on Feb. 20, 2008, the contents of each of which are incorporated herein by reference.
- The present invention concerns the combination of an endothelin receptor antagonist of formula (I)
- 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.
- PCT publication WO 02/053557 describes endothelin receptor antagonists including the compound of formula (I) (the International Nonproprietary Name of which is macitentan) and the use of said endothelin receptor antagonists in the treatment of various diseases, including cancer in general.
- 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.
- The combination of endothelin receptor A (ETAR) antagonists with paclitaxel in the treatment of ovarian cancer has already been suggested in literature.
- For example, L. Rosano et al (Cancer Res. (2003), 63, 2447-2453) teach that the selective ETAR antagonist ABT-627 (atrasentan) combined with paclitaxel produced additive antitumor, apoptotic and antiangiogenic effects.
- Besides, L. Rosano et al (Mol. Cancer Ther. (2007), 6(7), 2003-2011) disclosed that ZD4054, a specific ETAR antagonist, inhibits tumor growth and enhances paclitaxel activity in human ovarian carcinoma in vitro and in vivo.
- On the other hand, L. Rosano et al (Mol. Cancer Ther. (2006), 5(4), 833-842) also showed that BQ 788, a selective endothelin receptor B (ETBR) antagonist, contrarily to ETAR antagonists, was ineffective in inhibiting cell adhesiveness of ovarian tumor cells in vitro.
- The applicant has now found that the compound of formula (I), which is both an ETAR and an ETBR antagonist, produces surprisingly high effects in several in vivo models of ovarian cancer when combined with paclitaxel. Besides, in one of these in vivo models, the applicant found that the use of the combination of the compound of formula (I) with paclitaxel prevents or treats the formation of ascites. As a result, the compound of formula (I) 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 the compound of formula (I) below
- or a pharmaceutically acceptable salt of this compound, in combination with paclitaxel, or a pharmaceutically acceptable salt thereof, as well as to said product for therapeutic use, simultaneously, separately or over a period of time, in the treatment of ovarian cancer.
- The following paragraphs provide definitions of the various terms used in the present patent application and are intended to apply uniformly throughout the specification and claims, unless an otherwise expressly set out definition provides a broader or narrower definition.
- The term “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.
- “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.
- By therapeutic administration “over a period of time” is meant in the present application the administration of two or more ingredients at different times, and in particular an administration method according to which the entire administration of one of the active ingredients is completed before the administration of the other or others begins. In this way it is possible to administer one of the active ingredients for several months before administering the other active ingredient or ingredients. In this case, no simultaneous administration occurs. 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).
- By “prevention of ascite formation” or “preventing 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.
- By “treatment of ascite formation” or “treating 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.
- In a preferred embodiment of this invention, the product containing the abovementioned compound of formula (I) or a pharmaceutically acceptable salt 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.
- According to one variant of this invention, the compound of formula (I) or its pharmaceutically acceptable salt will be intended to be administered by intravenous or intraperitoneal route.
- According to another variant of this invention, the compound of formula (I) or its pharmaceutically acceptable salt will be intended to be administered by oral route.
- Paclitaxel or its pharmaceutically acceptable salt will preferably be administered by intravenous or intraperitoneal route.
- Though the exact administration doses of a product according to this invention will have to be determined by the treating physician, it is expected that a dose of 0.01 to 10 mg (and preferably 0.1 to 5 mg and more preferably 0.1 to 1 mg) of compound of formula (I) 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, the compound of formula (I) as defined previously, or a pharmaceutically acceptable salt of this compound, in combination with paclitaxel, or a pharmaceutically acceptable salt thereof, as well as at least one non-toxic excipient.
- Preferably, such a pharmaceutical composition will be in a liquid form suitable for intravenous or intraperitoneal administration. In particular, said pharmaceutical composition may contain the compound of formula (I) or a pharmaceutically acceptable salt 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).
- Alternatively, the compound of formula (I) may be formulated as a tablet as described in WO 2007/031933, whereas paclitaxel may be formulated as a solution in a mixture of polyoxyethylated castor oil (e.g. Cremophor® EL) and ethanol.
