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WO2025195333A1 - Formulation pharmaceutique d'inhibiteurs d'erbb2 - Google Patents

Formulation pharmaceutique d'inhibiteurs d'erbb2

Info

Publication number
WO2025195333A1
WO2025195333A1 PCT/CN2025/082972 CN2025082972W WO2025195333A1 WO 2025195333 A1 WO2025195333 A1 WO 2025195333A1 CN 2025082972 W CN2025082972 W CN 2025082972W WO 2025195333 A1 WO2025195333 A1 WO 2025195333A1
Authority
WO
WIPO (PCT)
Prior art keywords
weight
triazolo
yloxy
methoxyquinazolin
pyrimidin
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/CN2025/082972
Other languages
English (en)
Inventor
Zheng Wang
Huisheng GAO
Ding Zhou
Ziqiang CHENG
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
F Hoffmann La Roche AG
Hoffmann La Roche Inc
Original Assignee
F Hoffmann La Roche AG
Hoffmann La Roche Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by F Hoffmann La Roche AG, Hoffmann La Roche Inc filed Critical F Hoffmann La Roche AG
Publication of WO2025195333A1 publication Critical patent/WO2025195333A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1635—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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1682—Processes
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1682—Processes
    • A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present disclosure relates to pharmaceutical compositions and dosage forms comprising (R) -N- (4- ( [1, 2, 4] triazolo [1, 5-c] pyrimidin-7-yloxy) -3-methylphenyl) -5- ( (3, 3-difluoro-1-methylpiperidin-4-yl) oxy) -6-methoxyquinazolin-4-amine in particular wherein the pharmaceutical compositions and dosage forms are useful in the treatment of subjects having cancer.
  • the present disclosure also provides methods for preparing the pharmaceutical compositions and dosage forms provided herein, and methods of treating subjects having cancer utilizing the pharmaceutical compositions and dosage forms provided herein. Specifically, the present disclosure relates to a pharmaceutical composition in the form of capsule.
  • the type I tyrosine kinase receptor family consists of four structurally related receptors: EGFR (ErbB1 or HER1) , ErbB2 (HER2) , ErbB3 (HER3) , and ErbB4 (HER4) (Reviewed in Riese and Stern, Bioessays , 1998, 20: 41-48; Olayioye et al., EMBO Journal , 2000, 19: 3159-3167; and Schlessinger, Cell , 2002, 110: 669-672) .
  • EGFR ErbB1 or HER1
  • HER2 ErbB2
  • HER3 ErbB3
  • HER4 ErbB4
  • the structures of the four family members are nearly the same, consisting of an extracellular region or ectodomain or ligand binding region, a single transmembrane-spanning region, and an intracellular cytoplasmic tyrosine kinase domain.
  • ErbB2 plays a role in development of cancers. ErbB2 overexpression occurs in 20-25%of breast cancer (BC) patients (Leyland-Jones B, J Clin Oncol. , 2009, 5278-86) . About 1.7 million new BC incidences are diagnosed every year (Cardoso F, et al., Breast , 2018, 131-138) and 80%of BC are invasive, which require chemotherapy, radiation or target therapy besides surgery (Dai X., et al., Am J Cancer Res , 2015, 2929-2943) . Brain metastases are a frequent occurrence in metastatic breast cancer patients. Overall survival for breast cancer brain metastases (BCBM) patients ranges from 2-25. 3 months (Leone J.P.
  • anti-ErbB2 agents have been developed for clinical use, including monoclonal antibodies such as Trastuzumab, antibody drug conjugates (ADC) such as T-DM1, and tyrosine kinase inhibitors (TKIs) such as lapatinib, neratinib, afatinib and tucatinib (Kabraji S. et al., Clinical Cancer Research , 2018, 3351; Askoxylakis V., et al., JNCI J Natl Cancer Inst , 2015, 763-763; Tanaka, Y.
