WO2017204582A1 - Composition pharmaceutique comprenant un dérivé amide ou un sel pharmaceutiquement acceptable de celui-ci inhibant la croissance de cellules cancéreuses et un stabilisant ayant un point de fusion bas - Google Patents

Composition pharmaceutique comprenant un dérivé amide ou un sel pharmaceutiquement acceptable de celui-ci inhibant la croissance de cellules cancéreuses et un stabilisant ayant un point de fusion bas Download PDF

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Publication number
WO2017204582A1
WO2017204582A1 PCT/KR2017/005480 KR2017005480W WO2017204582A1 WO 2017204582 A1 WO2017204582 A1 WO 2017204582A1 KR 2017005480 W KR2017005480 W KR 2017005480W WO 2017204582 A1 WO2017204582 A1 WO 2017204582A1
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pharmaceutical composition
composition according
pharmaceutical
formula
melting point
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PCT/KR2017/005480
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English (en)
Inventor
Myeong Ki JUNG
Caleb Hyungmin PARK
Jin Cheul Kim
Youg Il KIM
Jae Hyun Park
Jong Soo Woo
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Hanmi Pharm. Co., Ltd.
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Priority to KR1020187037359A priority Critical patent/KR20190003805A/ko
Publication of WO2017204582A1 publication Critical patent/WO2017204582A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—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
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising an amide derivative or a pharmaceutically acceptable salt thereof or a hydrate of a pharmaceutically acceptable salt thereof, which effectively inhibits growth of cancer cells, and a stabilizer having a low melting point; and a pharmaceutical dosage form prepared using and comprising the same.
  • Cells are involved with many signal transduction pathways. Such signal transduction pathways are organically connected to each other, form a complex mechanism and regulate cell proliferation, growth, death and the like (William G. Kaelin et al. , Nature Reviews Cancer , 2005, 5:689-698). Accordingly, when a regulation function in cells is unbalanced due to genetic or environmental causes, signal transduction is abnormally amplified or destroyed, which may cause diseases such as tumors (Douglas Hanahan et al ., The Hallmarks of Cancer , 2000, 100:57-70).
  • Protein tyrosine kinases have an important role in an intracellular signal transduction (Irena Melnikova, et al ., Targeting protein kinases , 2004, 3:993-994), and abnormal expression or mutations thereof are frequently observed in cancer cells.
  • Protein tyrosine kinases are enzymes that catalyze transfer of phosphate groups from ATP to tyrosine on a protein substrate.
  • growth factor receptor proteins perform intracellular signal transduction by such tyrosine kinase activities.
  • An interaction between a growth factor and receptors thereof is essential for normal regulation of cell growth. However, when regulation of signal by the receptor malfunctions due to receptor mutation or overexpression, tumor cells are induced, which may ultimately lead to cancer.
  • Purity of an active substance of a drug is an important factor in providing a safe and effective pharmaceutical formulation. Impurities of drugs can induce various side effects during treatment. Problematic drug impurities include impurities that are not possible to completely remove or that are generated in a process of preparing active substances and/or the final drug formulation/pharmaceutical dosage form and decomposition products during storage that are generated from the final pharmaceutical dosage form due to various environmental factors such as temperature, moisture and light.
  • An object of the present invention is to provide a pharmaceutical composition allowing for a lower impurity level after manufacturing of the final pharmaceutical dosage form, comprising amide derivatives or pharmaceutically acceptable salts thereof or hydrates of pharmaceutically acceptable salts thereof for inhibiting growth of cancer cells.
  • Another object of the present invention is to provide a pharmaceutical dosage form prepared using and comprising the pharmaceutical composition.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound N -(3-(2-(4-(4-methylpiperazin-1-yl)phenylamino)thieno[3,2- d ]pyrimidine-4-yloxy)phenyl) acrylamide, represented by Formula 1, or a pharmaceutically acceptable salt thereof or a hydrate of a pharmaceutically acceptable salt thereof as the active pharmaceutical ingredient (API); and one or more low melting point stabilizer(s) and, optionally, one or more pharmaceutically acceptable excipient(s).
  • API active pharmaceutical ingredient
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound represented by Formula 1, or a pharmaceutically acceptable salt thereof, or a hydrate of a pharmaceutically acceptable salt thereof, and one or more low melting point stabilizer(s) for preventing and/or treating cancers, tumors, inflammatory diseases, autoimmune diseases or immune-mediated diseases.
  • the present invention also provides a pharmaceutical dosage form prepared using and comprising the pharmaceutical composition.
  • the pharmaceutical composition of the present invention can provide a lower level of impurities for the active pharmaceutical ingredient generated during the dosage form manufacturing process.
  • a pharmaceutical dosage form prepared using and comprising the same is capable of maintaining quality during long-term storage.
