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WO2005046665A1 - Polychimiotherapie comportant un inhibiteur de mek et un inhibiteur du recepteur erbb1/2 - Google Patents

Polychimiotherapie comportant un inhibiteur de mek et un inhibiteur du recepteur erbb1/2 Download PDF

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Publication number
WO2005046665A1
WO2005046665A1 PCT/IB2004/003667 IB2004003667W WO2005046665A1 WO 2005046665 A1 WO2005046665 A1 WO 2005046665A1 IB 2004003667 W IB2004003667 W IB 2004003667W WO 2005046665 A1 WO2005046665 A1 WO 2005046665A1
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Prior art keywords
inhibitor
mek
gefitinib
mek inhibitor
patient
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PCT/IB2004/003667
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English (en)
Inventor
Judith S. Seabolt-Leopold
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Warner-Lambert Company Llc
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Publication of WO2005046665A1 publication Critical patent/WO2005046665A1/fr

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    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • 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
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • 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 relates to a method for treating cancer utilizing a combination of known oncolytic agents. Specifically, this invention relates to the combination of a MEK inhibitor and an inhibitor of the erbB1 and/or erbB2 receptors.
  • BACKGROUND OF THE INVENTION Cancer chemotherapy has advanced dramatically in recent years. Many tumors can be effectively treated utilizing compounds, which are either naturally occurring products or synthetic agents. Cancer chemotherapy can entail the use of a combination of agents, generally as a means to reduce the toxic effects of the individual agents when used alone, and in some instances because the combination has greater therapeutic effects than when either agent is used alone. Cancer has been viewed as a disease of the intracellular signaling system, or signal transduction mechanism.
  • Cells receive instructions from many extracellular sources, instructing them to either proliferate or not to proliferate.
  • the purpose of the signal transduction system is to receive these and other signals at the cell surface, get them into the cell, and then pass the signals on to the nucleus, the cytoskeleton, and transport and protein synthesis machinery.
  • the most common cause of cancer is a series of defects, either in these proteins, when they are mutated, or in the regulation of the quantity of the protein in the cell such that it is over or under produced.
  • Most often, there are key lesions in the cell which lead to a constitutive state whereby the cell nucleus receives a signal to proliferate, when this signal is not actually present. This can occur through a variety of mechanisms.
  • the cell may start to produce an authentic growth factor for its own receptors when it should not, the so-called autocrine loop mechanism. Mutations to the cell surface receptors, which usually signal into the cell by means of tyrosine kinases, can lead to activation of the kinase in the absence of ligand, and passing of a signal which is not really there. Alternatively, many surface kinases can be overexpressed on the cell surface leading to an inappropriately strong response to a weak signal. There are many levels inside the cell at which mutation or overexpression can lead to the same spurious signal arising in the cell, and there are many other kinds of signaling defects involved in cancer.
  • One component of the present combination invention touches upon cancers which are driven by the three mechanisms just described, and which involve cell surface receptors of the epidermal growth factor receptor tyrosine kinase family.
  • This family consists of the EGF receptor (also known as the erbB1 receptor), the erbB2 receptor, and its constitutively active oncoprotein mutant Neu, the erbB3 receptor and the erbB4 receptor.
  • EGF receptor also known as the erbB1 receptor
  • the erbB2 receptor the constitutively active oncoprotein mutant Neu
  • the erbB3 receptor the erbB4 receptor.
  • the Ras-Raf-MEK-ERK pathway appears to be an important pathway for the transmission of mitogenic signals from the plasma membrane to the nucleus.
  • Activated raf activates by phosphorylation the signaling kinases MEK1 and MEK2 (MEK 1/2).
  • ERK activation results in phosphorylation and activation of ribosomal S9 kinase and transcription factors, such as c-Fos, c-Jun and c-Myc, resulting in the switching on of a number of genes involved in proliferation.
  • ribosomal S9 kinase and transcription factors such as c-Fos, c-Jun and c-Myc.
  • a variety of growth factors such as the erbB family, PDGF, FGF and VEGF, transmit signals through the Ras-Raf-MEK-ERK pathway.