  • monoclonal antibodies such as Trastuzumab
  • ADC antibody drug conjugates
  • TKIs tyrosine kinase inhibitors
  • lapatinib, neratinib, afatinib and tucatinib Kabraji S. et al., Clinical Cancer Research , 2018, 3351
  • ADC and TKIs are believed as central nervous system (CNS) penetrable. Limited clinical efficacies were observed when treating BCBM patients with non-brain penetrable aforementioned antibody, ADC and TKIs.
  • (R) -N- (4- ( [1, 2, 4] triazolo [1, 5-c] pyrimidin-7-yloxy) -3-methylphenyl) -5- ( (3, 3-difluoro-1-methylpiperidin-4-yl) oxy) -6-methoxyquinazolin-4-amine is a potent inhibitor of type I receptor tyrosine kinases and related kinases: EGFR (ErbB1 or HER1) , ErbB2 (HER2) , ErbB3 (HER3) , and ErbB4 (HER4) .
  • (R) -N- (4- ( [1, 2, 4] triazolo [1, 5-c] pyrimidin-7-yloxy) -3-methylphenyl) -5- ( (3, 3-difluoro-1-methylpiperidin-4-yl) oxy) -6-methoxyquinazolin-4-amine has been considered as an efficient blood-brain barrier (BBB) -penetrable ErbB2 (HER2) inhibitor exhibiting high selectivity against wild type EGFR to minimize EGFR mediated diarrhea and skin rash, and thus is useful for treating ErbB2 positive BC patients with or without brain metastasis.
  • BBB blood-brain barrier
  • HER2 ErbB2
  • compositions of the present invention and capsules comprising said pharmaceutical compositions also have beneficial pharmacokinetic properties.
  • Figure 3 shows that they have a good pharmacokinetic profile. These pharmacokinetic properties may be beneficial for treating brain metastases.
  • a first embodiment provided herein is a pharmaceutical composition comprising:
  • a second embodiment provided herein is a capsule comprising a composition as described herein.
  • a third embodiment also provided herein is a kit comprising the pharmaceutical composition as described herein, in the form of a capsule, in particular enteric capsule, comprising a therapeutically effective amount of (R) -N- (4- ( [1, 2, 4] triazolo [1, 5-c] pyrimidin-7-yloxy) -3-methylphenyl) -5- ( (3, 3-difluoro-1-methylpiperidin-4-yl) oxy) -6-methoxyquinazolin-4-amine, prescribing information also known as “leaflet” , a blister package or bottle (HDPE or glass) , particularly a moisture protective primary packaging, more particularly Alu/Alu blister or a plastic bottle with desiccant and a container, in particular wherein the prescribing information particularly includes the advice to a patient regarding the administration of the (R) -N- (4- ( [1, 2, 4] triazolo [1, 5-c] pyrimidin-7-yloxy) -3-methylphenyl) -5
  • a fourth embodiment provided herein is a process for the manufacture of granules comprising (R) -N- (4- ( [1, 2, 4] triazolo [1, 5-c] pyrimidin-7-yloxy) -3-methylphenyl) -5- ( (3, 3-difluoro-1-methylpiperidin-4-yl) oxy) -6-methoxyquinazolin-4-amine, a filler, a binder, and a glidant, as herein described, the process comprising the following steps:
  • step (f) milling the dried granules from step (e) .
  • step (g) optionally blending the granules from step (f) with an extragranular part (e.g., a lubricant) .
  • an extragranular part e.g., a lubricant
  • a fifth embodiment provided herein is a pharmaceutical composition as described herein, for the treatment of cancers comprising but not limited to, for example, heart (sarcoma [angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma] , myxoma, rhabdomyoma, fibroma, lipoma and teratoma) , mediastinum and pleura, and other intrathoracic organs, vascular tumors and tumor-associated vascular tissue; respiratory tract, for example, nasal cavity and middle ear, accessory sinuses, larynx, trachea, bronchus and lung such as small cell lung cancer (SCLC) , non-small cell lung cancer (NSCLC) , bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma) , alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma,
  • Figure 1 illustrates the appearance of enteric capsules exposed in 0.1N HCl solution after 120 min.
  • Figure 3 represents the Dog pharmacokinetic (PK) results of formulation P (Plasma concentration in ng/mL vs Time in hour) .