  • FIG. 1 depicts the results of a stability test comparing the amount of total impurities (in % by weight) produced during manufacturing for the tablet of Example 1 with those of Comparative Examples 1 to 4, which comprise no polyethylene glycol as low melting point stabilizer.
  • FIG. 2 depicts the results of a stability test comparing the amount of total impurities (in % by weight) produced during manufacturing for the tablets of Examples 1 and 4 against the f ormulation of Comparative Example 5, which did not undergo any tableting step.
  • FIG. 3 depicts the results of a stability test comparing the amount of total impurities (in % by weight) produced during manufacturing for the tablets of Examples 1 and 5 to 8, all containing polyethylene glycol, but possessing differing tablet hardness.
  • FIG. 4 depicts the results of a stability test comparing the amount of total impurities (in % by weight) produced during manufacturing for the tablets of Examples 1 to 3 with Comparative Examples 1 and 10 with differing levels of polyethylene glycol.
  • FIG. 5 depicts the results of a stability test comparing the amount of total impurities (in % by weight) produced during manufacturing for the tablet of Examples 1 with those of Examples 9 to 13 in which polyethylene glycol is replaced with other low melting point stabilizers.
  • FIG. 6 depicts the results of a stability test comparing the amount of total impurities (in % by weight) produced during manufacturing for the tablet of Example 1 with those of Comparative Examples 6 to 9 in which non-low melting point stabilizer is contained.
  • FIG. 7 is the X-ray powder diffraction pattern of solid form 1X (a dihydrochloride hydrate, preferably monohydrate, of the compound of Formula 1) when irradiated with a Cu-K ⁇ light source.
  • solid form 1X a dihydrochloride hydrate, preferably monohydrate, of the compound of Formula 1
  • FIG. 8 is the 13 C cross polarization/magic angle spinning total suppression of sidebands solid state nuclear magnetic resonance (CP/MAS TOSS ssNMR) of solid form 1X (a dihydrochloride hydrate, preferably monohydrate, of the compound of Formula 1)
  • CP/MAS TOSS ssNMR solid state nuclear magnetic resonance
  • the term to which this invention belongs generally refer to a range of numbers that one of skill in the art would consider equivalent to the recited values (i.e., having the same function or result). In many instances these terms may include numbers that are rounded to the nearest significant figure.
  • the term “about” may refer to being within 5% of a particular value or range ( e.g. range of parts by weight, wt% etc. ), and preferably within 1% to 2%.
  • “about 10 wt%” refers to 9.5 wt% to 10.5 wt%, and preferably, 9.8 wt% to 10.2 wt%.
  • the inventors have studied to prepare a pharmaceutical composition having improved stability, comprising amide derivatives or pharmaceutically acceptable salts thereof or hydrates of pharmaceutically acceptable salts thereof for inhibiting growth of cancer cells.
  • the inventors have found that use of low melting point stabilizers in the pharmaceutical composition leads to a lower level of certain impurities in the pharmaceutical dosage form comprising them.
  • a pharmaceutical composition comprising as the active pharmaceutical ingredient a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof or a hydrate of a pharmaceutically acceptable salt thereof; one or more low melting point stabilizer(s) and, optionally, one or more pharmaceutically acceptable excipient(s).
  • a compound represented by the following Formula 1 or a pharmaceutically acceptable salt thereof or a hydrate of a pharmaceutically acceptable salt thereof may be used as the active pharmaceutical ingredient (API).
  • the compound of Formula 1 according to the present invention may be prepared by various methods, for instance, those described in WO 2011/162515.
  • the pharmaceutically acceptable salts may be those which can generally be used in the relevant art.
  • salts of inorganic acids such as hydrochloric acid, sulfuric acid, disulfuric acid, nitric acid, phosphoric acid, perchloric acid or bromic acid
  • salts of organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, succinic acid, benzoic acid, citric acid, maleic acid, malonic acid, malic acid, tartaric acid, gluconic acid, lactic acid, gestisic acid, fumaric acid, lactobionic acid, salicylic acid, phthalic acid, embonic acid, aspartic acid, glutamic acid, camphorsulfonic acid, benzenesulfonic acid, or acetylsalicylic acid (aspirin); and metal salts obtained by a reaction with alkali metals such as calcium, sodium, magnesium, strontium or potassium, may be used, but the present invention is
  • the active pharmaceutical ingredient is a hydrochloride salt of the compound of Formula 1.
  • the hydrochloride salt of the compound of Formula 1 is amorphous.
  • the hydrochloride salt of the compound of Formula 1 is crystalline.
  • the crystalline hydrochloride salt is anhydrous.
  • the crystalline hydrochloride salt is a hydrate.
  • the crystalline hydrochloride salt is a dihydrochloride.
  • this dihydrochloride salt is a hydrate, preferably a monohydrate.
  • the crystalline hydrochloride salt is a monohydrochloride.
  • this monohydrochloride salt is a hydrate.