  • mutations in ras proto-oncogenes can result in constitutive activation of this pathway.
  • Ras genes are mutated in approximately 30% of all human cancers, and the frequencies of ras mutations are particularly high in colon and pancreatic cancers (50% and 90%, respectively).
  • MEK 1 and 2 have a central role in the transmission of proliferative signals from the plasma membrane to the nucleus. This makes these proteins a potentially better target for cancer therapy because their inhibition would abrogate a number of different signaling pathways. Therefore, a MEK inhibitor may be active against a broad range of cancers, such as, but not limited to, melanoma, breast, colon, lung, ovarian and pancreatic cancers.
  • CI-1040 2-(2-Chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-3, 4-difluoro-benzamide, also known as CI-1040 is a potent and highly selective inhibitor of both MEK isoforms, MEK1 and MEK 2. Inhibition of MEK activity by CI-1040 results in a significant decrease in the levels of phosphorylated ERK1 and ERK2. This decrease produces a G1 block and impairs the growth of tumor cells, both in culture and in mice.
  • CI-1040 has demonstrated anticancer activity against a broad spectrum of tumor types, including those of colon and pancreatic origin (Sebolt-Leopold J., et al, Blockade of the MAP kinase pathway suppresses growth of colon tumors in vivo. Nature Med 1999; 5:810-16; and Sebolt-Leopold JS, Summary of the preclinical pharmacology of CI-1040. RR 700-00156. June 27, 2000.). CI-1040 is described in PCT Publication No.
  • WO 99/01426 which is incorporated herein by reference for its teaching of how to make CI-1040, how to formulate it into dosage forms, and how to use it for chronic oral treatment of solid tumors, such as breast, colon, prostate, skin and pancreatic cancers.
  • CI-1040 is also described in US Patent No. 6,251,943 for use in the treatment or prevention of septic shock.
  • ⁇ /-[(R)-2,3-Dihydroxy-propoxy]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)- benzamide (“Compound A”) is a potent and highly selective inhibitor of MEK1/2, which significantly inhibits the phosphorylation of ERK1 and ERK2.
  • Compound A is described in PCT Publication No. WO 02/06213, which is incorporated herein by reference for its teaching of how to make it, how to formulate it into dosage forms, and how to use it for chronic oral treatment of solid tumors, such as breast, colon, prostate, skin and pancreatic cancers. It is more potent and metabolically more stable than its predecessor, CI-1040.
  • gefitinib 4-Quinazolinamine,/V -(3-chIoro-4 -fluorophenyl)-7-methoxy-6-[3-4- morpholin)propoxy], also known as gefitinib, inhibits the intracellular phosphorylation of numerous tyrosine kinases associated with transmembrane cell surface receptors, including the tyrosine kinases associated with the epidermal growth factor receptor. It is marketed in the United States as IressaTM (AstraZeneca Pharmaceuticals LP). It is orally administered daily as a brown film-coated tablet. The recommended daily dose of gefitinib is one 250 mg tablet with or without food.
  • the present invention provides a method for treating cancer in a patient in need of such treatment, the method comprising administering to the patient a combination of a therapeutically effective amount of a MEK inhibitor and a therapeutically effective amount of an erbB1 and/or erbB2 receptor inhibitor.
  • the combination of the present invention may be administered simultaneously, the MEK inhibitor may be administered before the erbB1 and/or erbB2 receptor inhibitor, or the erbB1 and/or erbB2 receptor inhibitor may be administered before the MEK inhibitor.
  • the erbB1 receptor inhibitor may be gefitinib and the MEK inhibitor may be CI-1040 or ⁇ /-[(R)-2,3-dihydroxy- propoxy]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide.
  • the method of the present invention provides that CI-1040 or ⁇ /-[(R)-2,3- dihydroxy-propoxy]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide may be administered before gefitinib or gefitinib may be administered before CI-1040 or ⁇ /-[(R)-2,3- dihydroxy-propoxy]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide.