  • the parameters Dv (10) , Dv (50) and Dv (90) represent the particle size at the 10%, 50%, 90%of the cumulative number or volume undersize particle size distribution.
  • a “Dv (10) ” for a material represents a particle size wherein 10%of the number or volume of the material consists of particles having a particle size equal to the Dv (10) value or smaller.
  • a “Dv (50) ” for a material represents a particle size wherein 50%of the number of volume of the material consists of particles having a particle size equal to the Dv (50) value or smaller.
  • a “Dv (90) ” for a material represents a particle size wherein 90%of the number or volume of the material consists of particles having a particle size equal to the Dv (90) value or smaller.
  • (R) -N- (4- ( [1, 2, 4] triazolo [1, 5-c] pyrimidin-7-yloxy) -3-methylphenyl) -5- ( (3, 3-difluoro-1-methylpiperidin-4-yl) oxy) -6-methoxyquinazolin-4-amine is a solid in crystalline or amorphous form, more particularly in crystalline form, even more particularly as Fumarate Type A, Fumarate Type B, Fumarate Type C, Fumarate Type E, Freebase Type A, Freebase Type B, Freebase Type C, Freebase Type D, Freebase Type E, Freebase Type F, Freebase Type G, HCl Salt Type A, HCl Salt Type B, Mesylate Type A, Mesylate Type B, Phosphate Type A, L-tartrate Type A or Adipate Type A as disclosed in WO 2023/066296, most particularly as Fumarate Type A.
  • Fumarate Type A of (R) -N- (4- ( [1, 2, 4] triazolo [1, 5-c] pyrimidin-7-yloxy) -3-methylphenyl) -5- ( (3, 3-difluoro-1-methylpiperidin-4-yl) oxy) -6-methoxyquinazolin-4-amine has been disclosed in WO 2023/066296 as “Fumarate Type A” together with a process for its preparation.
  • compositions comprising solvates, salts, and polymorphic forms of (R) -N- (4- ( [1, 2, 4] triazolo [1, 5-c] pyrimidin-7-yloxy) -3-methylphenyl) -5- ( (3, 3-difluoro-1-methylpiperidin-4-yl) oxy) -6-methoxyquinazolin-4-amine or stereoisomers, and isotopically labeled versions.
  • Fumarate type A is (R) -N- (4- ( [1, 2, 4] triazolo [1, 5-c] pyrimidin-7-yloxy) -3-methylphenyl) -5- ( (3, 3-difluoro-1-methylpiperidin-4-yl) oxy) -6-methoxyquinazolin-4-amine fumarate (1/1.5) as shown below:
  • “Fumarate Type A” refers to a crystalline form of compound (I) , Fumarate Type A, characterized by an X-ray powder diffraction pattern which comprises at least peaks at 2 ⁇ ( ⁇ 0.2°) of 6.9 and 11.5; typically, by an X-ray powder diffraction pattern which comprises at least peaks at 2 ⁇ ( ⁇ 0.2°) of 5.8, 6.9, 11.5, 12.1 and 17.7; more typically, by an X-ray powder diffraction pattern which comprises at least peaks at 2 ⁇ ( ⁇ 0.2°) of 5.8, 6.9, 11.5, 12.1, 17.7, 20.8 and 24.0 ; more typically, by an X-ray powder diffraction pattern which comprises at least peaks at 2 ⁇ ( ⁇ 0.2°) of 5.8, 6.9, 11.5, 12.1, 17.7, 18.9, 20.8, 23.1, 23.7, 24.0 and 28.8.
  • a crystalline form of compound of formula (I) , Fumarate Type A characterized by a differential scanning ca
  • crystal refers to crystalline materials composed of two or more different molecules, one of which is the API, in the same crystal lattice that are associated by nonionic and noncovalent bonds.
  • salt refers to any of numerous compounds that result from replacement of part or all of the acid hydrogen of an acid to form an ionic or electrovalent compound.
  • crystal of salt refers to crystalline forms wherein a salified API and a co-former (or vice versa) are in the same crystal lattice that are associated by nonionic and noncovalent bonds.