  • the salts of the compound of Formula 1 may be prepared in a crystalline form, an amorphous form, or a mixture thereof, and preferably in a crystalline form.
  • the crystalline form of a hydrochloride salt of Formula 1 compound in particular the crystalline dihydrochloride monohydrate, has excellent stability and is thus preferable in that it has a physicochemical property which facilitates its formulation.
  • the crystalline form of a dihydrochloride hydrate is used as the active pharmaceutical ingredient (API).
  • this dihydrochloride monohydrate has the crystalline form designated as 1X (see PCT/KR2016/015535). This crystalline form 1X is associated with high water solubility, and has excellent non-hygroscopicity/non-humidification and stability
  • XRPD X-ray powder diffraction
  • peaks may be those having a relative intensity (I/Io) of about 10% or more.
  • said crystalline form 1X has an XRPD pattern with peaks at diffraction angles as contained in Table A when irradiated with a Cu-K ⁇ light source.
  • said crystalline form 1X is characterised by an X-ray powder diffraction pattern as shown in Figure 7 when irradiated with a Cu-K ⁇ light source.
  • the above crystalline form 1X may have a 13 C CP/MAS TOSS ssNMR spectrum comprising peaks at the following 13 C chemical shifts: 44.6 ⁇ 0.2 ppm and 56.6 ⁇ 0.2 ppm (ssNMR1-1).
  • the above crystalline form 1X may have a 13 C CP/MAS TOSS ssNMR spectrum comprising peaks at the following 13 C chemical shifts: 44.6 ⁇ 0.2 ppm, 45.4 ⁇ 0.2 ppm, 50.8 ⁇ 0.2 ppm and 56.6 ⁇ 0.2 ppm (ssNMR1-2).
  • the above crystalline form 1X may have a 13 C CP/MAS TOSS ssNMR spectrum comprising peaks at the following 13 C chemical shifts: 149.6 ⁇ 0.2 ppm, 152.6 ⁇ 0.2 ppm and 164.3 ⁇ 0.2 ppm (ssNMR1-3).
  • the above crystalline form 1X may have a 13 C CP/MAS TOSS ssNMR spectrum comprising peaks at the following 13 C chemical shifts: 116.5 ⁇ 0.2 ppm, 130.7 ⁇ 0.2 ppm, 146.8 ⁇ 0.2 ppm, 149.6 ⁇ 0.2 ppm, 152.6 ⁇ 0.2 ppm and 164.3 ⁇ 0.2 ppm (ssNMR1-4).
  • the above crystalline form 1X may have a 13 C CP/MAS TOSS ssNMR spectrum comprising peaks at the following 13 C chemical shifts: 44.6 ⁇ 0.2 ppm, 56.6 ⁇ 0.2 ppm, 149.6 ⁇ 0.2 ppm, 152.6 ⁇ 0.2 ppm and 164.3 ⁇ 0.2 ppm (ssNMR1-5).
  • said crystalline form 1X has a 13 C CP/MAS TOSS ssNMR spectrum comprising peaks at the 13 C chemical shifts collected in Table B below (expressed in ppm ⁇ 0.2 ppm):
  • said crystalline form 1X is characterised by a 13 C CP/MAS TOSS ssNMR spectrum as shown in Figure 8 when irradiated with a Cu-K ⁇ light source.
  • the above crystalline form 1X may have
  • the above crystalline form 1X may have
  • the above crystalline form (ex.1) may also be characterized by any other combination of lists of XRPD peaks (XRPD1-1 to XRPD1-7) and 13 C chemical shifts (ssNMR1-1 to ssNMR1-5) as listed above.
  • X-ray powder diffraction (XRPD) analyses of samples were performed in the range from 3° 2 ⁇ to 40° 2 ⁇ using a D8 Advance (Bruker ASX, Germany) analyzer.
  • XRPD X-ray powder diffraction
  • Scan range: 3° to 40°
  • Anti-scatter slit 0.3°
  • Goniometer radius 435 mm.
  • Solid State Nuclear Magnetic Resonance Spectroscopy was performed in the solid state, for example, as follows. A sample in an amount of 100 mg was weighed and added into a 4 mm sample tube. 13 C NMR spectra ( 13 C CP/MAS TOSS ssNMR) were recorded at room temperature using a Bruker Avance II 500 MHz Solid NMR system (Bruker, Germany) analyzer with 4 mm probe type CP/MAS BB-1H under the following conditions:
  • Pulse Sequence CP (Cross Polarization) SPINAL64 with decoupling (decoupling power of 80 kHz),
  • Said crystalline form 1X may have a water content of about 3.1% (theoretical water content value of 3.11% for monohydrate) measured using a Karl Fischer titrator (795KFT Titrino (Metrohm, Switzerland)) and a melting point of about 202°C to 225°C measured by differential scanning calorimetry (STA-1000 from Scinco, Korea).
