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WO2010126036A1 - Association pharmacologique - Google Patents

Association pharmacologique Download PDF

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Publication number
WO2010126036A1
WO2010126036A1 PCT/JP2010/057449 JP2010057449W WO2010126036A1 WO 2010126036 A1 WO2010126036 A1 WO 2010126036A1 JP 2010057449 W JP2010057449 W JP 2010057449W WO 2010126036 A1 WO2010126036 A1 WO 2010126036A1
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WIPO (PCT)
Prior art keywords
acid
prostate cancer
preparation
hormone
tyrosine kinase
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Ceased
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English (en)
Japanese (ja)
Inventor
万寿夫 山岡
義一 大田
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Takeda Pharmaceutical Co Ltd
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Takeda Pharmaceutical Co Ltd
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Publication of WO2010126036A1 publication Critical patent/WO2010126036A1/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
    • A61K31/33—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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08—Peptides having 5 to 11 amino acids
    • A61K38/09—Luteinising hormone-releasing hormone [LHRH], i.e. Gonadotropin-releasing hormone [GnRH]; Related peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a novel pharmaceutical comprising a combination of leuprorelin acetate and lapatinib.
  • Luteinizing hormone-releasing hormone known as LHRH (or GnRH)
  • LHRH Luteinizing hormone-releasing hormone
  • FSH follicle stimulating hormone
  • Patent Document 1 discloses a hormonal drug, (i) EGF or a substance having substantially the same activity, (ii) insulin or a substance having substantially the same activity, or (iii) FGF or substantially the same. Delayed change of hormone-dependent cancer to hormone-independent cancer, characterized by neutralizing substances with the same activity or combining drugs that inhibit their receptor stimulation Agents are described.
  • Patent Document 2 includes GnRH agonists and SERM agents (such as raloxifene), sex hormone synthesis inhibitors (lyase inhibitors), receptor tyrosine kinase inhibitors (such as Iressa), side effect mitigators / bone metabolism regulators (alendronate) , Ipriflavone, etc.), immunotherapeutic agents, cytokines / chemokine inhibitors, endothelin receptor antagonists and the like.
  • SERM agents such as raloxifene
  • sex hormone synthesis inhibitors lyase inhibitors
  • receptor tyrosine kinase inhibitors such as Iressa
  • side effect mitigators / bone metabolism regulators such as Ipriflavone, etc.
  • An object of the present invention is to provide an excellent therapeutic agent for prostate cancer, which is a combination of leuprorelin acetate and lapatinib, and suppresses the change of hormone-dependent prostate cancer to hormone-independent cancer.
  • the present inventors have unexpectedly suppressed the change of hormone-dependent prostate cancer to hormone-independent cancer by lapatinib, a tyrosine kinase inhibitor, unexpectedly As a result of further finding and studying, the present invention has been completed.
  • the present invention [A] A prophylactic / therapeutic agent for prostate cancer comprising a combination of leuprorelin acetate and lapatinib; [B] A method for preventing or treating prostate cancer, comprising administering to a mammal a combination of an effective amount of leuprorelin acetate and an effective amount of lapatinib; [C] Use of leuprorelin acetate and lapatinib for the manufacture of a prophylactic / therapeutic agent for prostate cancer; [D] an inhibitor of change from hormone-dependent prostate cancer to hormone-independent prostate cancer comprising lapatinib; [E] a method for suppressing change from hormone-dependent prostate cancer to hormone-independent prostate cancer, comprising administering an effective amount of lapatinib to a mammal; and [F] hormone-dependent prostate cancer to hormone Use of lapatinib to produce a change inhibitor for independent prostate cancer; About.
  • Prostate cancer prophylactic / therapeutic agent comprising a combination of a prostatic cancer drug and a tyrosine kinase inhibitor
  • Prostate cancer drug is formula 5-oxo-Pro-His-Trp-Ser-Tyr-Y-Leu-Arg-Pro-Z [Wherein Y represents a residue selected from DLeu, DAla, DTrp, DSer (tBu), D2Nal and DHis (ImBzl), Z represents NH—C 2 H 5 , NH—NH—CO—NH 2 , NH— The agent of the above-mentioned [1], which is a peptide represented by C 2 H 4 —NH 2 or Gly-NH 2 , or a salt thereof; [3] Prostate cancer therapeutic agent, 5-oxo-Pro-His -Trp-Ser-Tyr-DLeu-Leu-Arg-Pro-NH-C 2 H 5 or above its acetate [1]
  • lapatinib can effectively suppress the change of hormone-dependent prostate cancer to hormone-independent cancer.
  • FIG. 1 shows a growth curve of LNCaP-FGC cells in a medium containing lapatinib.
  • prostate cancer therapeutic agent used in the present invention examples include, for example, the general formula [I] 5-oxo-Pro-His-Trp-Ser-Tyr-Y-Leu-Arg-Pro-Z [Wherein Y represents a residue selected from DLeu, DAla, DTrp, DSer (tBu), D2Nal and DHis (ImBzl), Z represents NH—C 2 H 5 , NH—NH—CO—NH 2 , NH— C 2 H 4 —NH 2 or Gly-NH 2 are respectively represented] or a salt thereof.
  • a peptide in which Y is DLeu and Z is NH-C 2 H 5 ie, 5-oxo-Pro-His-Trp-Ser-Tyr-DLeu-Leu-Arg-Pro-NH-C 2 H 5 Peptide
  • a salt thereof particularly an acetate thereof (leuprorelin acetate: manufactured by Takeda Pharmaceutical Company Limited) is preferable.
  • the peptide exemplified as the therapeutic agent for prostate cancer may be a pharmacologically acceptable salt.
  • a basic group such as an amino group, an inorganic acid (eg, hydrochloric acid, sulfuric acid, nitric acid, boric acid, etc.) or an organic acid (eg, carbonic acid, bicarbonate, succinic acid) , Acetic acid, propionic acid, trifluoroacetic acid and the like).
  • the peptide When the peptide has an acidic group such as a carboxyl group, an inorganic base (eg, an alkali metal such as sodium or potassium; an alkaline earth metal such as calcium or magnesium) or an organic base (eg, organic amines such as triethylamine) Salts with basic amino acids such as arginine) and the like.
  • the peptide may form a metal complex compound (eg, copper complex, zinc complex, etc.).
  • GnRH analogs Treatment with GnRH analogs (Treatment with GnRH analogs: Controversies and perspectives) published by The Parthenon Publishing Group Ltd. 1996. It can be produced by the method described in Table 3-503165, JP-A-3-101695, 7-97334, and 8-259460, or the like.
  • leuprorelin leuprorelin acetate
  • preferred specific examples include, for example: (1) Goserelin (U.S. Pat. No. 4,100,004, No. 52-136172), (2) Buserelin (U.S. Patent No. 4,024,248, German Patent No. 2438352, Japanese Patent Laid-Open No. 51-41359), (3) Triptorelin (U.S. Pat. No. 4,010,125, JP-A 52-31073), (4) Nafarelin (U.S. Pat. No.
  • the therapeutic agent for prostate cancer preferably, a peptide represented by the formula 5-oxo-Pro-His-Trp-Ser-Tyr-DLeu-Leu-Arg-Pro-NH-C 2 H 5 or a salt thereof (Hereinafter sometimes referred to simply as “leuprorelin or a salt thereof”, more preferably leuprorelin acetate), tablets, capsules, elixirs, sustained-release preparations, etc., with sugar coating as required Orally or aseptic solutions or suspensions with water or other pharmaceutically acceptable liquids, injections such as sustained-release preparations (especially sustained-release microcapsules), implants (in vivo A biodegradable polymer molded into a biodegradable polymer based on an organic solvent that can be administered to a living body).
  • sustained-release preparation is a sustained-release microcapsule
  • it is preferably a long-term sustained-release microcapsule that releases a prostate cancer therapeutic drug over 2 months or more.