  • An embodiment of the present invention provides a pharmaceutical composition comprising gefitinib, CI-1040 and a pharmaceutically acceptable carrier.
  • Another embodiment of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising gefitinib, ⁇ /-[(R)-2,3-dihydroxy-propoxy]-3,4-difluoro-2-(2-fluoro-4-iodo- phenylamino)-benzamide and a pharmaceutically acceptable carrier.
  • Another aspect of the invention is a kit comprising in one compartment a dosage of
  • the invention includes: (a) a blister pack containing separate formulations of each active, such as a tablet or capsule form of CI-1040 or Compound A, and a tablet form of gefitinib; and (c) a kit with separate formulations of each active packaged together in a box with instructions for combination administration.
  • a blister pack containing separate formulations of each active, such as a tablet or capsule form of CI-1040 or Compound A, and a tablet form of gefitinib
  • a kit with separate formulations of each active packaged together in a box with instructions for combination administration DETAILED DESCRIPTION OF THE INVENTION
  • the patient to be treated according to this invention includes any warm-blooded animal, such as, but not limited to human, horse, dog, guinea pig, or mouse.
  • the patient is human.
  • Typical cancers to be treated according to this invention include, but are not limited to, brain, breast, lung, such as non-small cell lung, ovarian, pancreatic, prostate, renal, colon, cervical, acute leukemia, gastric cancer, melanoma and other cancers susceptible to treatment with an erbBI and/or erbB2 receptor inhibitors, such as gefitinib, and/or MEK inhibitors, such as CI-1040 and Compound A.
  • treatment for the purpose of the present invention includes treatment, inhibition, control, prophylaxis or prevention, amelioration or elimination of a named condition, such as cancer, once the named condition has been established.
  • CI-1040 and Compound A are selective MEK 1 and MEK 2 inhibitors.
  • a selective MEK 1 or MEK 2 inhibitor is those compounds which inhibit the MEK 1 or MEK 2 enzymes without substantially inhibiting other enzymes such as MKK3, ERK, PKC, Cdk2A, phosphorylase kinase, EGF and PDGF receptor kinases, and C-src.
  • a selective MEK 1 or MEK 2 inhibitor has an IC 50 for MEK 1 or MEK 2 that is at least one-fiftieth (1/50) that of its IC 50 for one of the above-named other enzymes.
  • a selective inhibitor may have an IC 50 that is at least 1/100, 1/500, or even 1/1000, 1/5000 or less than that of its IC 50 for one or more of the above-named enzymes.
  • a compound which is a MEK inhibitor may be determined by using an assay known to one of skill in the art that measures MEK inhibition.
  • MEK inhibition may be determined using the assays titled, "Enzyme Assays” in United States Patent No. 5,525,625, column 6, beginning at line 35.
  • the complete disclosure of United States Patent No. 5,525,625 is hereby incorporated by reference.
  • a compound is an MEK inhibitor if a compound shows activity in the assay titled, "Cascade Assay for Inhibitors of the MAP Kinase Pathway," column 6, line 36 to column 7, line 4 of the United States Patent No.
  • MEK inhibition can be measured in the assay described in WO 02/06213 A1 , the complete disclosure of which is hereby incorporated by reference.
  • Examples of MEK inhibitors according to the present invention include, but are not limited to the MEK inhibitors disclosed in the following US Patent and PCT Publications: US Pat No.
  • a pharmaceutically or therapeutically effective amount or dosage of CI-1040, Compound A or gefitinib may be understood to comprise an amount sufficient to prevent or inhibit the growth of tumor cells or the progression of cancer metastasis in the combinations of the present invention.
  • Therapeutic or pharmacological effectiveness of the doses and administration regimens may also be characterized as the ability to induce, enhance, maintain or prolong remission in patients experiencing specific tumors.
  • the compounds to be utilized in the methods or combinations of the present invention may be administered in dosages or doses commonly employed clinically.
  • Those skilled in the art will be able to determine, according to known methods, the appropriate therapeutically effective amount or dosage of each compound, as used in the combination of the present invention, to administer to a patient, taking into account factors such as age, weight, general health, the compound administered, the route of administration, the nature and advancement of the cancer requiring treatment, and the presence of other medications.