  • a pharmaceutical composition according to the present invention comprises a hydrochloride salt of the compound of formula 1 as the active pharmaceutical ingredient, wherein at least 50 % by weight of the active pharmaceutical ingredient is in the form of the crystalline form 1X as defined hereinbefore.
  • a pharmaceutical composition according to the present invention at least 80 % by weight, more preferably at least 90 % by weight, most preferably at least 95 % by weight of the active pharmaceutical ingredient is in the form of the crystalline form 1X as defined hereinbefore.
  • the active pharmaceutical ingredient may be contained in an amount that is generally effective for exhibiting pharmacological activity, and may be contained in a range of 1 mg to 1000 mg per unit pharmaceutical dosage form in the present invention, e.g. 50 mg or 75 mg or 150 mg or 200 mg or 400 mg or 600 mg or 800 mg in the form of the compound of Formula 1 or their corresponding amount in the form of a pharmaceutically acceptable salt or a hydrate of a pharmaceutically acceptable salt.
  • the content of the dihydrochloride monohydrate per unit pharmaceutical dosage form is in an amount corresponding to 200 mg of the free base (Formula 1).
  • the content of the dihydrochloride monohydrate per unit pharmaceutical dosage form is in an amount corresponding to 400 mg of the free base (Formula 1).
  • the amount of active pharmaceutical ingredient (in wt%) in the pharmaceutical composition is in the range of about 1% to 65%, preferably about 55% to 65%.
  • the pharmaceutical composition of the present invention comprises one or more low melting point stabilizer(s) defined by certain characteristics.
  • a low melting point stabilizer suitable to be used in a pharmaceutical composition according to the invention inhibits the generation of certain impurities during a dosage form manufacturing process and has a melting point of 80 °C or below.
  • the low melting point stabilizer may be selected from the group consisting of polyethylene glycols (for example, PEG 1000, 1500, 1540, 2000, 3000, 4000, 6000, 8000, 20000 and 35000), glyceryl behenate, glyceryl monostearate, sorbitan fatty acid esters such as sorbitan monopalmitate or sorbitan monostearate, a polyoxyethylene-polyoxypropylene block copolymer such as Polyoxyl 150 distearate, and Poloxamer (e.g., 188 and 407), ethylene glycol stearate, fatty acids with melting points of 80 °C or less such as lauric acid, palmitic acid, or stearic acid, and any mixtures of the foregoing.
  • the level of the low melting point stabilizer may be about 0.15 to 0.6 parts by weight based on 1 part by weight of the active pharmaceutical ingredient.
  • the low melting point stabilizer used at this range provides reduction in the impurities produced during a dosgae form manufacture, such as tablet manufacture without compromising processability and drug release characteristics.
  • the low melting point stabilizer is polyethylene glycol.
  • polyethylene glycol with a molecular weight range from 1000 to 35000 is used.
  • polyethylene glycol with a molecular weight in a range from 1000 to 8000 is used.
  • a molecular weight range from 2000 to 8000 may be preferably used in a solid formulation.
  • Properties such as melting point vary with the grade.
  • PEG 8000 also known as Macrogol 8000 (Ph. Eur.)
  • the low melting point stabilizer is polyethylene glycol having a content of, based on 1 part by weight of the API, about 0.15 to 0.6 parts by weight, more specifically about 0.2 to 0.5 parts by weight, even more specifically about 0.2 to 0.3 parts by weight, and still more specifically about 0.21 to 0.26 parts by weight of polyethylene glycol.
  • the polyethylene glycol used is PEG 8000.
  • the low melting point stabilizer is thought to provide protection against friction:
  • Low melting point stabilizers such as e.g. polyethylene glycol 8000 (PEG 8000), may act as stabilizer as they may protect the active pharmaceutical ingredient from mechanical stress during dry granulation and compression.
  • the low melting point stabilizer When the low melting point stabilizer is used at a content of less than about 0.15 parts by weight, it may fail to inhibit generation of impurities. When the low melting point stabilizer is used at a content of greater than about 0.6 parts by weight, it may cause problems in drug release.
  • the pharmaceutical composition according to the present invention may further comprise one or more pharmaceutically acceptable excipients.
  • the pharmaceutically acceptable excipients may be those generally used in the field.
  • the pharmaceutically acceptable excipients may be selected from the group consisting of diluents, binders, disintegrants, lubricants, colorants, glidants, sorbents, and any mixtures thereof, and any excipient generally used in the pharmaceutical field.
  • Diluents also referred to as fillers
  • Diluents increase the bulk of a solid pharmaceutical composition, and may make a pharmaceutical dosage form containing the pharmaceutical composition easier for the patient and care giver to handle.
  • Diluents which may be used in the pharmaceutical composition include diluents commonly used in solid pharmaceutical compositions.
