WO2012121957A1 - Association - Google Patents

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Publication number
WO2012121957A1
WO2012121957A1 PCT/US2012/027173 US2012027173W WO2012121957A1 WO 2012121957 A1 WO2012121957 A1 WO 2012121957A1 US 2012027173 W US2012027173 W US 2012027173W WO 2012121957 A1 WO2012121957 A1 WO 2012121957A1
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WO
WIPO (PCT)
Prior art keywords
compound
administered
suitably
thrombocytopenia
administration
Prior art date
Application number
PCT/US2012/027173
Other languages
English (en)
Inventor
Andres BRAINSKY
Original Assignee
Glaxosmithkline Llc
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 Glaxosmithkline Llc filed Critical Glaxosmithkline Llc
Publication of WO2012121957A1 publication Critical patent/WO2012121957A1/fr

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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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/436—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4152—1,2-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. antipyrine, phenylbutazone, sulfinpyrazone

Definitions

  • the present invention relates to a method of treating thrombocytopenia in a mammal, suitably a human, and to combinations useful in such treatment.
  • the method relates to a novel combination comprising tacrolimus: 3S- [3R * [E(1 S ⁇ 3S ⁇ 4S * )],4S * ,5R ⁇ 8S * ,9E, 12R * , 14R * .15S * , 16R * , 18S * , 19S * ,26aR *
  • tacrolimus is marketed as tacrolimus, and is marketed under the trade name Prograf .
  • Tacrolimus is
  • Tacrolimus also FK-506 or Fujimycin
  • IL-2 interleukin-2
  • T-cells T-cells
  • IL-2 interleukin-2
  • It is also used in a topical preparation in the treatment of severe atopic dermatitis (eczema), severe refractory uveitis after bone marrow transplants, and the skin condition vitiligo.
  • eczema severe atopic dermatitis
  • severe refractory uveitis after bone marrow transplants and the skin condition vitiligo.
  • It is a 23-membered macrolide lactone discovered in 1984 from the fermentation broth of a Japanese soil sample that contained the bacteria Streptomyces tsukubaensis.
  • the TPO receptor agonist 3'-[(2Z)-[1 -(3,4-dimethylphenyl)-1 ,5-dihydro-3-methyl- 5-oxo-4H-pyrazol-4-ylidene]hydrazino]-2'-hydroxy-[1 ,1 '-biphenyl]-3-carboxylic acid is known by the generic name eltrombopag.
  • the bis-monoethanolamine salt of eltrombopag is generically known as eltrombopag olamine.
  • Eltrombopag olamine is marketed under the trade name Promacta® in the United States and Revolade® outside the United States.
  • Eltrombopag olamine is represented by the following Structure II:
  • Eltrombopag is a compound which is disclosed and claimed, along with pharmaceutically acceptable salts, hydrates, solvates and esters thereof, as being useful as an agonist of the TPO receptor, particularly in enhancing platelet production and particularly in the treatment of thrombocytopenia, in International Application No. PCT/US01/16863, having an International filing date of May 24, 2001 ; International Publication Number WO 01/89457 and an International Publication date of November 29, 2001 .
  • Eltrombopag is disclosed and claimed as being useful in the treatment of cancer and pre-cancerous syndromes in International Application No. PCT/US08/054046, having an International filing date of February 15, 2008; International Publication Number WO 08/101 141 and an International Publication date of August 21 , 2008.
  • One embodiment of this invention provides a combination comprising: compound of the Structure
  • One embodiment of this invention provides a method of treating thrombocytopenia and transplant rejection in a human in need thereof which comprises the in vivo administration of a therapeutically effective amount of a combination of tacrolimus, and eltrombopag olamine, to such human.
  • One embodiment of this invention provides a method of treating thrombocytopenia and transplant rejection in a human in need thereof which comprises the in vivo administration of a therapeutically effective amount of a combination of tacrolimus, and eltrombopag olamine, to such human,
  • One embodiment of this invention provides a method of treating thrombocytopenia and transplant rejection in a human in need thereof which comprises the in vivo administration of a therapeutically effective amount of a combination of tacrolimus, and eltrombopag olamine, to such human,
  • the present invention relates to combinations that exhibit the ability to enhance platelet production.
  • the method relates to methods of treating thrombocytopenia and transplant rejection by the co-administration of:
  • Compound A is a known immunosuppressive drug compound marketed under the generic name tacrolimus.
  • Tacrolimus can generally be prepared as described in Japanese Kokai Patent Publication No. 61-148181/1986 and European Patent Publication No. 0323042.