  • chiral center denotes a carbon atom bonded to four non-identical substituents.
  • chiral denotes the ability of non-superimposability with the mirror image, while the term “achiral” refers to embodiments which are superimposable with their mirror image.
  • Chiral molecules are optically active, i.e., they have the ability to rotate the plane of plane-polarized light.
  • pharmaceutically acceptable excipient can be used interchangeably and denote any pharmaceutically acceptable ingredient in a pharmaceutical composition having no therapeutic activity and being non-toxic to the subject administered, such as disintegrators, binders, fillers, solvents, buffers, tonicity agents, stabilizers, antioxidants, surfactants, carriers, diluents, lubricants, or a combination thereof. used in formulating pharmaceutical products.
  • Filler or “diluent” which can be used interchangeably refers to a relatively inert substance in the form of particles, powder, beads, flakes or spheres, which improves the physical properties or increases the bulk or weight of a pharmaceutical composition.
  • a filler refers notably to an excipient which fills out the size of a tablet or capsule, making it practical to produce and convenient for the consumer to use.
  • Suitable diluents include e.g. pharmaceutically acceptable fillers, such as microcrystalline cellulose (e.g.
  • microcrystalline cellulose coated with colloidal silica cellulose powder, Isomalt, lactose, lactose spray-dried, lactose anhydrous, lactose monohydrate, maltodextrin, mannitol, dibasic calcium phosphate, sorbitol, sugars, sucrose, dextrose, sugar alcohols, hydrolyzed starch, corn starch, starch, pregelatinized starch, polysaccharides, dibasic calcium phosphate (i.e. Fujicalin) , calcium sulfate and combination thereof.
  • filler is anhydrous dibasic calcium phosphate.
  • mammals include, but are not limited to, domesticated animals (e.g., cows, sheep, cats, dogs, and horses) , primates (e.g., humans and non-human primates such as monkeys) , rabbits, and rodents (e.g., mice and rats) .
  • the individual or subject is a human.
  • “Patient” or “patients” refers to a human (such as a male or female human) who has been diagnosed with cancer, in particular the cancer is ErbB2 positive, more particularly wherein the cancer is selected from breast, gastric biliary, colorectal, brain, lug, NSCLC, pancreatic, head and neck, ovarian and uterine cancer, most particularly wherein the cancer is selected from breast, gastric biliary, colorectal, brain, lug, NSCLC, pancreatic, head and neck, ovarian and uterine cancer wherein the cancer is/are ErbB2 positive.
  • a "HER2-expressing cancer” is one that involves cancer cells or tumor cells having HER2 protein present at their cell surface.
  • HER2-positive cancer or "HER2-overexpressing cancer” may be defined as one which has significantly higher levels of HER2 at the cell surface of a cancer or tumor cell, compared to a noncancerous cell of the same tissue type. Such overexpression may be caused by gene amplification or by increased transcription or translation.
  • HER-ligand overexpressing cancer is one which produces significantly higher levels of the HER2 ligand compared to a noncancerous cell of the same tissue type.
  • HER ligand refers to a polypeptide which binds to and/or activates a HER receptor. Examples include, without limitation, epidermal growth factor (EGF) , transforming growth factor alpha (TGF-alpha) ; amphiregulin; betacellulin; heparin-binding epidermal growth factor (HBEGF) ; a heregulin; epiregulin; neuregulin-2 (NRG-2) ; NRG-3; NRG-4 or cripto (CR-1) .
  • HER ligands which bind EGFR include EGF, TGF-alpha, amphiregulin, betacellulin, HBEGF and epiregulin.
  • HER receptor or HER ligand expression or overexpression may be determined in a diagnostic or prognostic assay by evaluating increased levels of the HER protein present on the surface of a cell (e.g. via an immunohistochemistry assay; IHC) .
  • IHC immunohistochemistry assay
  • one may measure levels of HER-encoding nucleic acid in the cell, e.g. via fluorescent in situ hybridization (FISH; see WO98/45479 published October 1998) , southern blotting, or polymerase chain reaction (PCR) techniques, such as real time quantitative PCR (RT-PCR) .