  • Such doses may be calculated in the normal fashion, for example on body surface area.
  • an effective amount or a therapeutically effective amount may be calculated in mg/kg of body weight.
  • Commercially available capsules, tablets, or other formulations (such as liquids and film-coated tablets) can be administered according to the disclosed methods.
  • Gefitinib for monotherapy generally is administered orally at a dose of about 250 mg daily with or without food. If necessary to manage poorly tolerated diarrhea or skin adverse drug reactions, therapy can be briefly interrupted for up to 14 days. The product is supplied commercially in 250 mg tablets. The daily doses of gefitinib may, for example, range from about 100 mg to about 1000 mg per day in the combinations of this invention.
  • CI-1040 for monotherapy generally may be administered until progression of the disease state is observed, for example, CI-1040 may be administered daily from about 2 - 4 weeks to the duration of the life of the patient. Multiple treatment periods can be practiced, as dictated by the attending medical practitioner and the particular patient and condition being treated.
  • CI-1040 may be administered at doses from about 100 mg to about 1600 mg once a day ("qd"), or from about 400 to about 800 mg two or three times a day ("bid” or "tid", respectively) with or without food.
  • CI-1040 may be administered at 800 mg twice a day with food.
  • CI-1040 typically is administered orally, for example, as capsules having active ingredient in the amounts of 5, 25, and 200 mg per capsule.
  • Compound A for monotherapy generally may be administered until progression of the disease state is observed, for example, Compound A may be administered daily from about 2 - 4 weeks to the duration of the life of the patient.
  • Compound A may be administered at a daily dose range between about 0.1 and about 1000 mg/kg per day, preferably between about 1 and about 300 mg/kg body weight, and daily dosages will be between about 1 and about 500 mg for an adult subject of normal weight, preferably between about 1 mg and 50 mg.
  • Compound A may be administered at a daily dose range may be between about 1 mg and about 20 mg, in a single dosage or in divided doses.
  • Compound A may be administered orally, for example, as capsules, such as hard gelatin capsules, or other formulations, such as liquids and film-coated tablets having active ingredient in the amounts of, for example, 0.25 mg, 0.5 mg, 1 mg, 5 mg, 10 mg, 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, or 400 mg can be administered.
  • Multiple treatment periods can be practiced, as dictated by the attending medical practitioner and the particular patient and condition being treated. In some instances, dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed, as determined by those skilled in the art.
  • the effective dosage level of a MEK inhibitor may range from about 5% to about 100% of the effective dosage level when used without gefitinib.
  • the effective dosage level of gefitinib may range from about 5% to about 100% of the effective dosage level when used without a MEK inhibitor.
  • the dosage level of gefitinib and the MEK inhibitor may be adjusted to achieve the optimum effective dosage level. The practice of the methods of this invention may be accomplished through various administration regimens.
  • One method of treating or inhibiting cancer cells or tumors of this invention comprises the contemporaneous or simultaneous administration of pharmaceutically or therapeutically effective amounts of a MEK inhibitor, such as CI-1040 and Compound A, and gefitinib to a patient in need of such treatment.
  • a joint administration of both compounds may be conducted over a period of time deemed appropriate by a medical professional for the recipient in question.
  • One regimen may include administration of both compounds over a period of from 2 to 4 weeks. Repetition of the joint administration may be conducted for a series of dosage periods, as necessary to achieve the desired reduction or diminution of cancer cells.
  • the series of joint administration may be separated by non-treatment periods of from, for example, 2 to 6 weeks to allow conventional patient rest and recovery.
  • Methods of this invention also include administration to a patient in need thereof a pharmaceutically or therapeutically effective amount of CI-1040 or Compound A for or over a specific period or regimen, followed by administration to the patient of a subsequent regimen of a pharmaceutically or therapeutically effective amount of gefitinib.