  • Compound A is in the form of a monohydrate. Tacrolimus is marketed
  • Eltrombopag is a compound which is disclosed and claimed, along with pharmaceutically acceptable salts, hydrates, solvates and esters thereof, as being useful as an agonist of the TPO receptor, particularly in enhancing platelet production and particularly in the treatment of thrombocytopenia, in International Application No. PCT/US01/16863, having an International filing date of May 24, 2001 ; International Publication Number WO 01/89457 and an International Publication date of November 29, 2001 .
  • Eltrombopag is disclosed and claimed as being useful in the treatment of cancer and pre-cancerous syndromes in International Application No. PCT/US08/054046, having an International filing date of February 15, 2008; International Publication Number WO 08/101 141 and an International Publication date of August 21 , 2008.
  • Compound B is in the form of a bis-monoethanolamine salt.
  • This salt form can be prepared by one of skill in the art from the description in International Application No. PCT/US03/16255 having an International filing date of May 21 , 2003; International Publication Number WO 03/098992 and an International Publication date of December 4, 2003.
  • the administration of a therapeutically effective amount of the combinations of the invention are advantageous over the individual component compounds in that the combinations will provide one or more of the following improved properties when compared to the individual administration of a therapeutically effective amount of a component compound: i) a greater platelet enhancing effect than the most active single agent, ii) a greater effect on transplant rejection than the most active single agent, iii) a dosing protocol that provides enhanced platelet enhancing activity with reduced side effect profile, iv) a dosing protocol that provides enhanced treatment for transplant rejection with reduced side effect profile, v) a reduction in the toxic effect profile, vi) an increase in the therapeutic window, or vii) an increase in the bioavailability of one or both of the component compounds.
  • the compounds of the invention may contain one or more chiral atoms, or may otherwise be capable of existing as two enantiomers. Accordingly, the compounds of this invention include mixtures of enantiomers as well as purified enantiomers or enantiomerically enriched mixtures. Also, it is understood that all tautomers and mixtures of tautomers are included within the scope of Compound A, and pharmaceutically acceptable salts or hydrates thereof, and Compound B, and pharmaceutically acceptable salts thereof.
  • the compounds of the invention may form a solvate which is understood to be a complex of variable stoichiometry formed by a solute (in this invention, Compound A or a salt thereof and/or Compound B or a salt thereof) and a solvent.
  • solvents for the purpose of the invention may not interfere with the biological activity of the solute.
  • suitable solvents include, but are not limited to, water, methanol, dimethyl sulfoxide, ethanol and acetic acid.
  • the solvent used is a pharmaceutically acceptable solvent.
  • the solvent used is water.
  • thrombocytopenia and derivatives thereof as used herein is to be broadly interpreted as any decrease in the number of blood platelets below what is considered normal or desired for a healthy individual. Thrombocytopenia is known to have many causative factors, including but not limited to, radiation therapy, chemotherapy, immune therapy, immune thrombocytopenic purpura (ITP, Bussel J.
  • MDS myelodysplasia syndrome
  • AML aplastic anemia
  • CML viral infections (including, but not limited to; HIV, hepatitis C, parvovirus) liver disease, myeloablation, bone marrow transplant, stem cell transplant, peripheral blood stem cell transplant, progenitor cell defect, polymorphisms in stem cells and progenitor cells, defects in Tpo, neutropenia (Sawai, N. J. Leukocyte Biol., 2000, 68, 137-43), dendritic cell mobilization (Kuter D. J. Seminars in Hematology, 2000, 37, Suppl 4, 41 -49), proliferation, activation or differentiation.
  • the combinations of this invention are advantageous in treating thrombocytopenia as the combination is expected to reduce any adverse immunological effect on platelet production.
  • the combinations of this invention are advantageous in treating transplant rejection as the combination is expected to reduce the adverse side effects, suitably thrombocytopenia, caused by the administration of tacrolimus alone.
  • Prophylactic use of the combinations of this invention is contemplated whenever a decrease in blood or blood platelets is anticipated.
  • Prophylactic use of the combinations of this invention results in a build up of platelets or a commencement of platelet production prior to an anticipated loss of platelets, for example with the use of tacrolimus.
  • contemplated herein is a method of treating thrombocytopenia using a combination of the invention where Compound A, or a pharmaceutically acceptable salt or hydrate thereof, and/or Compound B or a pharmaceutically acceptable salt thereof are administered as pro-drugs.
  • Pharmaceutically acceptable pro-drugs of the compounds of the invention are readily prepared by those of skill in the art.