  • diluent(s) is/are selected from the group consisting of solid organics, as
  • sorbitol e.g. monosaccharides like glucose; oligosaccharides like sucrose, or disaccharides, as lactose in various crystalline modifications, as precipitated, spray-dried, drum-dried, or co-processed with further excipients as microcrystalline cellulose, or sorbitol, mannitol, xylitol, lactitol, erythritol, dulcitol, ribitol, erythritol);
  • - cellulose and its derivates e.g. powdered cellulose or microcrystalline cellulose
  • modified starches e.g. pre-gelatinized, or partially hydrolysed
  • Preferred diluent(s) is/are mannitol and microcrystalline cellulose or mixtures thereof.
  • the diluent(s) may be contained in an amount of about 2 to 50 wt%, specifically about 5 to 40 wt%, more specifically about 8 to 30 wt%, and preferably about 10 to 25 wt% based on the total weight of the pharmaceutical composition.
  • Binders help to bind the active pharmaceutical ingredient and other excipients together. Binders which may be used in the pharmaceutical composition include binders commonly used in solid pharmaceutical compositions. In one embodiment of the present invention, binder(s) is/are selected from the group consisting of
  • modified starches e.g. pre-gelatinized or partially hydrolysed
  • polyvinylpyrrolidones e.g. Kollidon® K30
  • polyvinylacetates e.g. polyvinylalcohols or co-polymerisates thereof (e.g. Copovidone);
  • Preferred binder is hydroxypropyl cellulose.
  • the binder may be contained in an amount of about 1 to 25 wt%, specifically about 1 to 10 wt%, and more specifically about 1 to 5 wt%, and preferably about 3 wt% based on the total weight of the pharmaceutical composition.
  • Disintegrants increase the dissolution rate of a solid pharmaceutical composition in the patient's body.
  • Disintegrants which may be used in the pharmaceutical composition include disintegrants commonly used in solid pharmaceutical compositions.
  • disintegrant(s) is/are selected from the group consisting of sodium starch glycolate, crospovidone, croscarmellose, sodium carboxymethylcellulose and dried corn starch, and any mixtures thereof, but the present invention is not limited thereto.
  • a preferred disintegrant is crospovidone.
  • the disintegrant may be contained in an amount of about 1 to 30 wt%, and more specifically about 2 to 6 wt%, and preferably about 3 wt% based on the total weight of the pharmaceutical composition.
  • Lubricants are added to a pharmaceutical composition for ease in processing, to prevent adhesion to the equipment used during processing.
  • Lubricants which may be used in the pharmaceutical composition include lubricants commonly used in solid pharmaceutical compositions.
  • lubricant(s) is/are selected from the group consisting of stearic acid, magnesium stearate, calcium stearate, sodium stearylfumarate, glycerol tribehenate, polyethylene glycol, and any mixtures thereof, but the present invention is not limited thereto.
  • a preferred lubricant is magnesium stearate.
  • the lubricant may be contained in an amount of about 0.5 to 5 wt%, and more specifically 0.5 to 2 wt%, and preferably about 1 wt% based on the total weight of the pharmaceutical composition.
  • Glidants improve the flowability of a non-compacted solid pharmaceutical composition and improve the accuracy of dosing.
  • Glidants which may be used in the pharmaceutical composition include glidants commonly used in solid pharmaceutical compositions.
  • Glidants which may be used in the pharmaceutical composition include, but are not limited to, colloidal silicon dioxide, magnesium trisilicate, starch, talc, tribasic calcium phosphate, and any combinations thereof.
  • the present invention also provides a pharmaceutical dosage form prepared using and comprising the pharmaceutical composition described above.
  • the pharmaceutical dosage form is a solid one.
  • the pharmaceutical dosage form is a liquid one, for example a syrup.
  • the solid pharmaceutical dosage form is a tablet.
  • Such tablets may be formulated using art-known compression and tableting methods, for instance, dry granulation or wet granulation using process aids such as solvents.
  • a tablet as an example of the pharmaceutical dosage form according to the present invention may have a hardness of 6 to 22 kp.
  • the tablet of the present invention has a hardness of less than 6 kp, friability may increase, and when the tablet has a hardness of greater than 22 kp, a dissolution rate may decrease.
  • the pharmaceutical composition may comprise a coating, i.e. be coated with a coating agent selected from the group consisting of an immediate release film former, an enteric coating agent, a sustained release coating agent and any mixtures thereof.
  • a coating agent selected from the group consisting of an immediate release film former, an enteric coating agent, a sustained release coating agent and any mixtures thereof.
  • such coating may additionally comprise colorants/pigments such as iron oxide or titanium dioxide, or plasticizers.