  • An example of such a regimen would include administration to a patient of a therapeutically or pharmaceutically effective amount of Compound A for from 14 to 28 days, followed by administration of a pharmaceutically or therapeutically effective amount of gefitinib for a subsequent and connecting period of from 7 to 14 days.
  • Administration of gefitinib may be separated by non- treatment periods of from, for example, 2 days to a week to allow conventional patient rest and recovery.
  • Another method of practicing this invention comprises sequential administrations of a regimen of gefitinib administration, followed by a regimen of CI-1040 or Compound A administration.
  • a regimen of gefitinib administration would include an initial administration of a pharmaceutically or therapeutically effective amount of gefitinib for 7 to 14 days with non- treatment periods of from 2 days to a week to allow conventional patient rest and recovery, followed by administration of a therapeutically or pharmaceutically effective amount of Compound A for from 14 to 28 days.
  • Repetitive sequences of this type of gefitinib regimen followed by Compound A regimen may be continued, as needed, with optional interim periods of non-treatment as determined by a medical professional.
  • the compounds of the methods or combinations of the present invention may be formulated prior to administration.
  • compositions of the present invention may be formulated either separately or in combination with pharmaceutically acceptable carriers as known in the art and administered in a wide variety of dosage forms as known in the art.
  • the active ingredient will usually be mixed with a carrier, or diluted by a carrier or enclosed within a carrier.
  • Such carriers include, but are not limited to, solid diluents or fillers, excipients, sterile aqueous media and various non-toxic organic solvents.
  • Dosage unit forms or pharmaceutical compositions include tablets, capsules, such as gelatin capsules, pills, powders, granules, aqueous and nonaqueous oral solutions and suspensions, lozenges, troches, hard candies, sprays, creams, salves, suppositories, jellies, gels, pastes, lotions, ointments, injectable solutions, elixirs, syrups, and parenteral solutions packaged in containers adapted for subdivision into individual doses.
  • MEK inhibitors such as CI-1040 and Compound A, can be formulated for administration by the oral or parenteral routes. They can also be administered topically, such as transdermally, as skin patches or lotions, or as suppositories.
  • Simultaneous administration of a MEK inhibitor and gefitinib may be by the same (both actives by either local or systemic injection) or different routes.
  • CI-1040 for example, can be formulated with gefitinib, for instance in solution for intravenous injection or infusion, the active agents will more typically be formulated individually in their normal preparations, and will be administered individually.
  • CI-1040, for example, and gefitinib can be formulated individually and packaged together, in a kit for example, for convenience in usage.
  • the agents can be formulated together in a single formulation, in which case the gefitinib will be present at concentrations ranging from about 1 to about 1000 parts by weight relative to the MEK inhibitor, and the MEK inhibitor will be present at concentrations of about 1000 to about 1 part by weight relative to the gefitinib.
  • the agents will be administered at about equal doses, or as otherwise approved by health regulatory agencies. Dosage unit forms can be adapted for various methods of administration, including controlled release formulations, such as subcutaneous implants.
  • Administration methods include oral, rectal, parenteral (intravenous, intramuscular, and subcutaneous), intracistemal, intravaginal, intraperitoneal, intravesical, local (drops, powders, ointments, gels, or cream), and by inhalation (a buccal or nasal spray).
  • oral administration tablets containing various excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine may be employed along with various disintegrants such as starch (and preferably corn, potato or tapioca starch), alginic acid and certain complex silicates, together with granulation binders like polyvinylpyrrolidone, sucrose, gelatin and acacia.
  • lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for tabletting purposes.
  • Solid compositions of a similar type may also be employed as fillers in gelatin capsules; preferred materials in this connection also include lactose or milk sugar as well as high molecular weight polyethylene glycols.
  • the active ingredient may be combined with various sweetening or flavoring agents, coloring matter or dyes, and, if so desired, emulsifying and/or suspending agents as well, together with such diluents as water, ethanol, propylene glycol, glycerin and various like combinations thereof.
  • Parenteral formulations include pharmaceutically acceptable aqueous or nonaqueous solutions, dispersion, suspensions, emulsions, and sterile powders for the preparation thereof.