  • day refers to a time within one calendar day which begins at midnight and ends at the following midnight.
  • treating means: (1 ) to ameliorate or prevent the condition of one or more of the biological manifestations of the condition, (2) to interfere with (a) one or more points in the biological cascade that leads to or is responsible for the condition or (b) one or more of the biological manifestations of the condition, (3) to alleviate one or more of the symptoms, effects or side effects associated with the condition or treatment thereof, or (4) to slow the progression of the condition or one or more of the biological manifestations of the condition.
  • Prophylactic therapy is also contemplated thereby.
  • prevention is not an absolute term.
  • prevention is understood to refer to the prophylactic administration of a drug to substantially diminish the likelihood or severity of a condition or biological manifestation thereof, or to delay the onset of such condition or biological manifestation thereof.
  • Prophylactic therapy is appropriate, for example, when a subject is considered at high risk for developing thrombocytopenia, such as when a subject has a strong family history of thrombocytopenia or when open wounds and cuts can be expected such as when a subject is anticipating surgery.
  • the term "effective amount” means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought, for instance, by a researcher or clinician.
  • therapeutically effective amount means any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder.
  • the term also includes within its scope amounts effective to enhance normal physiological function.
  • ком ⁇ онент and derivatives thereof, as used herein is meant either, simultaneous administration or any manner of separate sequential administration of a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof, and Compound B or a pharmaceutically acceptable salt or solvate thereof.
  • the compounds are administered in a close time proximity to each other.
  • the compounds are administered in the same dosage form, e.g. one compound may be administered topically and the other compound may be administered orally.
  • Compound A is administered by IV and Compound B is administered orally.
  • the combination kit as used herein is meant the pharmaceutical composition or compositions that are used to administer Compound A, or a pharmaceutically acceptable salt or hydrate thereof, and Compound B, or a pharmaceutically acceptable salt thereof, according to the invention.
  • the combination kit can contain Compound A, or a pharmaceutically acceptable salt or hydrate thereof, and Compound B, or a pharmaceutically acceptable salt thereof, in a single pharmaceutical composition, such as a tablet, or in separate pharmaceutical compositions.
  • the combination kit will contain Compound A, or a pharmaceutically acceptable salt or hydrate thereof, and Compound B, or a pharmaceutically acceptable salt thereof, in separate pharmaceutical compositions.
  • the combination kit can comprise Compound A, or a pharmaceutically acceptable salt or hydrate thereof, and Compound B, or a pharmaceutically acceptable salt thereof, in separate pharmaceutical compositions in a single package or in separate pharmaceutical compositions in separate packages.
  • a combination kit comprising the components: Compound A, or a pharmaceutically acceptable salt or hydrate thereof, in association with a pharmaceutically acceptable carrier; and
  • Compound B or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier.
  • a first container comprising Compound A, or a pharmaceutically acceptable salt or hydrate thereof, in association with a pharmaceutically acceptable carrier;
  • a second container comprising Compound B, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier, and a container means for containing said first and second containers.
  • the "combination kit” can also be provided by instruction, such as dosage and administration instructions.
  • dosage and administration instructions can be of the kind that is provided to a doctor, for example by a drug product label, or they can be of the kind that is provided by a doctor, such as instructions to a patient.
  • Compound A means — Compound A, or a pharmaceutically acceptable salt or hydrate, suitably the monohydrate, thereof— .
  • Compound B means — Compound B, or a pharmaceutically acceptable salt, suitably the bis-monoethanolamine salt, thereof— .
  • the combinations of this invention are administered within a "specified period”.
  • the specified period can include simultaneous administration. When both compounds of the invention are administered once a day the specified period refers to timing of the
  • the specified period will be about 24 hours; suitably they will both be administered within about 12 hours of each other - in this case, the specified period will be about 12 hours; suitably they will both be administered within about 1 1 hours of each other - in this case, the specified period will be about 1 1 hours; suitably they will both be administered within about 10 hours of each other - in this case, the specified period will be about 10 hours; suitably they will both be administered within about 9 hours of each other - in this case, the specified period will be about 9 hours; suitably they will both be administered within about 8 hours of each other - in this case, the specified period will be about 8 hours; suitably they will both be administered within about 7 hours of each other - in this case, the specified period will be about 7 hours; suitably they will both be administered within about 6 hours of each other - in this case, the specified period will be about 6 hours; suit
  • Compound A and Compound B in less than about 45 minutes apart is considered simultaneous administration.