- The production of the pharmaceutical 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, 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 the compound of formula (I) as defined previously, or a pharmaceutically acceptable salt 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 the compound of formula (I) as defined previously, or a pharmaceutically acceptable salt 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 the compound of formula (I) as defined previously or a pharmaceutically acceptable salt 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 the compound of formula (I) as defined previously or a pharmaceutically acceptable salt of this compound, with paclitaxel or a pharmaceutically acceptable salt thereof.
- Besides, preferences indicated for the product according to this invention of course apply mutatis mutandis to the pharmaceutical compositions and uses of this invention.
- Particular embodiments of the invention are described in the following section, which serves to illustrate the invention in more detail without limiting its scope in any way.
- An aqueous 0.5% (by weight) solution of methylcellulose is prepared by stiffing 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.
- 43 mice are injected i.p. with 106 SKOV3ip1 cells. Ten days later, the tumor weight is evaluated in three of the mice. Treatment with a suspension of the compound of formula (I) in the vehicle solution (10 mice), paclitaxel (Mead Johnson, Princeton, N.J., USA) diluted 1:6 in phosphate buffered saline (PBS) for i.p. injections (10 mice), a suspension of the compound of formula (I) in the vehicle solution as well as paclitaxel diluted 1:6 in PBS for further dilution and i.p. injections (10 mice), or the vehicle solution only (10 mice), the vehicle solution being as described above, is administered to the mice using the following doses, frequencies and routes:
-
- paclitaxel: 5 mg/kg (125 μg paclitaxel in 200 μL PBS per mouse), once a week, i.p. route;
- compound of formula (I): 100 mg/kg (as suspension in the vehicle solution at a concentration of up to 25 mg/mL), once a day, oral route.
- After one month of treatment, the tumor incidence and weight are determined in each of the mice. At the same time, the ascite incidence and volume are also determined.
- The following results were obtained with respect to tumor incidence and weight:
-
Tumor Treatment Body weight (g) Tumor weight (g) group Mean ± S.D. incidence Median (range) p Control 23.1 ± 2.5 8/10 1.1 (0-1.8) Paclitaxel 23.6 ± 1.9 9/9 0.4 (0.1-0.5) 0.01 CF(I) 25.5 ± 2.6 7/10 2.3 (0-4.6) 0.08 Paclitaxel + CF(I) 23.3 ± 2.3 5/9 0.1 (0-0.3) 0.001 S.D. = standard deviation CF(I) = compound of formula (I) - The following results were obtained with respect to ascite incidence and volume:
-
Treatment Body weight (g) Ascite Ascites (mL) group Mean ± S.D. incidence Median (range) p Control 23.1 ± 2.5 8/10 0.4 (0-0.9) Paclitaxel 23.6 ± 1.9 4/9 0.1 (0-0.2) 0.005 CF(I) 25.5 ± 2.6 7/10 0.4 (0-4.7) 0.27 Paclitaxel + CF(I) 23.3 ± 2.3 0/9 0 0.002 S.D. = standard deviation CF(I) = compound of formula (I) - As can be seen, the combination of the compound of formula (I) with paclitaxel markedly increased the response to the paclitaxel treatment alone:
-
- four out of nine mice were tumor-free after the combination treatment while all mice still had tumors in the paclitaxel-treated group;
- the tumor was on average four times bigger in the paclitaxel-treated group than in the combination treated group; and
- no mouse treated with the combination developed ascites even though 5 out of 9 still had tumors, whereas ascites were present in 4 out of 9 mice treated with paclitaxel alone and in 7 out of 10 mice treated with the compound of formula (I) alone.
- The vehicle solution is the same as that described for the “Human SKOV3ip1 tumor growth inhibition assay in mice” (see above).