  • the formulation can be prepared by mixing in the required unit dose form.
  • Sterile compositions for injection can be formulated according to conventional pharmaceutical practice, such as dissolving or suspending active substances in vehicles such as water for injection, naturally occurring vegetable oils such as sesame oil, coconut oil and the like.
  • aqueous solutions for injection include physiological saline, isotonic solutions containing glucose and other adjuvants (eg, D-sorbitol, D-mannitol, sodium chloride, etc.) and the like.
  • glucose and other adjuvants eg, D-sorbitol, D-mannitol, sodium chloride, etc.
  • alcohol eg, ethanol, etc.
  • polyalcohol eg, propylene glycol, polyethylene glycol, etc.
  • nonionic surfactant eg, polysorbate 80 (TM), HCO-50, etc.
  • the oily liquid for example, sesame oil, soybean oil and the like are used, and they may be used in combination with solubilizing agents such as benzyl benzoate and benzyl alcohol.
  • the above preparation includes, for example, a buffer (eg, phosphate buffer, sodium acetate buffer, etc.), a soothing agent (eg, benzalkonium chloride, procaine, etc.), a stabilizer (eg, human serum albumin). , Polyethylene glycol, etc.), preservatives (eg, benzyl alcohol, phenol, etc.), antioxidants and the like.
  • the prepared injection solution is usually filled in a sealed container such as an appropriate ampoule or vial.
  • a sustained-release preparation (especially a sustained-release microcapsule) containing the above-mentioned therapeutic agent for prostate cancer (preferably leuprorelin or a salt thereof, more preferably leuprorelin acetate) can be obtained by a method known per se, for example, JP-A-60-1000051, JP-A-62-201816, JP-A-4-321622, JP-A-6-192068, JP-A-9-132524, JP-A-9-221417, JP-A-11-279054. No., WO 99/36099, and the like.
  • sustained release preparations “long-term sustained release microcapsules capable of zero-order release of physiologically active substances over 2 months or more” described in JP-A-4-321622 are particularly preferably used.
  • An example of a method for producing the sustained release microcapsule will be described below.
  • a prostate cancer therapeutic agent preferably leuprorelin or a salt thereof, more preferably leuprorelin acetate
  • a prostate cancer therapeutic agent in water is about 20% to 70% (w / w), preferably 25 to 65% (w / w). ), More preferably 35 to 60% (w / w), and if necessary, gelatin or a drug-holding substance such as a basic amino acid is dissolved or suspended to obtain an internal aqueous phase solution.
  • a pH adjuster for maintaining the stability and solubility of a therapeutic agent for prostate cancer preferably leuprorelin or a salt thereof, more preferably leuprorelin acetate
  • carbonic acid Acetic acid, oxalic acid, citric acid, phosphoric acid, hydrochloric acid, sodium hydroxide, arginine, lysine or a salt thereof
  • Acetic acid oxalic acid
  • citric acid phosphoric acid
  • hydrochloric acid sodium hydroxide
  • arginine lysine or a salt thereof
  • a stabilizer for a prostate cancer therapeutic agent preferably leuprorelin or a salt thereof, more preferably leuprorelin acetate
  • albumin preferably leuprorelin or a salt thereof, more preferably leuprorelin acetate
  • citric acid ethylenediaminetetraacetate sodium, dextrin, sodium bisulfite
  • ethylenediaminetetraacetate sodium e.g., methylparaben, propylparaben, etc.
  • benzyl alcohol eg, chlorobutanol, thimerosal, and the like
  • polyol compounds such as polyethylene glycol or as preservatives.
  • the inner aqueous phase solution thus obtained is added to a solution (oil phase) containing a polymer, and then an emulsification operation is performed to form a W / O type emulsion (W / O emulsion).
  • a known dispersion method is used, and examples thereof include an intermittent shaking method, a method using a propeller-type stirrer or a turbine-type stirrer, a colloid mill method, a homogenizer method, and an ultrasonic irradiation method.
  • the W / O type emulsion thus prepared is subjected to a microencapsulation step.
  • an underwater drying method or a phase separation method can be applied.
  • the W / O type emulsion is further added to the third phase aqueous phase to form a W / O / W type three phase emulsion, and then in the oil phase.
  • the solvent is evaporated to prepare microcapsules.
  • An emulsifier may be added to the aqueous phase of the outer phase.
  • examples thereof include any anionic surfactant (eg sodium oleate) as long as it generally forms a stable O / W emulsion. , Sodium stearate, sodium lauryl sulfate, etc.), nonionic surfactant (eg, polyoxyethylene sorbitan fatty acid ester [Tween 80, Tween 60, Atlas Powder Co., Ltd.], polyoxyethylene castor oil derivative [HCO-60, HCO -50, Nikko Chemicals, etc.), or polyvinylpyrrolidone, polyvinyl alcohol, carboxymethylcellulose, lecithin, gelatin and the like, and one of these may be used, or some of them may be used in combination.
  • anionic surfactant eg sodium oleate
  • nonionic surfactant eg, polyoxyethylene sorbitan fatty acid ester [Tween 80, Tween 60, Atlas Powder Co.,
  • the concentration at the time of use can be appropriately selected from the range of about 0.01% to 20%, more preferably about 0.05% to 10%.
  • a commonly used method is employed for evaporation of the oil phase solvent. As this method, the pressure is gradually reduced while stirring with a propeller type stirrer or a magnetic stirrer, or the degree of vacuum is adjusted using a rotary evaporator or the like. In this case, when the solidification of the high molecular weight polymer proceeds to some extent, by gradually heating the W / O / W type emulsion, the desorption of the solvent can be made more complete and the required time can be shortened. .
  • the microcapsules thus obtained are separated by centrifugation or filtration, and then free prostate cancer therapeutic agent (preferably leuprorelin or a salt thereof, more preferably attached to the surface of the microcapsules.
  • free prostate cancer therapeutic agent preferably leuprorelin or a salt thereof, more preferably attached to the surface of the microcapsules.
  • Leuprorelin acetate e.g., leuprorelin acetate
  • drug-retaining substance emulsifier, and the like
  • emulsifier emulsifier
  • an aggregation inhibitor eg, mannitol, sorbitol, lactose, glucose, etc.
  • a coacervation agent is gradually added to the W / O emulsion with stirring to precipitate and solidify the polymer.
  • the coacervation agent may be a polymer, mineral oil, or vegetable oil compound that is miscible with the polymer polymer solvent and does not dissolve the encapsulating polymer.
  • microcapsules thus obtained are collected by filtration and then repeatedly washed with heptane or the like to remove the coacervation agent. Furthermore, the removal of the free drug and the removal of the solvent are carried out by the same method as the underwater drying method. In order to prevent aggregation of particles during washing, an aggregation inhibitor may be added.
  • the microcapsules obtained above are lightly pulverized if necessary, and then sieved to remove the excessively large microcapsules.
  • the average particle diameter of the microcapsules is in the range of about 0.5 to 1000 ⁇ m, more preferably in the range of about 2 to 500 ⁇ m. When used as a suspension injection, it may be in a range satisfying its dispersibility and needle penetration, and is preferably in the range of about 2 to 100 ⁇ m, for example.
  • polystyrene-maleic acid copolymer examples include biodegradable polymers such as ⁇ -hydroxymonocarboxylic acids (eg, glycolic acid, lactic acid), ⁇ -hydroxydicarboxylic acids (eg, malic acid), ⁇ -hydroxytricarboxylic acid.
  • biodegradable polymers such as ⁇ -hydroxymonocarboxylic acids (eg, glycolic acid, lactic acid), ⁇ -hydroxydicarboxylic acids (eg, malic acid), ⁇
  • the bonding mode of the monomer may be random, block or graft.
  • the ⁇ -hydroxymonocarboxylic acids, ⁇ -hydroxydicarboxylic acids, or ⁇ -hydroxytricarboxylic acids have an optically active center in the molecule, any of D-, L-, and DL-forms may be used.