  • the compounds when the combination of the invention is administered for a "specified period", the compounds will be co-administered for a "duration of time".
  • duration of time and derivatives thereof, as used herein is meant that both compounds of the invention are administered within a "specified period" for an indicated number of consecutive days, optionally followed by a number of consecutive days where only one of the component compounds is administered.
  • the “duration of time” and in all dosing protocols described herein do not have to commence with the start of treatment and terminate with the end of treatment, it is only required that the number of consecutive days in which both compounds are administered and the optional number of consecutive days in which only one of the component compounds is administered, or the indicated dosing protocol, occur at some point during the course of treatment.
  • both compounds will be administered within a specified period for at least 1 day - in this case, the duration of time will be at least 1 day; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 2 consecutive days - in this case, the duration of time will be at least 2 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 3 consecutive days - in this case, the duration of time will be at least 3 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 5 consecutive days - in this case, the duration of time will be at least 5 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 7 consecutive days - in this case, the duration of time will be at least 7 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 14 consecutive days - in this case, the duration of time will be at least 14 days; suitably,
  • both compounds are administered within a specified period for over 30 days, the treatment is considered chronic treatment and will continue until an altering event, such as a reassessment in cancer status or a change in the condition of the patient, warrants a modification to the protocol.
  • both compounds will be administered within a specified period for at least 1 day, followed by the administration of Compound
  • the duration of time will be at least 2 days; suitably, during the course of treatment, both compounds will be administered within a
  • the duration of time will be at least 3 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 1 day, followed by administration of Compound A alone for at least 2 days - in this case, the duration of time will be at least 3 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at
  • the duration of time will be at least 4 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 1 day, followed
  • the duration of time will be at least 5 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 1 day, followed by administration of
  • the duration of time will be at least 7 days; suitably, during the course of treatment, both compounds will be administered within a
  • the duration of time will be at least 8 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 1 day, followed by administration of Compound A alone for at least 7 days - in this case, the duration of time will be at least 8 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at
  • the duration of time will be at least 3 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 2
  • the duration of time will be at least 4 days; suitably, during the course of treatment, both compounds will be administered within a specified
  • the duration of time will be at least 5 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 2 consecutive days, followed by administration of Compound
  • the duration of time will be at least 6 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 2 consecutive days, followed by administration of
  • the duration of time will be at least 8 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 2 consecutive days,
  • the duration of time will be at least 9 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 3 consecutive
  • the duration of time will be at least 4 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 3 consecutive days,
  • the duration of time will be at least 5 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 3 consecutive
  • the duration of time will be at least 6 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 3
  • the duration of time will be at least 7 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 3 consecutive days, followed by administration of Compound A alone for at least 5 consecutive days - in this case, the duration of time will be at least 8 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 3 consecutive days, followed by administration of Compound
  • the duration of time will be at least 9 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 3 consecutive days, followed by administration of
  • the duration of time will be at least 10 days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 4 consecutive days, followed by
  • the duration of time will be at least 5 consecutive days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 4 consecutive days,
  • the duration of time will be at least 6 consecutive days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 4
  • the duration of time will be at least 7 consecutive days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 4 consecutive days, followed by administration of Compound
  • the duration of time will be at least 8 consecutive days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 4 consecutive days, followed by
  • the duration of time will be at least 1 1 consecutive days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 5
  • the duration of time will be at least 6 consecutive days; suitably, during the course of treatment, both compounds will be administered within a specified period for at
  • the duration of time will be at least 7 consecutive days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 5 consecutive days, followed by administration of Compound
  • the duration of time will be at least
  • both compounds will be administered within a specified period for at least 5 consecutive days, followed by
  • the duration of time will be at least 9 consecutive days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 5
  • the duration of time will be at least 10 consecutive days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 7 consecutive days, followed by administration of Compound
  • the duration of time will be at least
  • both compounds will be administered within a specified period for at least 14 consecutive days, followed by
  • the duration of time will be at least 21 consecutive days; suitably, during the course of treatment, both compounds will be administered within a specified period for at least 30
  • both compounds will be administered within a specified period for from 1 to 3 consecutive days, followed by administration of
  • both compounds will be administered within a specified period for 5 consecutive days, followed by administration
  • both compounds will be administered within a specified period for 2 consecutive days,
  • both compounds will be administered within a specified period for from 1 to 3 days over a 7 day period, and during the other days of the 7 day period Compound A will be administered alone.