- 43 female nude mice are injected i.p. with 106 IGROV cells into the peritoneal cavity. Ten days later, the tumor weight is evaluated in three of the mice. Treatment with a suspension of the compound of formula (I) in the vehicle solution (10 mice), paclitaxel diluted 1:6 in phosphate buffered saline (PBS) for i.p. injections (10 mice), a suspension of the compound of formula (I) in the vehicle solution as well as paclitaxel diluted 1:6 in PBS for i.p. injections (10 mice), or the vehicle solution only (10 mice), the vehicle solution being as described above, is administered to the mice using the following doses, frequencies and routes:
-
- paclitaxel: 5 mg/kg (125 μg paclitaxel in 200 μL PBS per mouse), once a week, i.p. route;
- compound of formula (I): 50 mg/kg (as suspension in the vehicle solution at a concentration of up to 25 mg/mL), once a day, oral route.
- After 4 weeks of treatment, the tumor incidence and weight are determined in each of the mice.
- The following results were obtained with respect to tumor incidence and weight:
-
Body Treatment weight (g) Tumor Tumor weight (g) group Mean ± S.D. incidence Median (range) p Control 28.0 ± 3.2 10/10 1.1 (0.4-2.1) Paclitaxel 28.5 ± 2.4 9/10 0.5 (0-0.9) 0.057 CF(I) 31.0 ± 4.4 10/10 0.7 (0.4-1.3) 0.195 Paclitaxel + CF(I) 29.4 ± 6.1 9/10 0.3 (0-0.6) 0.0006 S.D. = standard deviation CF(I) = compound of formula (I) - As can be seen, the maximal tumor size reduction was achieved in the human IGROV tumor model in mice using the combination of the compound of formula (I) with paclitaxel.
- The vehicle solution is the same as that described for the “Human SKOV3ip1 tumor growth inhibition assay in mice” (see above).
- 43 female nude mice are injected i.p. with 106 HeyA8-MDR cells into the peritoneal cavity. Ten days later, the tumor weight is evaluated in three of the mice. Mice groups and treatments (doses, frequencies and routes) for the mice groups are the same as those described in the experimental procedure for the “Human IGROV tumor growth inhibition assay in mice” (see above). After 4 weeks of treatment, the tumor incidence and weight are determined in each of the mice.
- The following results were obtained with respect to tumor incidence and weight:
-
Body Treatment weight (g) Tumor Tumor weight (g) group Mean ± S.D. incidence Median (range) p Control 28.5 ± 2.8 10/10 1.1 (0.1-3.2) Paclitaxel 27.7 ± 3.7 10/10 1.0 (0.5-2.3) 0.52 CF(I) 27.0 ± 2.2 6/10 0.1 (0-0.3) 0.004 Paclitaxel + CF(I) 27.0 ± 3.0 5/10 0.025 (0-0.7) 0.0005 S.D. = standard deviation CF(I) = compound of formula (I) - As can be seen, the maximal tumor size reduction was achieved in the multi-drug resistant human ovarian HeyA8-MDR tumor model in mice using the combination of the compound of formula (I) with paclitaxel. Using this combination, half of the mice treated were tumor-free at the end of the treatment.
Claims (9)
2. A method for the treatment of ovarian cancer, comprising administering, simultaneously, separately or over a period of time, to a patient in need thereof, a compound of formula (I):
3. The method according to claim 2 , wherein the compound of formula (I) in free or a pharmaceutically acceptable salt form is administered by intravenous or intraperitoneal route.
4. The method according to claim 2 , wherein the compound of formula (I) in free or a pharmaceutically acceptable salt form is administered by oral route.
5. The method according to claim 2 , wherein paclitaxel in free or a pharmaceutically acceptable salt form is administered by intravenous or intraperitoneal route.
6. A pharmaceutical composition containing, as active principle, the product of claim 1 , as well as at least one non-toxic excipient.
7. The pharmaceutical composition according to claim 6 , which is in a liquid form suitable for intravenous or intraperitoneal administration.
8. The pharmaceutical composition according to claim 7 , which contains the compound of formula (I), in free or a pharmaceutically acceptable salt form, and paclitaxel, in free or a pharmaceutically acceptable salt form, in solution in a mixture of polyoxyethylated castor oil and ethanol.
9. The pharmaceutical composition according to claim 8 , wherein the mixture of polyoxyethylated castor oil and ethanol is such that it contains from 40 to 60% in volume of polyoxyethylated castor oil in ethanol.