  • lactic acid-glycolic acid polymer hereinafter referred to as poly (lactide-co-glycolide), poly (lactic acid-co-glycolic acid) or lactic acid-glycolic acid copolymer may be referred to, and unless otherwise specified, Lactic acid, glycolic acid homopolymers (polymers) and copolymers (copolymers) are collectively called lactic acid homopolymers as lactic acid polymers, polylactic acids, or polylactides, and glycolic acid homopolymers as glycolic acid polymers, Preferred is glycolic acid or polyglycolide), poly ( ⁇ -cyanoacrylic acid ester), and the like.
  • the biodegradable polymer is more preferably a lactic acid-glycolic acid polymer, and more preferably a lactic acid-glycolic acid polymer having a free carboxyl group at the terminal.
  • the biodegradable polymer may be a salt.
  • the salt include inorganic bases (eg, alkali metals such as sodium and potassium; alkaline earth metals such as calcium and magnesium) and organic bases (eg, organic amines such as triethylamine; basic amino acids such as arginine). Etc.), and salts and complex salts with transition metals (eg, zinc, iron, copper, etc.).
  • the composition ratio (mol%) is preferably about 100/0 to about 40/60, more preferably about 100/0 to about 50/50.
  • a lactic acid homopolymer having a composition ratio of 100/0 is also preferably used.
  • the optical isomer ratio of lactic acid which is one of the minimum repeating units of the “lactic acid-glycolic acid polymer”, is about 75/25 to about 25/75 in D-form / L-form (mol / mol%). A range is preferred.
  • the weight average molecular weight of the “lactic acid-glycolic acid polymer” is usually about 3,000 to about 100,000, preferably about 3,000 to about 60,000, more preferably about 3,000 to about 50,000. 000.
  • the dispersity (weight average molecular weight / number average molecular weight) of the “lactic acid-glycolic acid polymer” is usually preferably about 1.2 to about 4.0, more preferably about 1.5 to 3.5.
  • the amount of free carboxyl groups of the “lactic acid-glycolic acid polymer” is usually preferably about 20 to about 1000 ⁇ mol (micromol), more preferably about 40 to about 1000 ⁇ mol (micromol) per unit mass (gram) of the polymer. Is particularly preferred.
  • the weight average molecular weight, number average molecular weight, and degree of dispersion are as follows: weight average molecular weights of 1110,000, 707,000, 455,645, 354,000, 189,000, 156,055, 98,900, 66 , 437, 37, 200, 17, 100, 9,830, 5,870, 2,500, 1,303, and 504, measured by gel permeation chromatography (GPC) using 15 types of monodisperse polystyrene as reference materials Polystyrene equivalent molecular weight and calculated dispersity.
  • GPC gel permeation chromatography
  • a high-speed GPC apparatus manufactured by Tosoh Corporation, HLC-8120GPC, detection method is based on differential refractive index
  • GPC column KF804L ⁇ 2 manufactured by Showa Denko
  • chloroform as a mobile phase are used.
  • the flow rate is 1 ml / min.
  • the above-mentioned free carboxyl group amount refers to that obtained by the labeling method (hereinafter referred to as “carboxyl group amount by labeling method”).
  • ONPH o-nitrophenylhydrazine hydrochloride
  • the free carboxyl group amount Cmol / L is obtained by alkali titration, and the absorbance at 544 nm when DL-lactic acid hydrazide is obtained by the ONPH labeling method is B (/ cm).
  • the molar amount of free carboxyl groups per unit mass (gram) of the polymer can be obtained by the following formula.
  • [COOH] (mol / g) (AYC) / (WB)
  • the “carboxyl group amount” is obtained by dissolving a biodegradable polymer in a toluene-acetone-methanol mixed solvent and titrating the carboxyl group with an alcoholic potassium hydroxide solution using phenolphthalein as an indicator. (Hereafter, the value obtained by this method is referred to as “carboxyl group amount by alkali titration method”), but the end point of titration may become unclear as a result of competing with the hydrolysis reaction of the polyester main chain during titration. It is desirable to quantify by the above labeling method.
  • the “lactic acid-glycolic acid polymer” is, for example, non-catalytic dehydration polycondensation from lactic acid and glycolic acid (Japanese Patent Laid-Open No. 61-28521) or ring opening using a catalyst from a cyclic diester compound such as lactide and glycolide. It can be produced by polymerization (Encyclopedic Handbook of Biomaterials and Bioengineering Part A: Materials, Volume 2, Marcel Dekker, Inc. 1995). The polymer obtained by the above-mentioned known ring-opening polymerization method does not necessarily have a free carboxyl group at the terminal of the obtained polymer.
  • the hydrolysis described in EP-A-0839525 By subjecting to a reaction, the polymer can be modified into a polymer having a certain amount of carboxyl groups per unit mass, and this can also be used.
  • the above-mentioned “lactic acid-glycolic acid polymer having a free carboxyl group at the terminal” is the same as or similar to a known production method (for example, non-catalytic dehydration polycondensation method, see JP-A-61-28521) It can be manufactured by a method.
  • the microcapsule is used as a dispersant (eg, Tween 80, HCO-60, carboxymethylcellulose, sodium alginate, etc.), preservative (eg, methylparaben, propylparaben, etc.), isotonic agent. (E.g., sodium chloride, mannitol, sorbitol, glucose, etc.) etc. and aqueous suspensions or dispersed with vegetable oils such as sesame oil and corn oil to form oily suspensions, and sustained-release injections that can actually be used To do.
  • a dispersant eg, Tween 80, HCO-60, carboxymethylcellulose, sodium alginate, etc.
  • preservative eg, methylparaben, propylparaben, etc.
  • isotonic agent e.g., sodium chloride, mannitol, sorbitol, glucose, etc.
  • vegetable oils such as sesame oil and corn oil to form oily suspensions, and sustained-release injection
  • a preparation (preferably, leuprorelin or a salt thereof (preferably leuprorelin acetate) comprising the above-mentioned therapeutic agent for prostate cancer (preferably leuprorelin or a salt thereof, more preferably leuprorelin acetate).
  • the agent containing the sustained-release microcapsule is easily administered as it is as an injection or implant (preferably injection) into the subcutaneous, intramuscular, blood vessel, etc. (preferably subcutaneous). can do.
  • the above-mentioned various preparations can be molded and administered, and can also be used as a raw material for producing such preparations.
  • the dosage of the above preparation is the content, dosage form, prostate cancer therapeutic agent (preferably leuprorelin or leuprorelin or a salt thereof, more preferably leuprorelin acetate),
  • prostate cancer therapeutic agent preferably leuprorelin or leuprorelin or a salt thereof, more preferably leuprorelin acetate
  • the duration of the salt, more preferably leuprorelin acetate varies depending on the animal to be administered [eg, warm-blooded mammal (eg, human, mouse, rat, rabbit, sheep, pig, cow, horse, etc.], etc.)
  • any effective amount of the therapeutic agent for prostate cancer preferably leuprorelin or a salt thereof, more preferably leuprorelin acetate may be used.
  • the dose per dose to the warm-blooded mammal is about 0.01 mg to 100 mg / kg body weight, preferably about 0.02 mg to 50 mg / kg body weight, more preferably 0.05 mg to 20 mg / kg body weight.
  • a prostate cancer therapeutic agent preferably leuprorelin or a salt thereof, more preferably leuproate acetate
  • about 0.1 to 50 mg, preferably about 0.1 to 20 mg, more preferably about 0.1 to 15 mg may be administered subcutaneously or intramuscularly.
  • sustained-release microcapsules containing the above-mentioned therapeutic agent for prostate cancer preferably leuprorelin or a salt thereof, more preferably leuprorelin acetate
  • the dose varies depending on the drug sustained release period of the release type microcapsule.