  • Exemplary coating agents used for the present invention may include hydroxy propyl cellulose, hydroxy propylmethyl cellulose, a polyvinyl alcohol and a polyvinyl alcohol-polyethylene glycol graft polymer (Kollicoat IR, BASF) as the immediate release film former; a (meth)acrylic acid copolymer (EUDRAGIT, Evonik Industries), phthalic acid hydroxy propylmethyl cellulose and phthalic acid cellulose acetate as the enteric coating agent; and cellulose acetate, ethyl cellulose and a polyvinyl acetate as the sustained release coating agent.
  • the coating agent may be used in an amount of 1 to 10 wt%, preferably 1 to 5 wt%, more preferably 2 to 4 wt% based on the total weight of the pharmaceutical composition before coating.
  • Step 1.1 Pre-mixing: Polyethylene glycol, active pharmaceutical ingredient (i.e. compound of Formula 1 in any form as herein described, preferably as a dihydrochloride monohydrate), a part of magnesium stearate, hydroxypropyl cellulose, microcrystalline cellulose and mannitol are mixed.
  • active pharmaceutical ingredient i.e. compound of Formula 1 in any form as herein described, preferably as a dihydrochloride monohydrate
  • Step 1.2 Dry granulating: The pre-mix from step 1.1 is dry granulated using a dry granulator to obtain granules.
  • Step 2 Mixing: Crospovidone and the rest of magnesium stearate is added in one step or in subsequent steps to the granules from step 1.2 and mixed to obtain the final blend.
  • Step 3 Tablet cores The final blend form the previous step is compressed into tablet cores using a tablet press.
  • Step 4.1 Dispersion: The ready-to-use coating mixture is suspended in a mixture of purified water and alcohol at room temperature to obtain the film-coating suspension.
  • Step 4.2 Film-coating: The tablet cores from step 3 are coated with the film-coating suspension from step 4.1.
  • the pharmaceutical composition of the present invention and the pharmaceutical dosage form prepared using the same comprise the compound of Formula 1 (or salts, hydrates, hydrates of salts as described hereinbefore), and effectively inhibit growth of cancer cells or tumors that are caused by the epidermal growth factor receptor tyrosine kinase or variants thereof.
  • the pharmaceutical composition of the present invention and the pharmaceutical dosage form prepared using and comprisng the same can be used for preventing and/or treating cancers, tumors, inflammatory diseases, autoimmune diseases or immune-mediated diseases.
  • the cancers or the tumors may be cancer cells or tumors induced by an epidermal growth factor receptor tyrosine kinase or a variant thereof, where a variant includes any EGFR kinases that differ from the wild type EGFR kinase sequence by means of one or more mutations, for example, substitution, addition and deletion.
  • the EGFR tyrosine kinase-induced cancers or tumors may include, for example, liver cancer, hepatocellular carcinoma, thyroid cancer, colon cancer, testicular cancer, bone cancer, oral cancer, basal cell carcinoma, ovarian cancer, a brain tumor, a gallbladder carcinoma, biliary tract cancer, head and neck cancer, colorectal cancer, a vesical carcinoma, tongue cancer, esophageal cancer, a glioma, a glioblastoma, renal cancer, a malignant melanoma, gastric cancer, breast cancer, a sarcoma, a pharynx carcinoma, uterine cancer, cervical cancer, prostate cancer, rectal cancer, pancreatic cancer, lung cancer, skin cancer, and other solid cancers, but not limited thereto.
  • this EGFR tyrosine kinase-induced cancer is lung cancer.
  • this lung cancer is non-small cell lung cancer (NSCLC) (including for example locally advanced or metastatic NSCLC (stage IIIB/IV), NSCLC adenocarcinoma, NSCLC with squamous histology, NSCLC with non-squamous histology), in particular NSCLC adenocarcinoma.
  • NSCLC non-small cell lung cancer
  • this EGFR tyrosine kinase-induced cancer harbors an EGFR exon 20 insertion or an EGFR exon 19 deletion (Del19) or an EGFR L858R mutation or an EGFR T790M mutation, or any combination thereof.
  • this EGFR tyrosine kinase-induced cancer harbors one or more EGFR mutations wherein at least one EGFR mutation is selected from Del19 (deletion in exon 19), L858R and T790M, and any combination thereof.
  • this EGFR tyrosine kinase-induced cancer harbors the EGFR mutation Del19.
  • this EGFR tyrosine kinase-induced cancer harbors the EGFR mutation L858R.
  • this EGFR tyrosine kinase-induced cancer harbors the EGFR mutation T790M.
  • this EGFR tyrosine kinase-induced cancer harbors at least two EGFR mutations selected from the group consisting of Del19/T790M and L858R/T790M.
  • this EGFR tyrosine kinase-induced cancer is non-small cell lung cancer (NSCLC), in particular NSCLC adenocarcinoma, harboring an EGFR exon 20 insertion or an EGFR exon 19 deletion (Del19) or an EGFR L858R mutation or an EGFR T790M mutation, or any combination thereof.