  • both compounds will be administered within a specified period for 2 days over
  • Compound B is subsequently administered for 1 or more consecutive days. Unless otherwise defined, the "sequential administration" and in all dosing protocols described herein, do not have to commence with the start of treatment and terminate with the end of
  • Compound B or the indicated dosing protocol, occur at some point during the course of treatment. Also, contemplated herein is a drug holiday utilized between the sequential
  • a drug holiday is a period of days after the
  • the drug holiday will be a period of days selected from: 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 1 1 days, 12 days, 13 days and 14 days.
  • one of Compound A and Compound B is administered for from 1 to 30 consecutive days, followed by an optional drug holiday, followed by administration of the
  • one of Compound A and Compound B is administered for from 1 to 21 consecutive days, followed by an optional drug holiday, followed by administration of the other of
  • Compound A and Compound B for from 1 to 21 consecutive days.
  • Compound A and Compound B is administered for from 1 to 14 consecutive days, followed by a drug holiday of from 1 to 14 days, followed by administration of the other of
  • Compound A and Compound B for from 1 to 14 consecutive days.
  • Compound A and Compound B is administered for from 2 to 7 consecutive days, followed by a drug holiday of from 2 to 10 days, followed by administration of the other of
  • Compound B will be administered first in the sequence, followed by an
  • B is administered for from 1 to 21 consecutive days, followed by an optional drug
  • Compound B is administered for from 3 to 21 consecutive days, followed by a
  • Compound B is administered for from 3 to 21 consecutive days, followed by a drug holiday of from 3 to 14 days, followed by
  • Compound A for from 3 to 21 consecutive days.
  • Compound A for from 3 to 21 consecutive days.
  • B is administered for 21 consecutive days, followed by an optional drug holiday, followed by
  • Compound A for 14 consecutive days.
  • Compound B is administered for 14 consecutive days, followed by a drug holiday of from 1 to 14 days,
  • Compound B is administered for 7 consecutive days, followed by a drug holiday of from
  • Compound B is administered for 3 consecutive days, followed by a drug
  • Compound B is administered for 3 consecutive days, followed by a drug holiday of from 3 to 10 days, followed by administration of Compound
  • Compound A will be administered first in the sequence, followed by an
  • A is administered for from 1 to 21 consecutive days, followed by an optional drug
  • Compound A is administered for from 3 to 21 consecutive days, followed by a
  • Compound A is administered for from 3 to 21 consecutive days, followed by a drug holiday of from 3 to 14 days, followed by
  • A is administered for 21 consecutive days, followed by an optional drug holiday, followed by
  • Compound B is administered for 14 consecutive days, followed by a drug holiday of from 1 to 14 days,
  • Compound A is administered for 7 consecutive days, followed by a drug holiday of from
  • Compound A is administered for 3 consecutive days, followed by a drug
  • Compound A is administered for 3 consecutive days, followed by a drug holiday of from 3 to 10 days, followed by administration of Compound
  • Compound A is administered for 7 consecutive days.
  • Compound A is N-(2-aminoethyl)-2 2 days, followed by administration of Compound B for 1 day.
  • Compound A is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2 2 2 days, followed by administration of Compound B for 1 day.
  • Compound A is N-(2-aminoethyl)-2 2 days, followed by administration of Compound B for 1 day.
  • Compound B is administered for 1 day, followed by administration of
  • Compound A for 7 consecutive days.
  • Compound B is administered for 1 day,
  • the dosing protocol will be:
  • a daily oral dose selected from: about 0.5mg, about 1 mg and about 5mg, by weight of the free or unsalted compound;
  • a daily oral dose of a combination independently selected from 2 or 3 of the following: about 0.5mg, about 1 mg and about 5mg, by weight of the free or unsalted compound;
  • a daily intravenous infusion selected from 0.01 mg/kg/day to about 0.05 mg/kg/day;
  • a daily dose selected from: about 12.5mg, about 25mg, about 50mg, about 75mg, and about 10Omg, by weight of the free or unsalted compound;
  • the selected combination is suitably administered for a week, suitably for a month, suitably for a year, suitably for over one year.
  • the amount of Compound A administered as part of the combination according to the present invention will be an amount selected from about 0.5mg to about
  • the amount of Compound B administered as part of the combination according to the present invention can be 0.5mg, 1 mg, 1 .5mg, 2mg, 2.5mg, 3mg, 3.5mg, 4mg, 4.5mg, 5mg, 5.5mg, 6mg, 6.5mg, 7mg, 7.5mg, 8mg, 8.5mg, 9mg, 9.5mg, 10mg.
  • the amount of Compound A administered as part of the combination according to the present invention will be an amount selected from about 12.5mg to about 100mg.