  • the prostate The therapeutic agent for cancer preferably leuprorelin or a salt thereof, more preferably leuprorelin acetate
  • an adult patient with prostate cancer weight 60 k
  • a therapeutic agent for prostate cancer preferably leuprorelin or a salt thereof, more preferably leuprorelin acetate
  • a therapeutic agent for prostate cancer is usually about 0.1 to 30 mg, preferably about 0.1 to 20 mg at a time. More preferably, about 1 to 15 mg may be administered subcutaneously or intramuscularly. In the case of other animals, an amount converted per 60 kg body weight can be administered.
  • the tyrosine kinase inhibitor suppresses the change from hormone-dependent prostate cancer to hormone-independent prostate cancer. Prolonged period can be treated more effectively for prostate cancer.
  • the tyrosine kinase inhibitor preferably suppresses the change from hormone-dependent prostate cancer to hormone-independent prostate cancer. Further, as the tyrosine kinase inhibitor, a receptor tyrosine kinase inhibitor is preferable.
  • gefitinib imatinib mesylate (Gleevec TM ), ODI-774, cemaxanib, SU-6668, SU-101 Lapatinib (Tykerb®), CI-1033, cetuximab, 2- [1- [3- [4- [2-[(E) -2- (4-trifluoromethylphenyl) ethenyl] oxazole -4-yl] methoxyphenyl] propyl] -1H-imidazol-2-yl] -1-ethanol, 1- ⁇ 3- [3-( ⁇ 2-[(E) -2- (2,4-difluorophenyl] ) Ethenyl] -1,3-oxazol-4-yl ⁇ methoxy) phenyl] propyl ⁇ -1H-1,2,3-triazole, 1- 4- ⁇ 4-[(2- ⁇ (E) -2- [4- (trifluoromethylphenyl) eth
  • the time of administration of the prostate cancer therapeutic agent and the tyrosine kinase inhibitor is not limited, and the prostate cancer therapeutic agent or a preparation thereof and a tyrosine kinase inhibitor or a preparation thereof are administered. It may be administered to the subject at the same time, or may be administered with a time difference.
  • the dose of the tyrosine kinase inhibitor may be determined according to the dose used clinically, and can be appropriately selected depending on the administration subject, administration route, disease, combination and the like.
  • the administration form of a pharmaceutical comprising a combination of a prostate cancer therapeutic agent and a tyrosine kinase inhibitor (hereinafter sometimes abbreviated as a concomitant drug of the present invention) is not particularly limited. It only needs to be combined with an inhibitor.
  • administration forms include (1) administration of a single preparation obtained by simultaneously formulating a prostatic cancer therapeutic agent and a tyrosine kinase inhibitor, and (2) a prostatic cancer therapeutic agent and a tyrosine kinase inhibitor.
  • Simultaneous administration of two kinds of preparations obtained by separately formulating the same, and (3) the same administration route of two kinds of preparations obtained by separately formulating the therapeutic agent for prostate cancer and the tyrosine kinase inhibitor (4) Simultaneous administration by different administration routes of two types of preparations obtained by separately formulating a prostatic cancer therapeutic agent and a tyrosine kinase inhibitor, (5) Prostate cancer therapeutic agent Administration of two preparations obtained by separately formulating a tyrosine kinase inhibitor and a tyrosine kinase inhibitor at different time intervals in different administration routes (eg, prostate cancer therapeutic agent; administration in order of tyrosine kinase inhibitor or vice versa) Administration in the order) and the like.
  • Prostate cancer therapeutic agent Administration of two preparations obtained by separately formulating a tyrosine kinase inhibitor and a tyrosine kinase inhibitor at different time intervals in different administration routes (eg, prostate cancer therapeutic
  • the preparation containing the tyrosine kinase inhibitor has low toxicity.
  • the tyrosine kinase inhibitor is mixed with a pharmacologically acceptable carrier according to a method known per se, for example, a preparation such as a tablet (sugar-coated tablet, film-coated tablet). ), Powders, granules, capsules (including soft capsules), liquids, injections, suppositories, sustained-release agents, etc., orally or parenterally (eg, topical, rectal, intravenous administration, etc.) Can be administered.
  • the injection can be administered intravenously, intramuscularly, subcutaneously, or into an organ, or directly to the lesion.
  • Examples of the pharmacologically acceptable carrier that may be used in the preparation of the preparation include various organic or inorganic carrier substances that are conventionally used as preparation materials.
  • excipients for example, excipients, lubricants, binders in solid preparations And disintegrants, solvents in liquid preparations, solubilizers, suspending agents, isotonic agents, buffers and soothing agents.
  • additives such as conventional preservatives, antioxidants, colorants, sweeteners, adsorbents, wetting agents and the like can be used in appropriate amounts.
  • examples of the excipient include lactose, sucrose, D-mannitol, starch, corn starch, crystalline cellulose, light anhydrous silicic acid and the like.
  • Examples of the lubricant include magnesium stearate, calcium stearate, talc, colloidal silica and the like.
  • Examples of the binder include crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, starch, sucrose, gelatin, methylcellulose, sodium carboxymethylcellulose and the like.
  • Examples of the disintegrant include starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl starch sodium, L-hydroxypropyl cellulose, and the like.
  • Examples of the solvent include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil, olive oil and the like.
  • solubilizer examples include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like.
  • suspending agent examples include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glyceryl monostearate; for example, polyvinyl alcohol, polyvinylpyrrolidone, Examples include hydrophilic polymers such as sodium carboxymethyl cellulose, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, and the like.
  • Examples of the isotonic agent include glucose, D-sorbitol, sodium chloride, glycerin, D-mannitol and the like.
  • Examples of the buffer include buffer solutions such as phosphate, acetate, carbonate and citrate.
  • Examples of soothing agents include benzyl alcohol.
  • Examples of the preservative include p-hydroxybenzoates, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like.
  • Examples of the antioxidant include sulfite, ascorbic acid, ⁇ -tocopherol and the like.
  • the content of the tyrosine kinase inhibitor in the preparation containing the tyrosine kinase inhibitor varies depending on the form of the preparation, but is usually about 0.01 to 100% by weight, preferably about 0.1 to 50% by weight based on the whole preparation. %, More preferably about 0.5 to 20% by weight. The same content may be used when a tyrosine kinase inhibitor is added to the preparation containing the therapeutic agent for prostate cancer.
  • the content of an additive such as a carrier in a preparation containing a tyrosine kinase inhibitor varies depending on the form of the preparation, but is usually about 1 to 99.99% by weight, preferably about 10 to 90% by weight, based on the whole preparation. Degree.
  • tyrosine kinase inhibitors include dispersants (eg, Tween 80 (Atlas Powder, USA), HCO 60 (Nikko Chemicals), polyethylene glycol, carboxymethylcellulose, sodium alginate, hydroxypropylmethylcellulose, dextrin, and the like.
  • Stabilizers eg, ascorbic acid, sodium pyrosulfite, etc.
  • surfactants eg, polysorbate 80, macrogol, etc.
  • solubilizers eg, glycerin, ethanol, etc.
  • buffers eg, phosphoric acid and Its alkali metal salts, citric acid and its alkali metal salts, etc.
  • isotonic agents eg, sodium chloride, potassium chloride, mannitol, sorbitol, glucose, etc.
  • pH regulators eg, hydrochloric acid, sodium hydroxide, etc.
  • Preservatives eg, ethyl paraoxybenzoate, benzoic acid, Luparaben, propylparaben, benzyl alcohol, etc.
  • solubilizers eg, concentrated glycerin, meglumine, etc.
  • solubilizers eg, propylene glycol, saccharose, etc.
  • the preparation for oral administration is prepared according to a method known per se, such as a tyrosine kinase inhibitor such as an excipient (eg, lactose, sucrose, starch, etc.), a disintegrant (eg, starch, calcium carbonate, etc.), a binder (eg, Starch, gum arabic, carboxymethylcellulose, polyvinylpyrrolidone, hydroxypropylcellulose, etc.) or a lubricant (eg, talc, magnesium stearate, polyethylene glycol 6000, etc.) is added and compression molded, and then, if necessary, taste masking In addition, it can be produced by coating by a method known per se for enteric or sustainable purposes.