  • NSCLC non-small cell lung cancer
  • this EGFR tyrosine kinase-induced cancer is non-small cell lung cancer (NSCLC), in particular NSCLC adenocarcinoma, harboring one or more EGFR mutations wherein at least one EGFR mutation is selected from Del19 (deletion in exon 19), L858R and T790M, and any combination thereof.
  • NSCLC non-small cell lung cancer
  • adenocarcinoma harboring one or more EGFR mutations wherein at least one EGFR mutation is selected from Del19 (deletion in exon 19), L858R and T790M, and any combination thereof.
  • this EGFR tyrosine kinase-induced cancer is non-small cell lung cancer (NSCLC), in particular NSCLC adenocarcinoma, harboring at least two EGFR mutations selected from the group consisting of Del19/T790M and L858R/T790M.
  • NSCLC non-small cell lung cancer
  • this EGFR tyrosine kinase-induced cancer is non-small cell lung cancer (NSCLC), in particular NSCLC adenocarcinoma, harboring the EGFR mutation Del19.
  • NSCLC non-small cell lung cancer
  • this EGFR tyrosine kinase-induced cancer is non-small cell lung cancer (NSCLC) harboring the EGFR mutation L858R.
  • NSCLC non-small cell lung cancer
  • this EGFR tyrosine kinase-induced cancer is non-small cell lung cancer (NSCLC), in particular NSCLC adenocarcinoma, harboring the EGFR mutation T790M.
  • NSCLC non-small cell lung cancer
  • inflammatory diseases examples include arthritis, rheumatoid arthritis, spondyloarthropathy, gouty arthritis, osteoarthritis, juvenile arthritis, other arthritic conditions, lupus, systemic lupus erythematosus (SLE), skin-related diseases, psoriasis, eczema, dermatitis, atopic dermatitis, pain, pulmonary disorders, lung inflammation, adult respiratory distress syndrome (ARDS), pulmonary sarcoidosis, chronic pulmonary inflammatory disease, chronic obstructive pulmonary disease (COPD), cardiovascular disease, atherosclerosis, myocardial infarction, congestive heart failure, cardiac reperfusion injury, inflammatory bowel disease, Crohn’s disease, ulcerative colitis, irritable bowel syndrome, asthma, Sjogren syndrome, autoimmune thyroid disorders, urticaria, multiple sclerosis, scleroderma, organ transplant rejection, xenograft,
  • SLE systemic lupus erythe
  • the present invention provides pharmaceutical compositions and pharmaceutical dosage forms as described herein for preventing and/or treating cancers, tumors, inflammatory diseases, autoimmune diseases or immune-mediated diseases as described herein.
  • the present invention provides a method of preventing and/or treating cancers, tumors, inflammatory diseases, autoimmune diseases or immune-mediated diseases in a subject in need thereof.
  • the method comprises administering a pharmaceutical composition or a pharmaceutical dosage form of the present invention, to a subject in need thereof.
  • the subject may be, for example, a mammal, and more specifically, a human.
  • the pharmaceutical composition of the present invention may be administered through several routes including oral, percutaneous, subcutaneous, intravenous or intramuscular injection.
  • the pharmaceutical composition of the present invention may be administered once or multiple times at an effective dose generally used.
  • an actual dose of the active pharmaceutical ingredient should be determined according to several related factors such as an administration route, patient’s age, sex, and body weight, and severity of disease. Therefore, the dose does not limit the scope of the present invention in any respect.
  • the pharmaceutical composition of the present invention is formulated into a conventional formulation in the field of pharmaceuticals, and may be administered through oral, oromucosal, sublingual, intrarectal, intravaginal, intranasal, local or parenteral administration.
  • the oral administration is preferable.
  • the pharmaceutical composition according to the present invention may be provided and (orally) administered in a pharmaceutical dosage form like, e.g., in a tablet form, e.g. containing a starch or lactose, a capsule form which may contain an excipient, or an elixir or syrup form containing a chemical agent for flavor or a colorant through oral, oromucosal, or sublingual administration.
  • the pharmaceutical composition may be parenterally injected through, for example, intravenous, intracavernous, intramuscular, subcutaneous and intraductal administration.
  • API active pharmaceutical ingredient
  • powdered dihydrochloride monohydrate salt of the compound of Formula 1 (Hanmi Fine Chemical Co., Ltd.) was used.
  • Crospovidone (BASF) was added to and mixed with the granules prepared above, and then magnesium stearate (PETER GREVEN) was added thereto to obtain a final mixture.
  • a tablet having hardness of 14 kp was prepared from the obtained final mixture using a tablet machine (GRC-18, Sejong Pharmatech Co., Ltd.).
  • the above prepared tablet was coated with a coating agent, Opadry Y-1-7000 (COLORCON), using an automatic coating system (SFC-30, Sejong Pharmatech Co., Ltd.) in an amount of 2 wt% with respect to a total weight of the tablet.