  • carriers include water, ethanol, polyols (propylene glycol, polyethylene glycol), vegetable oils, and injectable organic esters such as ethyl oleate. Fluidity can be maintained by the use of a coating such as lecithin, a surfactant, or maintaining appropriate particle size.
  • Carriers for solid dosage forms include (a) fillers or extenders, (b) binders, (c) humectants, (d) disintegrating agents, (e) solution retarders, (f) absorption acccelerators, (g) adsorbants, (h) lubricants, (i) buffering agents, and (j) propeliants.
  • Pharmaceutical compositions may also contain adjuvants such as preserving, wetting, emulsifying, and dispensing agents; antimicrobial agents such as parabens, chlorobutanol, phenol, and sorbic acid; isotonic agents such as a sugar or sodium chloride; absorption-prolonging agents such as aluminum monostearate and gelatin; and absorption- enhancing agents.
  • compositions of Compound A in hard gelatin capsules may include dosages of the active pharmaceutical agent, for example, from 0.1 mg to 50 mg per capsule.
  • the compositions may include the active drug substance, such as ⁇ /-[(R)-2,3- Dihydroxy-propoxy]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide form IV, a diluent, such as microcrystalline cellulose, and a disintegrant, such as croscarmellose sodium.
  • the composition may also contain a lubricant, such as stearic acid or magnesium stearate.
  • Examples of these oral formulations in hard gelatin capsules include those in which the active drug substance comprises from about 0.1-20% of the formulation, by weight, a diluent comprises from about 75-95%, a disintegrant comprises from about 3-7% and, optionally, a lubricant comprises from about 0.1-2%.
  • a 0.25 mg capsule may contain from about 0.15 to about 0.25 % active drug substance, by weight, from about 93-95% microcrystalline cellulose, from about 4-6% croscarmellose sodium and, optionally, from about 0.5-1.5% magnesium stearate.
  • a 1 mg capsule may contain from about 0.7 to about 0.85 % active drug substance, by weight, from about 92.5-95% microcrystalline cellulose, from about 4-6% croscarmellose sodium and, optionally, from about 0.5-1.5% magnesium stearate.
  • a 5 mg capsule may contain from about 4% to about 6 % active drug substance, by weight, from about 87-93% microcrystalline cellulose, from about 4-6% croscarmellose sodium and, optionally, from about 0.5-1.5% magnesium stearate.
  • a 25 mg capsule may contain from about 14% to about 17 % active drug substance, by weight, from about 76-83% microcrystalline cellulose, from about 4-6% croscarmellose sodium and, optionally, from about 0.5-1.5% magnesium stearate.
  • Hard gelatin capsule oral formulation of the type just described may be prepared by methods known in the art.
  • An example includes blending and milling the active drug agent with the desired amount of disintegrant, such as croscarmellose sodium, and half the desired amount of diluent, such as microcrystalline cellulose.
  • the second half of the diluent may then be milled and blended with the first mixture of active agent, diluent and disintegrant and the resulting composition blended.
  • An optional lubricant, such as magnesium stearate may then be added with additional blending.
  • the total composition may then be measured and placed in hard gelatin capsules.
  • the dry composition may be pressed into slugs using a tablet press, followed by additional milling of the resulting slugs.
  • ⁇ /-[(R)-2,3-Dihydroxy-propoxy]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)- benzamide form IV can be prepared by a process comprising the steps of: a) entering an amount of ⁇ /-[(R)-2,3-Dihydroxy-propoxy]-3,4-difluoro-2-(2-fluoro-
  • step a) stirring the components of step a) to create a mixture of ⁇ /-[(R)-2,3- Dihydroxy-propoxy]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide in alkanol and water; c) cooling the mixture of ⁇ /-[(R)-2,3-Dihydroxy-propoxy]-3,4-difluoro-2-(2-fluoro- 4-iodo-phenylamino)-benzamide in alkanol and water to a temperature from about 20°C to less than about 30°C; d) separating the ⁇ /-[(R)-2,3-Dihydroxy-prop
  • step a) entering an amount of ⁇ /-[(R)-2,3-Dihydroxy-propoxy]-3,4-difluoro-2-(2-fluoro- 4-iodo-phenylamino)-benzamide into a volume of a C C lower alkanol and water, the amount of ethanol to water being at a ratio of from about 1 :9 to about 1 :11 , at a temperature of from about 32°C to about 38°C; b) stirring the components of step a) to create a mixture of ⁇ /-[(R)-2,3- Dihydroxy-propoxy]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide in alkanol and water; c) cooling the mixture of ⁇ /-[(R)-2,3-Dihydroxy-propoxy]-3,4-difluoro-2-(2-fluoro-
  • C 1 -C 4 lower alkanols which may be used in this process include methanol, ethanol, propanol, isopropanol, etc., with ethanol being a preferred alkanol.