  • a tyrosine kinase inhibitor such as an excipient (eg, lactose, sucrose, starch, etc.), a disintegrant (eg, starch, calcium carbonate, etc.), a binder (eg, Starch,
  • Examples of the coating agent used for coating include hydroxypropylmethylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, polyoxyethylene glycol, Tween 80, Pluronic F68, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, hydroxymethylcellulose acetate succinate. Eudragit (Rohm, Germany, methacrylic acid / acrylic acid copolymer) and pigments (eg, Bengala, titanium dioxide) are used.
  • the preparation for oral administration may be either an immediate release preparation or a sustained release preparation.
  • a suppository can be produced by a tyrosine kinase inhibitor as an oily or aqueous solid, semisolid or liquid suppository according to a method known per se.
  • oily base used in the manufacture of suppositories include glycerides of higher fatty acids (eg, cacao butter, witepsol (manufactured by Dynamite Nobel, Germany), etc.), intermediate fatty acids (eg, miglyols (manufactured by Dynamite Nobel, Germany), etc.], or vegetable oils (eg, sesame oil, soybean oil, cottonseed oil, etc.).
  • the aqueous base include polyethylene glycols and propylene glycol.
  • aqueous gel base examples include natural gums, cellulose derivatives, vinyl polymers, and acrylic acid polymers.
  • sustained-release preparation examples include sustained-release microcapsules. In order to obtain a sustained-release type microcapsule, a method known per se can be adopted. For example, it is preferable to form and administer a sustained-release preparation shown in [2] below. [1] Injectable preparation of tyrosine kinase inhibitor and preparation thereof, [2] Sustained release preparation or rapid release preparation of tyrosine kinase inhibitor and preparation thereof, [3] Sublingual tablet of tyrosine kinase inhibitor, A buccal or intraoral quick disintegrating agent and its preparation will be specifically described.
  • injection and preparation thereof An injection prepared by dissolving a tyrosine kinase inhibitor in water is preferable.
  • the injection may contain benzoate and / or salicylate.
  • the injection is obtained by dissolving both a tyrosine kinase inhibitor and optionally a benzoate and / or salicylate in water.
  • benzoic acid and salicylic acid salts include alkali metal salts such as sodium and potassium, alkaline earth metal salts such as calcium and magnesium, ammonium salts, meglumine salts, and other organic acid salts such as trometamol.
  • the concentration of the tyrosine kinase inhibitor in the injection is about 0.5 to 50 w / v%, preferably about 3 to 20 w / v%.
  • the concentration of benzoate or / and salicylate is 0.5 to 50 w / v%, preferably 3 to 20 w / v%.
  • additives generally used for injections such as stabilizers (ascorbic acid, sodium pyrosulfite, etc.), surfactants (polysorbate 80, macrogol, etc.), solubilizers (glycerin, ethanol, etc.) Buffers (phosphoric acid and its alkali metal salts, citric acid and its alkali metal salts, etc.), isotonic agents (sodium chloride, potassium chloride, etc.), dispersing agents (hydroxypropylmethylcellulose, dextrin), pH regulators (hydrochloric acid) , Sodium hydroxide, etc.), preservatives (ethyl paraoxybenzoate, benzoic acid, etc.), solubilizers (concentrated glycerin, meglumine, etc.), solubilizers (propylene glycol, sucrose, etc.), soothing agents (dextrose, benzyl alcohol, etc.) ) And the like can be appropriately blended.
  • stabilizers ascorbic acid, sodium pyro
  • these additives are mix
  • the injection is adjusted to pH 2 to 12, preferably pH 2.5 to 8.0, by adding a pH adjusting agent.
  • the injection is obtained by dissolving both a therapeutic agent for prostate cancer or a tyrosine kinase inhibitor and, optionally, benzoate and / or salicylate, and if necessary, the above-mentioned additives in water.
  • These dissolutions may be performed in any order, and can be appropriately performed in the same manner as in the conventional method for producing an injection.
  • the aqueous solution for injection is preferably heated, and can be provided as an injection by performing, for example, filtration sterilization, high-pressure heat sterilization, etc., as in the case of ordinary injections.
  • the aqueous solution for injection is preferably sterilized by high-pressure heat for 5 to 30 minutes, for example, at 100 to 121 ° C. Furthermore, it is good also as a formulation which provided the antibacterial property of the solution so that it could be used as a multi-dose preparation.
  • sustained-release preparation or immediate-release preparation and preparation thereof
  • a sustained-release preparation comprising a core containing a tyrosine kinase inhibitor coated with a coating agent such as a water-insoluble substance or a swellable polymer is preferable.
  • a once-daily administration type sustained-release preparation for oral administration is preferred.
  • water-insoluble substances used in the coating agent include cellulose ethers such as ethyl cellulose and butyl cellulose, cellulose esters such as cellulose acetate and cellulose propionate, polyvinyl esters such as polyvinyl acetate and polyvinyl butyrate, acrylic acid / Methacrylic acid copolymer, methyl methacrylate copolymer, ethoxyethyl methacrylate / cinnamoethyl methacrylate / aminoalkyl methacrylate copolymer, polyacrylic acid, polymethacrylic acid, methacrylic acid alkylamide copolymer, poly (methyl methacrylate) , Polymethacrylate, polymethacrylamide, aminoalkyl methacrylate copolymer, poly (methacrylic anhydride), glycidyl methacrylate copolymer, wrinkle Eudragit RS-100, RL-100, RS-30D, RL-30D, RL
  • the swellable polymer a polymer having an acidic dissociative group and exhibiting pH-dependent swelling is preferable.
  • the acidic polymer such as the stomach is less swelled, and the acidic polymer is swelled in a neutral region such as the small intestine and the large intestine.
  • the polymer which has the dissociation group of is preferable.
  • polymer having an acidic dissociative group and exhibiting pH-dependent swelling examples include, for example, Carbomer 934P, 940, 941, 974P, 980, and 1342, polycarbophil, calcium polycarbophil ( carcium polycarbophil) (all of which are manufactured by BF Goodwell, Inc.) and Hibiswako 103, 104, 105, 304 (all of which are manufactured by Wako Pure Chemical Industries, Ltd.).
  • the film agent used for the sustained release preparation may further contain a hydrophilic substance.
  • hydrophilic substance examples include hydroxyalkyl groups or carboxyalkyl groups such as polysaccharides, hydroxypropylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, etc., which may have sulfate groups such as pullulan, dextrin, and alkali metal alginate.
  • the content of the water-insoluble substance in the film of the sustained release preparation is about 30 to about 90% (w / w), preferably about 35 to about 80% (w / w), more preferably about 40 to 75% ( w / w), the swellable polymer content is about 3 to about 30% (w / w), preferably about 3 to about 15% (w / w).
  • the coating agent may further contain a hydrophilic substance, in which case the content of the hydrophilic substance in the coating agent is about 50% (w / w) or less, preferably about 5 to about 40% (w / w), More preferably, it is about 5 to about 35% (w / w).
  • the above% (w / w) represents the weight% with respect to the coating agent composition obtained by removing the solvent (eg, water, lower alcohol such as methanol, ethanol, etc.) from the coating agent solution.
  • the sustained-release preparation is prepared by preparing a core containing a drug as exemplified below, and then the obtained core is a film agent solution in which a water-insoluble substance or a swellable polymer is dissolved by heating or dissolved or dispersed in a solvent. Manufactured by coating.
  • nucleus containing a drug to be coated with a film agent
  • a nucleus is not particularly limited, but is preferably formed into particles such as granules or fine granules.
  • the core is a granule or a fine granule, the average particle size is preferably about 150 to 2,000 ⁇ m, more preferably about 500 to about 1,400 ⁇ m.