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US13/957,126 US20130317048A1 (en) | 2008-02-20 | 2013-08-01 | Combination comprising paclitaxel for treating ovarian cancer |
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IB2008050607 | 2008-02-20 | ||
IBPCT/IB2008/050607 | 2008-02-20 | ||
PCT/IB2009/050677 WO2009104149A1 (en) | 2008-02-20 | 2009-02-19 | Combination comprising paclitaxel for treating ovarian cancer |
US86793910A | 2010-08-17 | 2010-08-17 | |
US13/957,126 US20130317048A1 (en) | 2008-02-20 | 2013-08-01 | Combination comprising paclitaxel for treating ovarian cancer |
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PCT/IB2009/050677 Continuation WO2009104149A1 (en) | 2008-02-20 | 2009-02-19 | Combination comprising paclitaxel for treating ovarian cancer |
US86793910A Continuation | 2008-02-20 | 2010-08-17 |
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US20130317048A1 true US20130317048A1 (en) | 2013-11-28 |
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US13/957,126 Abandoned US20130317048A1 (en) | 2008-02-20 | 2013-08-01 | Combination comprising paclitaxel for treating ovarian cancer |
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EP (1) | EP2254570B1 (en) |
JP (1) | JP5514123B2 (en) |
KR (1) | KR20100132489A (en) |
CN (1) | CN101939001B (en) |
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AU (1) | AU2009215329B2 (en) |
CA (1) | CA2714608A1 (en) |
CY (1) | CY1115071T1 (en) |
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HR (1) | HRP20140215T1 (en) |
MX (1) | MX2010008994A (en) |
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PT (1) | PT2254570E (en) |
RU (1) | RU2494736C2 (en) |
SI (1) | SI2254570T1 (en) |
TW (1) | TWI441639B (en) |
WO (1) | WO2009104149A1 (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9173881B2 (en) | 2008-08-13 | 2015-11-03 | Actelion Pharmaceuticals Ltd. | Therapeutic compositions containing macitentan |
US9265762B2 (en) | 2005-09-12 | 2016-02-23 | Actelion Pharmaceuticals Ltd. | Stable pharmaceutical compositions comprising a pyrimidine-sulfamide |
Families Citing this family (6)
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MX2010001837A (en) | 2007-08-17 | 2010-03-10 | Actelion Pharmaceuticals Ltd | Iron with actively cooled soleplate and method for cooling the soleplate. |
TWI441639B (en) * | 2008-02-20 | 2014-06-21 | Actelion Pharmaceuticals Ltd | Combination comprising paclitaxel for treating ovarian cancer |
SG178828A1 (en) | 2009-08-10 | 2012-04-27 | Univ Texas | Treatment of brain metastases with inhibitors of endothelin receptors in combination with a cytotoxic chemotherapy agent |
JP5642892B2 (en) | 2011-02-04 | 2014-12-17 | アクテリオン ファーマシューティカルズ リミテッドActelion Pharmaceuticals Ltd | A combination containing macitentan for the treatment of glioblastoma multiforme |
CN103819411A (en) * | 2014-03-14 | 2014-05-28 | 成都克莱蒙医药科技有限公司 | New preparation method of macitentan intermediate |
KR102359214B1 (en) | 2014-04-04 | 2022-02-07 | 델 마 파마슈티컬스 | Use of dianhydrogalactitol and analogs or derivatives thereof to treat non-small-cell carcinoma of the lung and ovarian cancer |
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US8541433B2 (en) * | 2008-02-20 | 2013-09-24 | Actelion Pharmaceuticals, Ltd. | Combination comprising macitentan and paclitaxel for treating multi-drug resistant ovarian cancer |
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TW406020B (en) * | 1993-09-29 | 2000-09-21 | Bristol Myers Squibb Co | Stabilized pharmaceutical composition and its method for preparation and stabilizing solvent |