  • the amount of Compound B administered as part of the combination according to the present invention can be 12.5mg, 25mg, 50mg, 75mg, 100mg.
  • the method of the present invention may also be employed with other therapeutic methods to increase platelet count, and for the treatment of thrombocytopenia.
  • compositions While it is possible that, for use in therapy, therapeutically effective amounts of the combinations of the present invention may be administered as the raw chemical, it is preferable to present the combinations as a pharmaceutical composition or compositions.
  • compositions which include
  • Compound A and/or Compound B and one or more pharmaceutically acceptable carriers.
  • the combinations of the present invention are as described above.
  • the carrier(s) must be acceptable in the sense of being compatible with the other ingredients of the formulation, capable of pharmaceutical formulation, and not deleterious to the recipient thereof.
  • a process for the preparation of a pharmaceutical formulation including admixing
  • Compound A and/or Compound B with one or more pharmaceutically acceptable carriers may be presented in separate pharmaceutical compositions or formulated together in one pharmaceutical formulation.
  • compositions may be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose. As is known to those skilled in the art, the amount of active ingredient per dose will depend on the condition being treated, the route of administration and the age, weight and condition of the patient. Preferred unit dosage formulations are those containing a daily dose or sub-dose, or an appropriate fraction thereof, of an active ingredient. Furthermore, such pharmaceutical formulations may be prepared by any of the methods well known in the pharmacy art.
  • Compound A and Compound B may be administered by any appropriate route. Suitable routes include oral, rectal, nasal, topical (including buccal and sublingual), vaginal, and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal, and epidural). It will be appreciated that the preferred route may vary with, for example, the condition of the recipient of the combination and the cancer to be treated. It will also be appreciated that each of the agents administered may be administered by the
  • Compound B are administered in separate pharmaceutical compositions.
  • Solid or liquid pharmaceutical carriers are employed.
  • Solid carriers include, starch, lactose, calcium sulfate dihydrate, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid.
  • Liquid carriers include syrup, peanut oil, olive oil, saline, and water.
  • the carrier may include a prolonged release material, such as glyceryl monostearate or glyceryl distearate, alone or with a wax.
  • the amount of solid carrier varies widely but, suitably, may be from about 25 mg to about 1 g per dosage unit.
  • the preparation will suitably be in the form of a syrup, elixir, emulsion, soft gelatin capsule, sterile injectable liquid such as an ampoule, or an aqueous or nonaqueous liquid suspension.
  • the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like.
  • an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like.
  • Powders are prepared by comminuting the compound to a suitable fine size and mixing with a similarly comminuted pharmaceutical carrier such as an edible carbohydrate, as, for example, starch or mannitol. Flavoring, preservative, dispersing and coloring agent can also be present.
  • the formulations may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.
  • Compound A in combination with Compound B are administered to a human.
  • the therapeutically effective amount of the administered agents of the present invention will depend upon a number of factors including, for example, the age and weight of the subject, the precise condition requiring treatment, the severity of the condition, the nature of the formulation, and the route of administration. Ultimately, the therapeutically effective amount will be at the discretion of the attending physician.
  • the combinations of the invention are tested for efficacy, advantageous and synergistic properties generally according to known procedures.
  • the present invention relates to a method for increasing platelet count, and/or treating thrombocytopenia and/or treating transplantation rejection.
  • This invention provides a combination comprising tacrolimus, and 3'-[(2Z)-[1-(3,4- dimethylphenyl)-1 ,5-dihydro-3-methyl-5-oxo-4H-pyrazol-4-ylidene]hydrazino]-2'-hydroxy- [1 , 1 '-biphenyl]-3-carboxylic acid or a pharmaceutically acceptable salt thereof, suitably the bis-monoethanolamine salt thereof.
  • This invention also provides for a combination comprising tacrolimus and 3'-[(2Z)- [1-(3,4-dimethylphenyl)-1 ,5-dihydro-3-methyl-5-oxo-4H-pyrazol-4-ylidene]hydrazino]-2'- hydroxy-[1 , 1 '-biphenyl]-3-carboxylic acid or a pharmaceutically acceptable salt thereof, suitably the bis-monoethanolamine salt thereof, for use in therapy.
  • This invention also provides for a combination comprising tacrolimus, and 3'-[(2Z)-[1 -(3,4-dimethylphenyl)-1 ,5-dihydro-3-methyl-5-oxo-4H-pyrazol-4- ylidene]hydrazino]-2'-hydroxy-[1 , 1 '-biphenyl]-3-carboxylic acid or a pharmaceutically acceptable salt thereof, suitably the bis-monoethanolamine salt thereof, for use in treating thrombocytopenia and/or treating transplantation rejection.