  • the preparation of the nucleus can be carried out by a usual production method.
  • excipients for example, suitable excipients, binders, disintegrants, lubricants, stabilizers and the like are mixed with the drug, and prepared by a wet extrusion granulation method, a fluidized bed granulation method, or the like.
  • the drug content of the nucleus is about 0.5 to about 95% (w / w), preferably about 5.0 to about 80% (w / w), more preferably about 30 to about 70% (w / w) It is.
  • excipients contained in the core include saccharides such as sucrose, lactose, mannitol and glucose; starch, crystalline cellulose, calcium phosphate, corn starch and the like. Of these, crystalline cellulose and corn starch are preferable.
  • binder for example, polyvinyl alcohol, hydroxypropyl cellulose, polyethylene glycol, polyvinyl pyrrolidone, pluronic F68, gum arabic, gelatin, starch and the like are used.
  • disintegrant for example, carboxymethylcellulose calcium (ECG505), croscarmellose sodium (Ac-Di-Sol), cross-linked polyvinyl pyrrolidone (crospovidone), low-substituted hydroxypropylcellulose (L-HPC) and the like are used. Of these, hydroxypropylcellulose, polyvinylpyrrolidone, and low-substituted hydroxypropylcellulose are preferable.
  • talc, magnesium stearate and its inorganic salt are used as a lubricant and an aggregation inhibitor, and polyethylene glycol is used as a lubricant.
  • acids such as tartaric acid, citric acid, succinic acid, fumaric acid and maleic acid are used.
  • the nucleus may be prepared by spraying a binder dissolved in an appropriate solvent such as water or a lower alcohol (eg, methanol, ethanol, etc.) It can also be prepared by a rolling granulation method, a pan coating method, a fluidized bed coating method or a melt granulation method in which a mixture of this and an excipient, a lubricant or the like is added little by little.
  • an appropriate solvent such as water or a lower alcohol (eg, methanol, ethanol, etc.)
  • the inert carrier particles for example, those made of sucrose, lactose, starch, crystalline cellulose, waxes can be used, and those having an average particle size of about 100 ⁇ m to about 1,500 ⁇ m are preferable.
  • the surface of the nucleus may be coated with a protective agent.
  • a protective agent for example, the hydrophilic substance, the water-insoluble substance, or the like is used.
  • the protective agent is preferably polyethylene glycol or a polysaccharide having a hydroxyalkyl group or a carboxyalkyl group, more preferably hydroxypropylmethylcellulose or hydroxypropylcellulose.
  • the protective agent may contain as stabilizers acids such as tartaric acid, citric acid, succinic acid, fumaric acid and maleic acid, and lubricants such as talc.
  • the coating amount is about 1 to about 15% (w / w), preferably about 1 to about 10% (w / w), more preferably about 2 to about 8% (w / w) based on the nucleus. w / w).
  • the protective agent can be coated by a normal coating method. Specifically, the protective agent can be coated by spray coating the core by, for example, a fluidized bed coating method, a pan coating method or the like.
  • Coating of the core with a coating agent The core obtained in the above I is coated with a coating agent solution in which the water-insoluble substance, the pH-dependent swellable polymer, and the hydrophilic substance are dissolved by heating or dissolved or dispersed in a solvent. As a result, a sustained-release preparation is produced.
  • a coating agent solution in which the water-insoluble substance, the pH-dependent swellable polymer, and the hydrophilic substance are dissolved by heating or dissolved or dispersed in a solvent.
  • a sustained-release preparation is produced.
  • the method of coating the core with the coating agent solution include a spray coating method.
  • the composition ratio of the water-insoluble substance, the swellable polymer, or the hydrophilic substance in the coating agent solution is appropriately selected so that the content of each component in the film becomes the above-described content.
  • the coating amount of the coating agent is about 1 to about 90% (w / w), preferably about 5 to about 50% (w / w) with respect to the core (excluding the coating amount of the protective agent), more preferably About 5 to 35% (w / w).
  • the solvent of the film agent solution water or an organic solvent can be used alone or a mixture of the two can be used.
  • the mixing ratio of water and organic solvent (water / organic solvent: weight ratio) in the case of using the mixed liquid can be varied in the range of 1 to 100%, preferably 1 to about 30%.
  • the organic solvent is not particularly limited as long as it dissolves water-insoluble substances.
  • lower alcohols such as methyl alcohol, ethyl alcohol, isopropyl alcohol and n-butyl alcohol, lower alkanones such as acetone, acetonitrile, chloroform, Methylene chloride or the like is used. Of these, lower alcohols are preferred, and ethyl alcohol and isopropyl alcohol are particularly preferred.
  • Water and a mixed solution of water and an organic solvent are preferably used as the solvent for the film agent.
  • an acid such as tartaric acid, citric acid, succinic acid, fumaric acid, and maleic acid may be added to the coating agent solution for stabilizing the coating agent solution.
  • the operation in the case of coating by spray coating can be carried out by an ordinary coating method.
  • the coating agent solution is carried out by spray coating the core by a fluidized bed coating method, a pan coating method or the like. be able to. If necessary, plasticize glycerin fatty acid ester, hydrogenated castor oil, triethyl citrate, cetyl alcohol, stearyl alcohol, etc., using talc, titanium oxide, magnesium stearate, calcium stearate, light anhydrous silicic acid as lubricant. You may add as an agent. After coating with a coating agent, an antistatic agent such as talc may be mixed as necessary.
  • the immediate release preparation may be liquid (solution, suspension, emulsion, etc.) or solid (particle, pill, tablet, etc.). Oral administration agents and parenteral administration agents such as injections are used, but oral administration agents are preferred.
  • the immediate-release preparation usually contains a carrier, an additive or an excipient (hereinafter sometimes abbreviated as an excipient) commonly used in the pharmaceutical field in addition to the drug as the active ingredient. .
  • the formulation excipient used is not particularly limited as long as it is an excipient commonly used as a formulation excipient.
  • excipients for oral solid preparations include lactose, starch, corn starch, crystalline cellulose (Asahi Kasei Co., Ltd., Avicel PH101, etc.), powdered sugar, granulated sugar, mannitol, light anhydrous silicic acid, magnesium carbonate, calcium carbonate , L-cysteine and the like, preferably corn starch and mannitol.
  • lactose starch
  • corn starch crystalline cellulose
  • crystalline cellulose Asahi Kasei Co., Ltd., Avicel PH101, etc.
  • the content of the excipient is, for example, from about 4.5 to about 99.4 w / w%, preferably from about 20 to about 98.5 w / w%, more preferably from about 30 to about 9%, based on the total amount of the immediate-release preparation. 97 w / w%.
  • the content of the drug in the immediate release preparation can be appropriately selected from the range of about 0.5 to about 95%, preferably about 1 to about 60% with respect to the total amount of the immediate release preparation.
  • the immediate-release preparation is an oral solid preparation, it usually contains a disintegrant in addition to the above components.
  • disintegrants examples include carboxymethylcellulose calcium (manufactured by Gotoku Pharmaceutical Co., ECG-505), croscarmellose sodium (for example, Asahi Kasei Co., Ltd., Akizol), crospovidone (for example, BASF Corp., Kollidon CL) , Low substituted hydroxypropyl cellulose (Shin-Etsu Chemical Co., Ltd.), carboxymethyl starch (Matsutani Chemical Co., Ltd.), carboxymethyl starch sodium (manufactured by Kimura Sangyo Co., Ltd., Proprotab), partially pregelatinized starch (Asahi Kasei Co., PCS) can be used.
  • carboxymethylcellulose calcium manufactured by Gotoku Pharmaceutical Co., ECG-505
  • croscarmellose sodium for example, Asahi Kasei Co., Ltd., Akizol
  • crospovidone for example, BASF Corp., Kollidon CL
  • Low substituted hydroxypropyl cellulose Shin
  • a substance that disintegrates granules by contacting with water, absorbing water, swelling, or forming a channel between the active ingredient constituting the core and the excipient can be used.