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Abstract

L'invention concerne un procédé de traitement du cancer au moyen d'une association d'agents oncolytiques connus. Plus particulièrement, l'invention concerne l'association d'un inhibiteur de MEK et d'un inhibiteur du récepteur erbB1 et/ou erbB2.
PCT/IB2004/003667 2003-11-13 2004-11-05 Polychimiotherapie comportant un inhibiteur de mek et un inhibiteur du recepteur erbb1/2 WO2005046665A1 (fr)

Applications Claiming Priority (2)

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US51976303P 2003-11-13 2003-11-13
US60/519,763 2003-11-13

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WO2005046665A1 true WO2005046665A1 (fr) 2005-05-26

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006061712A3 (fr) * 2004-12-10 2006-07-27 Pfizer Utilisation d'inhibiteurs de mek dans le traitement d'une croissance cellulaire anormale
EP1982718A4 (fr) * 2006-02-09 2010-05-12 Daiichi Sankyo Co Ltd Composition pharmaceutique anticancereuse
WO2013107283A1 (fr) 2012-01-17 2013-07-25 Tianjin Binjiang Pharma, Inc. Composés benzohétérocycliques et leur utilisation
US12275688B2 (en) 2021-02-17 2025-04-15 Springworks Therapeutics, Inc. Crystalline solids of MEK inhibitor N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide and uses thereof

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US6251943B1 (en) * 1997-02-28 2001-06-26 Warner-Lambert Company Method of treating or preventing septic shock by administering a MEK inhibitor
US20020002162A1 (en) * 2000-03-27 2002-01-03 Lee Francis Y. Synergistic methods and compositions for treating cancer
WO2002036570A1 (fr) * 2000-11-02 2002-05-10 Astrazeneca Ab Quinoleines 4 substitues en position 4 utilisees comme agents antitumoraux
WO2003047582A1 (fr) * 2001-12-05 2003-06-12 Astrazeneca Ab Derives de la quinoleine, utilises en tant qu'agents antitumoraux
WO2004004644A2 (fr) * 2002-07-05 2004-01-15 Beth Israel Deaconess Medical Center Association d'un inhibiteur de cible mammalienne de rapamycine (mtor) et d'un inhibiteur de la tyrosine kinase aux fins du de traitement de neoplasmes

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006061712A3 (fr) * 2004-12-10 2006-07-27 Pfizer Utilisation d'inhibiteurs de mek dans le traitement d'une croissance cellulaire anormale
EP1982718A4 (fr) * 2006-02-09 2010-05-12 Daiichi Sankyo Co Ltd Composition pharmaceutique anticancereuse
WO2013107283A1 (fr) 2012-01-17 2013-07-25 Tianjin Binjiang Pharma, Inc. Composés benzohétérocycliques et leur utilisation
US9290468B2 (en) 2012-01-17 2016-03-22 Shanghai Kechow Pharma, Inc. Benzoheterocyclic compounds and use thereof
US9937158B2 (en) 2012-01-17 2018-04-10 Shanghai Kechow Pharma, Inc. Benzoheterocyclic compounds and use thereof
US12275688B2 (en) 2021-02-17 2025-04-15 Springworks Therapeutics, Inc. Crystalline solids of MEK inhibitor N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide and uses thereof

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