  • Example 4 Tablets sharing the same pharmaceutical composition as Example 1 shown in Table 2 were prepared except that the hardness of the tablet was adjusted to 7, 9, 11 or 18 kp. Example 4 was prepared after final mixing without tableting process.
  • Tablets were prepared in the same manner as in Example 1 except that sorbitan monopalmitate, sorbitan monostearate, Poloxamer 188, Poloxamer 407, ethylene glycol stearate, glyceryl behenate, glyceryl monostearate, lauric acid, palmitic acid, or stearic acid were used in place of polyethylene glycol 8000 (Ph. Eur).
  • Comparative Examples 1 to 5 Preparation of tablets with no polyethylene glycol.
  • Comparative Examples 1 to 4 were prepared in the same manner as in Example 1 with hardness values ranging from 9 to 18 kp, except that no polyethylene glycol was added. Comparative Example 5 was prepared after final mixing without tableting process.
  • Tablets were prepared in the same manner as in Example 1 except that citric acid, ascorbic acid, magnesium carbonate, or magnesium oxide were used in place of polyethylene glycol 8000 (Ph. Eur.) according to the pharmaceutical compositions described in the following Table 7.
  • HPLC Hydrophilic 2000 series, Japan
  • UV absorptiometer (measurement wavelength: 254 nm)
  • each impurity was determined by calculating the area under the corresponding peak in the chromatogram of high performance liquid chromatography (HPLC) determined under ultraviolet irradiation at 254 nm. The ratio of peak areas between the corresponding impurity and the API was calculated for all impurity species to yield total impurities content.
  • HPLC high performance liquid chromatography
  • inventive pharmaceutical compositions comprising the low melting point stabilizers were capable of significantly suppressing total impurities during tablet manufacture.
  • Such enhancement in manufacturing stability was more impressive for certain impurities, for example those having relative retention time (RRT) of 1.4 or 1.8 in HPLC runs according to above test method (data not shown).
  • Comparative Example 1 had high initial total impurities after tableting. However, inclusion of more than 0.15 parts by weight of polyethylene glycol based on 1 part by weight of the API afforded significant impurity suppression to an acceptable level.
  • Polyethylene glycol functions as a stabilizer and is characterized by having a low melting point. Therefore, in case when a tablet is prepared by employing a low melting point stabilizer having properties similar to those of polyethylene glycol, as shown in Table 12 and FIG. 5, the stabilizer can alleviate friction to which the tablet is exposed when a pressure increases in the tablet machine, thereby effectively inhibiting the generation of specific impurities from the API.

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Abstract

La présente invention concerne une composition pharmaceutique comprenant un composé de thiénopyrimidine, ou un sel pharmaceutiquement acceptable de celui-ci, ou un hydrate d'un sel pharmaceutiquement acceptable de celui-ci et un ou plusieurs stabilisant(s) à point de fusion bas inhibant la génération d'impuretés, et une forme pharmaceutique préparée au moyen de celle-ci et comprenant celle-ci.
PCT/KR2017/005480 2016-05-27 2017-05-25 Composition pharmaceutique comprenant un dérivé amide ou un sel pharmaceutiquement acceptable de celui-ci inhibant la croissance de cellules cancéreuses et un stabilisant ayant un point de fusion bas WO2017204582A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070154545A1 (en) * 2006-01-05 2007-07-05 Julia Hrakovsky Dry formulations of aripiprazole
WO2008001201A2 (fr) * 2006-06-28 2008-01-03 Wockhardt Ltd Compositions pharmaceutiques de clopidogrel
US20080194687A1 (en) * 2003-12-09 2008-08-14 Zambon Group S.P.A Pharmaceutical Preparation Containing Gabapentin
WO2010129053A2 (fr) * 2009-05-05 2010-11-11 Dana Farber Cancer Institute Inhibiteurs d'egfr et procédés de traitement de troubles
WO2011162515A2 (fr) * 2010-06-23 2011-12-29 Hanmi Holdings Co. , Ltd. Nouveaux dérivés fusionnés de pyrimidine pour l'inhibition de l'activité tyrosine kinase

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080194687A1 (en) * 2003-12-09 2008-08-14 Zambon Group S.P.A Pharmaceutical Preparation Containing Gabapentin
US20070154545A1 (en) * 2006-01-05 2007-07-05 Julia Hrakovsky Dry formulations of aripiprazole
WO2008001201A2 (fr) * 2006-06-28 2008-01-03 Wockhardt Ltd Compositions pharmaceutiques de clopidogrel
WO2010129053A2 (fr) * 2009-05-05 2010-11-11 Dana Farber Cancer Institute Inhibiteurs d'egfr et procédés de traitement de troubles
WO2011162515A2 (fr) * 2010-06-23 2011-12-29 Hanmi Holdings Co. , Ltd. Nouveaux dérivés fusionnés de pyrimidine pour l'inhibition de l'activité tyrosine kinase

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