  • These disintegrants can be used alone or in combination of two or more.
  • it is appropriately selected depending on the kind and blending amount of the product, the design of the release preparation, etc., for example, about 0.05 to about 30 w / w%, preferably about 0.5 to about 15 w, relative to the total amount of the immediate release preparation / w%.
  • the immediate-release preparation is an oral solid preparation, in addition to the above-described composition, an additive commonly used in the solid preparation may be further contained as desired.
  • additives examples include binders (for example, sucrose, gelatin, gum arabic powder, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, polyvinylpyrrolidone, pullulan, and dextrin), lubricants (for example, , Polyethylene glycol, magnesium stearate, talc, light anhydrous silicic acid (eg, Aerosil (Nippon Aerosil)), surfactants (eg, anionic surfactants such as sodium alkyl sulfate, polyoxyethylene fatty acid esters and polyoxyethylene) Sorbitan fatty acid esters, nonionic surfactants such as polyoxyethylene castor oil derivatives), colorants (eg tar dyes, caramel, bengara, titanium oxide, riboflavins), If necessary, flavoring agents (for example, sweeteners, fragrances, etc.), adsorbents, preservatives, wetting agents, antistatic agents, etc.
  • binders for
  • tartaric acid citric acid, succinic acid, fumaric acid, etc.
  • Organic acids may be added.
  • binder hydroxypropylcellulose, polyethylene glycol, polyvinylpyrrolidone and the like are preferably used.
  • the immediate-release preparation can be prepared by mixing the above-described components, further kneading, if necessary, and molding based on a normal preparation manufacturing technique.
  • the mixing is performed by a generally used method such as mixing and kneading.
  • a vertical granulator when an immediate-release preparation is formed in a particulate form, a vertical granulator, a universal kneader (manufactured by Hata Iron Works), fluidized by the same method as the core preparation method of the sustained-release preparation It can be prepared by mixing using a layer granulator FD-5S (manufactured by POWREC) or the like and then granulating by a wet extrusion granulation method, a fluidized bed granulation method or the like.
  • FD-5S manufactured by POWREC
  • the immediate-release preparation and the sustained-release preparation thus obtained are prepared as they are or separately as appropriate, together with preparation excipients, etc., by a conventional method, and simultaneously or in combination with any administration interval Alternatively, both of them may be formulated into a single oral preparation (eg, granules, fine granules, tablets, capsules, etc.) as they are or as appropriate together with formulation excipients. Both preparations may be made into granules or fine granules and filled in the same capsule or the like for preparation for oral administration.
  • Sublingual tablet, buccal or intraoral quick disintegrating agent and preparation thereof may be a solid preparation such as a tablet, or an oral mucosa patch (film). There may be.
  • a preparation containing a tyrosine kinase inhibitor and an excipient is preferable. Further, it may contain auxiliary agents such as a lubricant, an isotonic agent, a hydrophilic carrier, a water-dispersible polymer, and a stabilizer.
  • ⁇ -cyclodextrin or ⁇ -cyclodextrin derivatives may be contained in order to facilitate absorption and increase bioavailability.
  • the excipient include lactose, sucrose, D-mannitol, starch, crystalline cellulose, and light anhydrous silicic acid.
  • the lubricant include magnesium stearate, calcium stearate, talc, colloidal silica and the like, and magnesium stearate and colloidal silica are particularly preferable.
  • Examples of the isotonic agent include sodium chloride, glucose, fructose, mannitol, sorbitol, lactose, saccharose, glycerin, urea and the like, and mannitol is particularly preferable.
  • Examples of the hydrophilic carrier include swellable hydrophilic carriers such as crystalline cellulose, ethyl cellulose, crosslinkable polyvinyl pyrrolidone, light anhydrous silicic acid, silicic acid, dicalcium phosphate, calcium carbonate, and particularly crystalline cellulose (eg, microcrystalline cellulose). Is preferred.
  • water-dispersible polymers examples include gums (eg, tragacanth gum, acacia gum, guar gum, etc.), alginates (eg, sodium alginate, etc.), cellulose derivatives (eg, methylcellulose, carboxymethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, etc.) ), Gelatin, water-soluble starch, polyacrylic acid (eg, carbomer), polymethacrylic acid, polyvinyl alcohol, polyethylene glycol, polyvinylpyrrolidone, polycarbophil, ascorbyl palmitate, etc., hydroxypropyl methylcellulose, polyacrylic Acid, alginate, gelatin, carboxymethylcellulose, polyvinylpyrrolidone, polyethylene glycol and the like are preferable.
  • gums eg, tragacanth gum, acacia gum, guar gum, etc.
  • alginates eg, sodium alginate, etc.
  • cellulose derivatives
  • Hydroxypropyl methylcellulose is particularly preferable.
  • the stabilizer include cysteine, thiosorbitol, tartaric acid, citric acid, sodium carbonate, ascorbic acid, glycine, sodium sulfite and the like, and citric acid and ascorbic acid are particularly preferable.
  • the sublingual tablet, buccal or intraoral quick disintegrating agent can be produced by mixing a tyrosine kinase inhibitor and an excipient by a method known per se.
  • auxiliary agents such as the above-mentioned lubricants, tonicity agents, hydrophilic carriers, water-dispersible polymers, stabilizers, colorants, sweeteners, preservatives and the like may be mixed as desired.
  • a sublingual tablet, a buccal tablet or an intraoral quick disintegrating tablet is obtained by compression tableting.
  • it may be produced by moistening / wetting with a solvent such as water or alcohol as necessary before and after the tableting molding process, and drying after molding.
  • a tyrosine kinase inhibitor and the above-mentioned water-dispersible polymer preferably hydroxypropylcellulose, hydroxypropylmethylcellulose
  • excipients etc.
  • a solvent such as water
  • the resulting solution is cast into a film.
  • additives such as plasticizers, stabilizers, antioxidants, preservatives, colorants, buffers, sweeteners, and the like may be added.
  • glycols such as polyethylene glycol and propylene glycol to give the film a suitable elasticity, or bioadhesive polymers (eg, polycarbophil, carbopol, etc.) to enhance film adhesion to the mucosal lining of the oral cavity You may make it contain.
  • Casting is performed by pouring the solution onto a non-adhesive surface, spreading it to a uniform thickness (preferably about 10 to 1000 microns) with an application tool such as a doctor blade, and then drying the solution to form a film. Achieved.
  • the film thus formed may be dried at room temperature or under heating and cut to a desired surface area.
  • Preferable intraoral quick disintegrating agents include a solid rapid diffusion agent comprising a network of a tyrosine kinase inhibitor and a water-soluble or water-diffusible carrier that is inactive with the tyrosine kinase inhibitor.
  • the network is obtained by sublimating a solvent from the solid composition composed of a solution in which a tyrosine kinase inhibitor is dissolved in an appropriate solvent.
  • the composition of the intraoral quick disintegrating agent preferably contains a matrix forming agent and a secondary component in addition to the tyrosine kinase inhibitor.
  • the matrix-forming agent examples include gelatins, dextrins, and animal or vegetable proteins such as soybean, wheat and psyllium seed proteins; gums such as gum arabic, gar gum, agar and xanthan; polysaccharides Alginates; carboxymethylcelluloses; carrageenans; dextrans; pectins; synthetic polymers such as polyvinylpyrrolidone; and materials derived from gelatin-gum arabic complex and the like.
  • saccharides such as mannitol, dextrose, lactose, galactose and trehalose; cyclic saccharides such as cyclodextrin; inorganic salts such as sodium phosphate, sodium chloride and aluminum silicate; glycine, L-alanine, L-aspartic acid, L- Examples include amino acids having 2 to 12 carbon atoms such as glutamic acid, L-hydroxyproline, L-isoleucine, L-leucine and L-phenylalanine.