  • This invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a combination of tacrolimus, and 3'-[(2Z)-[1-(3,4-dimethylphenyl)-1 ,5-dihydro-3-methyl-5- oxo-4H-pyrazol-4-ylidene]hydrazino]-2'-hydroxy-[1 , 1 '-biphenyl]-3-carboxylic acid or a pharmaceutically acceptable salt thereof, suitably the bis-monoethanolamine salt thereof.
  • This invention also provides a combination kit comprising tacrolimus, and
  • This invention also provides for the use of a combination comprising tacrolimus, and 3'-[(2Z)-[1 -(3,4-dimethylphenyl)-1 ,5-dihydro-3-methyl-5-oxo-4H-pyrazol-4- ylidene]hydrazino]-2'-hydroxy-[1 , 1 '-biphenyl]-3-carboxylic acid or a pharmaceutically acceptable salt thereof, suitably the bis-monoethanolamine salt thereof, in the manufacture of a medicament.
  • This invention also provides for the use of a combination comprising tacrolimus, and 3'-[(2Z)-[1 -(3,4-dimethylphenyl)-1 ,5-dihydro-3-methyl-5-oxo-4H-pyrazol-4- ylidene]hydrazino]-2'-hydroxy-[1 , 1 '-biphenyl]-3-carboxylic acid or a pharmaceutically acceptable salt thereof, suitably the bis-monoethanolamine salt thereof, in the manufacture of a medicament to treat thrombocytopenia and/or treating transplantation rejection.
  • This invention also provides a method of treating thrombocytopenia and/or treating transplantation rejection which comprises administering a combination of tacrolimus, and 3'-[(2Z)-[1 -(3,4-dimethylphenyl)-1 ,5-dihydro-3-methyl-5-oxo-4H-pyrazol-4- ylidene]hydrazino]-2'-hydroxy-[1 , 1 '-biphenyl]-3-carboxylic acid or a pharmaceutically acceptable salt thereof, suitably the bis-monoethanolamine salt thereof, to a subject in need thereof.
  • the following examples are intended for illustration only and are not intended to limit the scope of the invention in any way.
  • An oral dosage form for administering a combination of the present invention is produced by filing a standard two piece hard gelatin capsule with the ingredients in the proportions shown in Table I, below.
  • An oral dosage form for administering one of the compounds of the present invention is produced by filing a standard two piece hard gelatin capsule with the ingredients in the proportions shown in Table II, below.
  • An oral dosage form for administering one of the compounds of the present invention is produced by filing a standard two piece hard gelatin capsule with the ingredients in the proportions shown in Table III, below.
  • sucrose, microcrystalline cellulose and the compounds of the invented combination are mixed and granulated in the proportions shown with a 10% gelatin solution.
  • the wet granules are screened, dried, mixed with the starch, talc and stearic acid, then screened and compressed into a tablet.
  • tacrolimus (of Compound A) 0.5mg
  • sucrose, microcrystalline cellulose and one of the compounds of the invented combination are mixed and granulated in the proportions shown with a 10% gelatin solution.
  • the wet granules are screened, dried, mixed with the starch, talc and stearic acid, then screened and compressed into a tablet.
  • sucrose, microcrystalline cellulose and one of the compounds of the invented combination are mixed and granulated in the proportions shown with a 10% gelatin solution.
  • the wet granules are screened, dried, mixed with the starch, talc and stearic acid, then screened and compressed into a tablet.
  • Example 7 Injectable Parenteral Composition
  • An injectable form for administering a compound of the presently invented combination is produced by stirring 1.5% by weight of tacrolimus (of Compound A) in 10% by volume propylene glycol in water.

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  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
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  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Cette invention concerne une méthode de traitement de la thrombocytopénie et/ou du rejet de greffe chez l'homme et des associations pharmaceutiques utiles dans ce traitement. En particulier, la méthode concerne une méthode de traitement qui comprend l'administration de tacrolimus, et d'un acide 3'-[(2Z)-[1-(3,4-diméthylphényl)-1,5-dihydro-3-méthyl-5-oxo-4H-pyrazol- 4-ylidène]hydrazino]-2'-hydroxy-[1,1'-biphényl]-3-carboxylique ou d'un sel de qualité pharmaceutique de celui-ci, de préférence, le sel de bis-monoéthanolamine, à un sujet humain en ayant besoin.