US7094781B2 (en) * | 2000-12-18 | 2006-08-22 | Actelion Pharmaceuticals Ltd. | Sulfamides and their use as endothelin receptor antagonists |
AU2003286647B2 (en) | 2002-10-24 | 2009-11-05 | The Board Of Trustees Of The University Of Illinois | Method and composition for preventing and treating solid tumors |
US20040121971A1 (en) | 2002-12-20 | 2004-06-24 | Gang Chen | Therapeutic use of tumor necrosis factor-alpha mutein |
GB0425854D0 (en) | 2004-11-25 | 2004-12-29 | Astrazeneca Ab | Therapeutic treatment |
SI1928409T1 (en) | 2005-09-12 | 2012-12-31 | Actelion Pharmaceuticals Ltd. | Stable pharmaceutical composition comprising a pyrimidine-sulfamide |
AR062501A1 (en) | 2006-08-29 | 2008-11-12 | Actelion Pharmaceuticals Ltd | THERAPEUTIC COMPOSITIONS |
KR20100005486A (en) * | 2008-07-07 | 2010-01-15 | 페어차일드코리아반도체 주식회사 | Switch control device and converter comprising the same |
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2009
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- 2009-02-19 SI SI200930849T patent/SI2254570T1/en unknown
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- 2009-02-19 ES ES09712334.3T patent/ES2446303T3/en active Active
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- 2009-02-19 PT PT97123343T patent/PT2254570E/en unknown
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Patent Citations (1)
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US8541433B2 (en) * | 2008-02-20 | 2013-09-24 | Actelion Pharmaceuticals, Ltd. | Combination comprising macitentan and paclitaxel for treating multi-drug resistant ovarian cancer |
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Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9265762B2 (en) | 2005-09-12 | 2016-02-23 | Actelion Pharmaceuticals Ltd. | Stable pharmaceutical compositions comprising a pyrimidine-sulfamide |
US10117870B2 (en) | 2005-09-12 | 2018-11-06 | Actelion Pharmaceuticals Ltd. | Stable pharmaceutical compositions comprising a pyrimidine-sulfamide |
US10946015B2 (en) | 2005-09-12 | 2021-03-16 | Actelion Pharmaceuticals Ltd | Stable pharmaceutical compositions comprising a pyrimidine-sulfamide |
US11648249B2 (en) | 2005-09-12 | 2023-05-16 | Actelion Pharmaceuticals Ltd | Stable pharmaceutical compositions comprising a pyrimidine-sulfamide |
US9173881B2 (en) | 2008-08-13 | 2015-11-03 | Actelion Pharmaceuticals Ltd. | Therapeutic compositions containing macitentan |
US9597331B2 (en) | 2008-08-13 | 2017-03-21 | Actelion Pharmaceuticals Ltd. | Therapeutic compositions containing macitentan |
Also Published As
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TW200940062A (en) | 2009-10-01 |
CN101939001B (en) | 2012-06-20 |
AR070456A1 (en) | 2010-04-07 |
AU2009215329A1 (en) | 2009-08-27 |
ES2446303T3 (en) | 2014-03-07 |
JP5514123B2 (en) | 2014-06-04 |
RU2494736C2 (en) | 2013-10-10 |
EP2254570A1 (en) | 2010-12-01 |
SI2254570T1 (en) | 2014-03-31 |
PL2254570T3 (en) | 2014-05-30 |
TWI441639B (en) | 2014-06-21 |
DK2254570T3 (en) | 2014-02-03 |
MX2010008994A (en) | 2010-09-07 |
CA2714608A1 (en) | 2009-08-27 |
US20100311774A1 (en) | 2010-12-09 |
EP2254570B1 (en) | 2013-12-18 |
RU2010138650A (en) | 2012-03-27 |
JP2011512399A (en) | 2011-04-21 |
AU2009215329B2 (en) | 2014-08-21 |
US8541433B2 (en) | 2013-09-24 |
KR20100132489A (en) | 2010-12-17 |
WO2009104149A1 (en) | 2009-08-27 |
CN101939001A (en) | 2011-01-05 |
HRP20140215T1 (en) | 2014-04-11 |
CY1115071T1 (en) | 2016-12-14 |
PT2254570E (en) | 2014-02-17 |
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