  • One or more of the matrix forming agents can be introduced into a solution or suspension before solidification. Such a matrix forming agent may be present in addition to the surfactant, or may be present with the surfactant excluded. In addition to forming the matrix, the matrix forming agent can help maintain the diffusion state of the tyrosine kinase inhibitor in the solution or suspension.
  • Suitable colorants include red, black and yellow iron oxides and FD & C dyes such as FD & C Blue No. 2 and FD & C Red No. 40 from Ellis and Everald.
  • Suitable flavorings include mint, raspberry, licorice, orange, lemon, grapefruit, caramel, vanilla, cherry and grape flavors and combinations thereof.
  • Suitable pH adjusting agents include citric acid, tartaric acid, phosphoric acid, hydrochloric acid and maleic acid.
  • Suitable sweeteners include aspartame, acesulfame K and thaumatin.
  • Suitable taste masking agents include sodium bicarbonate, ion exchange resins, cyclodextrin inclusion compounds, adsorbate materials, and microencapsulated apomorphine.
  • Formulations usually contain about 0.1 to about 50% by weight, preferably about 0.1 to about 30% by weight of tyrosine kinase inhibitor, for about 1 minute to about 60 minutes, preferably about 1 minute to about Formulations (above, sublingual tablets, buccals, etc.) capable of dissolving 90% or more of the tyrosine kinase inhibitor (in water) for 15 minutes, more preferably about 2 minutes to about 5 minutes,
  • An intraoral quick disintegrating agent that disintegrates within 1 to 60 seconds, preferably within 1 to 30 seconds, more preferably within 1 to 10 seconds after being placed in the oral cavity is preferred.
  • the content of the excipient in the whole preparation is about 10 to about 99% by weight, preferably about 30 to about 90% by weight.
  • the content of ⁇ -cyclodextrin or ⁇ -cyclodextrin derivative in the whole preparation is 0 to about 30% by weight.
  • the content of the lubricant in the whole preparation is about 0.01 to about 10% by weight, preferably about 1 to about 5% by weight.
  • the content of the tonicity agent in the whole preparation is about 0.1 to about 90% by weight, preferably about 10 to about 70% by weight.
  • the content of the hydrophilic carrier in the whole preparation is about 0.1 to about 50% by weight, preferably about 10 to about 30% by weight.
  • the content of the water-dispersible polymer in the whole preparation is about 0.1 to about 30% by weight, preferably about 10 to about 25% by weight.
  • the content of the stabilizer in the whole preparation is about 0.1 to about 10% by weight, preferably about 1 to about 5% by weight.
  • the preparation may further contain additives such as colorants, sweeteners, preservatives and the like as necessary.
  • the dosage of a preparation containing a tyrosine kinase inhibitor varies depending on the type of tyrosine kinase inhibitor, age, weight, symptoms, dosage form, administration method, administration period, etc. 60 kg) per person, usually as a tyrosine kinase inhibitor (preferably lapatinib), each from about 0.01 to about 1000 mg / kg, preferably from about 0.01 to about 100 mg / kg, more preferably about 0.1 To about 100 mg / kg, especially about 0.1 to about 50 mg / kg, especially about 1.5 to about 30 mg / kg, is administered intravenously in one to several divided doses per day.
  • the dosage varies depending on various conditions.
  • the tyrosine kinase inhibitor can be set in any amount as long as side effects are not a problem.
  • the daily dose as a tyrosine kinase inhibitor varies depending on the degree of symptoms, age, sex, body weight, sensitivity difference, timing of administration, interval, nature of pharmaceutical preparation, formulation, type, type of active ingredient, etc.
  • the amount of the drug is usually about 0.001 to 2000 mg, preferably about 0.01 to 500 mg, more preferably about 0.1 to 100 mg per kg body weight of the mammal by oral administration, for example. This is usually administered in 1 to 4 divided doses per day.
  • a preparation containing a tyrosine kinase inhibitor When a preparation containing a tyrosine kinase inhibitor is administered, it may be administered at the same time. However, after the tyrosine kinase inhibitor is administered first, a therapeutic agent for prostate cancer may be administered. The drug may be administered first, followed by the tyrosine kinase inhibitor. When administered at a time difference, the time difference varies depending on the active ingredient to be administered, dosage form, and administration method. For example, when a tyrosine kinase inhibitor is administered first, 1 minute to 3 days after administration of the tyrosine kinase inhibitor Within about 10 minutes to 1 day, and more preferably within 15 minutes to 1 hour.
  • the tyrosine kinase inhibitor is administered within 1 minute to 1 day, preferably within 10 minutes to 6 hours, more preferably within 15 minutes to 1 hour after administration of the prostate cancer therapeutic agent.
  • the method of administration is mentioned.
  • Reference Example 1 Leuprorelin acetate-containing microcapsules 5.8 g of leuprorelin acetate was dissolved in 6.7 ml of distilled water. Separately, 138 g of a dichloromethane solution containing polylactic acid (weight average molecular weight: 15000) (51.6 g) dissolved and filtered was added and stirred and emulsified with an auto-minimixer for 9 minutes (rotation speed: about 6000 rpm), then 15 ° C. Adjusted.
  • Lapatinib-containing injection (Table 1) (1) Lapatinib 5.0mg (2) Salt 20.0mg (3) Distilled water Make a total volume of 2 ml. Dissolve lapatinib 5.0 mg and salt 20.0 mg in distilled water, add water to make a total volume of 2.0 ml. The solution is filtered and filled into 2 ml ampoules under aseptic conditions. The ampoule is sterilized and then sealed to obtain an injection solution.
  • Example 1 The preparation obtained in Reference Example 1 and the preparation obtained in Reference Example 2 or 3 are combined.
  • Test example 1 A 10 mM DMSO solution of the test compound (lapatinib) was prepared and stored at 4 ° C. and added to the medium immediately before use.
  • LNCaP-FGC cells prostate cancer cells
  • penicillin and streptomycin were added to a phenol-free RPMI1640 medium containing 10% of charcoal / dextran-treated FBS, and cultured under conditions of 37 ° C. and 5% CO 2 .
  • DMSO alone was cultured in a medium supplemented with 1 ⁇ M (DMSO 0.01%) of a test compound (lapatinib).
  • Four dishes (n 4) were independently subjected to medium exchange, passage, and cell count.
  • the cells were seeded in 3.0 ⁇ 10 6 cells / 10 mL / 10 mm dish, and the medium was changed twice a week.
  • the cells were subcultured on days 15, 46, 64 and 92 (the culture start date is 0 days).
  • trypsin-EDTA was added to detach the cells, and the number of recovered cells was counted with a Coulter counter.
  • Final cell counts were made on day 99 for DMSO-only dishes and on day 102 for lapatinib dishes.
  • FIG. 1 shows a growth curve when culturing was continued in a medium containing a test compound.
  • DMSO-added FGC cells showed repopulation from the 64th day after the start of the culture, and acquired resistance to hormone therapy in vitro.
  • the rapatinib-added FGC cells the cells were alive even on the 102nd day after the start of the culture, but the regrowth was suppressed. That is, it has been clarified that the change from hormone-dependent prostate cancer to hormone-independent prostate cancer is suppressed by lapatinib.

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Abstract

Cette invention concerne un excellent agent de traitement du cancer de la prostate qui comprend une association d'acétate de leuproréline et de lapatinib et qui peut inhiber le passage du cancer de la prostate hormonodépendant au cancer de la prostate non hormonodépendant.
PCT/JP2010/057449 2009-04-30 2010-04-27 Association pharmacologique Ceased WO2010126036A1 (fr)

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WO2017061431A1 (fr) * 2015-10-05 2017-04-13 富山化学工業株式会社 Comprimé contenant de la solithromycine

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US20180049987A1 (en) * 2015-01-12 2018-02-22 Enteris Biopharma, Inc. Solid Oral Dosage Forms

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