PCT/US2012/027173 2011-03-08 2012-03-01 Association WO2012121957A1 (fr)

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US61/450,294 2011-03-08

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3041511A4 (fr) * 2013-09-02 2017-03-15 Hetero Research Foundation Compositions d'eltrombopag
CN107898784A (zh) * 2017-11-01 2018-04-13 天津国际生物医药联合研究院 艾曲波帕乙醇胺在抗结核分枝杆菌感染中的应用
EP3395331A1 (fr) 2017-04-26 2018-10-31 Alfred E. Tiefenbacher (GmbH & Co. KG) Composition de comprimé pharmaceutique comprenant eltrombopag olamine
EP3409272A1 (fr) 2018-03-07 2018-12-05 Alfred E. Tiefenbacher (GmbH & Co. KG) Composition pharmaceutique comprenant de l'eltrombopag olamine, du sucre réducteur et un liant polymérique
CN116098897A (zh) * 2022-11-11 2023-05-12 中国人民解放军军事科学院军事医学研究院 他克莫司在制备抗辐射损伤药物中的应用

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WO2001089457A2 (fr) * 2000-05-25 2001-11-29 Smithkline Beecham Corporation Mimiques de thrombopoietine
US20040138223A1 (en) * 2000-09-14 2004-07-15 Mitsuharu Nakamura Novel amide derivatives and medicinal use thereof ugs
US20100093698A1 (en) * 2008-09-08 2010-04-15 Sogole Bahmanyar Aminotriazolopyridines, compositions thereof, and methods of treatment therewith

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001089457A2 (fr) * 2000-05-25 2001-11-29 Smithkline Beecham Corporation Mimiques de thrombopoietine
US20040138223A1 (en) * 2000-09-14 2004-07-15 Mitsuharu Nakamura Novel amide derivatives and medicinal use thereof ugs
US20100093698A1 (en) * 2008-09-08 2010-04-15 Sogole Bahmanyar Aminotriazolopyridines, compositions thereof, and methods of treatment therewith

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3041511A4 (fr) * 2013-09-02 2017-03-15 Hetero Research Foundation Compositions d'eltrombopag
EP3395331A1 (fr) 2017-04-26 2018-10-31 Alfred E. Tiefenbacher (GmbH & Co. KG) Composition de comprimé pharmaceutique comprenant eltrombopag olamine
WO2018197088A1 (fr) 2017-04-26 2018-11-01 Alfred E. Tiefenbacher (Gmbh & Co. Kg) Composition pharmaceutique de comprimés comprenant de l'eltrombopag olamine
EP3395331B1 (fr) 2017-04-26 2019-08-21 Alfred E. Tiefenbacher (GmbH & Co. KG) Composition de comprimé pharmaceutique comprenant eltrombopag olamine
EP4019009A1 (fr) 2017-04-26 2022-06-29 Alfred E. Tiefenbacher (GmbH & Co. KG) Composition de comprimé pharmaceutique comprenant eltrombopag olamine
CN107898784A (zh) * 2017-11-01 2018-04-13 天津国际生物医药联合研究院 艾曲波帕乙醇胺在抗结核分枝杆菌感染中的应用
CN107898784B (zh) * 2017-11-01 2020-09-18 天津国际生物医药联合研究院 艾曲波帕乙醇胺在抗结核分枝杆菌感染中的应用
EP3409272A1 (fr) 2018-03-07 2018-12-05 Alfred E. Tiefenbacher (GmbH & Co. KG) Composition pharmaceutique comprenant de l'eltrombopag olamine, du sucre réducteur et un liant polymérique
WO2019086725A2 (fr) 2018-03-07 2019-05-09 Alfred E. Tiefenbacher (Gmbh & Co. Kg) Composition pharmaceutique comprenant de l'eltrombopag olamine, un sucre réducteur et un liant polymère
WO2019086725A3 (fr) * 2018-03-07 2019-07-11 Alfred E. Tiefenbacher (Gmbh & Co. Kg) Composition pharmaceutique comprenant de l'eltrombopag olamine, un sucre réducteur et un liant polymère
EP3409272B1 (fr) 2018-03-07 2020-06-24 Alfred E. Tiefenbacher (GmbH & Co. KG) Composition pharmaceutique comprenant de l'eltrombopag olamine, du sucre réducteur et un liant polymérique
CN116098897A (zh) * 2022-11-11 2023-05-12 中国人民解放军军事科学院军事医学研究院 他克莫司在制备抗辐射损伤药物中的应用

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