  • FISH fluorescent in situ hybridization
  • PCR polymerase chain reaction
  • various in vivo assays are available to the skilled practitioner. For example, one may expose cells within the body of the patient to an antibody which is optionally labeled with a detectable label, e.g. a radioactive isotope, and binding of the antibody to cells in the patient can be evaluated, e.g. by external scanning for radioactivity or by analyzing a biopsy taken from a patient previously exposed to the antibody.
  • a detectable label e.g. a radioactive isotope
  • HER receptor or HER ligand expression or overexpression may be determined in a diagnostic or prognostic assay by evaluating increased levels of the HER or levels of the HER ligand in a biological sample (such as cancer cell) from the subject to be treated.
  • a biological sample such as cancer cell
  • the test biological sample can be exposed to an anti-HER2 antibody which binds to and detects the expressed HER2 protein.
  • HER2 can also be detected at nucleic acid expression level, using methods such as qPCR, reverse transcriptase PCR, microarray, SAGE, FISH, and the like.
  • solvate refers herein to a molecular complex comprising a compound of formula (I) and a stoichiometric or non-stoichiometric amount of one or more solvent molecules (e.g., ethanol) .
  • therapeutically effective amount denotes an amount of a compound or molecule of the present disclosure that, when administered to a subject, (i) treats or prevents the particular disease, condition or disorder, (ii) attenuates, ameliorates or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition or disorder described herein.
  • the therapeutically effective amount will vary depending on the compound, the disease state being treated, the severity of the disease treated, the age and relative health of the subject, the route and form of administration, the judgement of the attending medical or veterinary practitioner, and other factors.
  • treating or “treatment” of a disease state include inhibiting the disease state, i.e., arresting the development of the disease state or its clinical symptoms, or relieving the disease state, i.e., causing temporary or permanent regression of the disease state or its clinical symptoms.
  • XRPD refers the analytical method of X-Ray Powder Diffraction. The repeatability of the angular values is in the range of 2Theta ⁇ 0.2°. The term “approximately” given in combination with an angular value denotes the repeatability which is in the range of 2Theta ⁇ 0.2°.
  • the relative XRPD peak intensity is dependent upon many factors such as structure factor, temperature factor, crystallinity, polarization factor, multiplicity, and Lorentz factor. Relative intensities may vary considerably from one measurement to another due to preferred orientation effects. According to USP 941 (US Pharmacopoeia, 37th Edition, General Chapter 941) , relative intensities between two samples of the same material may vary considerably due to “preferred orientation” effects.
  • Anisotropic materials adopting preferred orientation will lead to anisotropic distribution of properties such as modulus, strength, ductility, toughness, electrical conductivity, thermal expansion, etc., as described e.g. in Kocks U.F. et al. (Texture and Anisotropy: Preferred Orientations in Polycrystals and Their Effect on Materials Properties, Cambridge University Press, 2000) . In XRPD but also Raman spectroscopy, preferred orientations cause a change in the intensity distribution. Preferred orientation effects are particularly pronounced with crystalline APIs of relatively large particle size.
  • Binder refers to a substance that hold the ingredients of the formulation together. Binders ensure that the granules of the formulation are formed with the required mechanical strength, and give volume to low active dose tablets, capsules or any other forms. Suitable binders are hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, carboxypolymethylene, methylcellulose, ethylcellulose, carboxymethylcellulose sodium, carboxymethylcellulose calcium, carboxymethyl starch, starch or mixture thereof. Particular examples of binder described herein are polyvinlypyrrolidon (PVP; e.g.
  • Povidone K30 hydroxypropyl methylcellulose (HPMC; e.g METHOCEL TM E5) , and hydroxypropylcellulose (HPC; e.g. Klucel TM hydroxypropylcellulose) , and proteins like gelatin.
  • the binder is hydroxypropylcellulose (HPC; e.g. Klucel TM hydroxypropylcellulose) .
  • Capsule refers to a conventional hard pharmaceutical capsule intended for oral administration to a human or animal being, said capsule consisting of two co-axial, telescopically-joined parts, referred to as body and cap.
  • body and cap co-axial, telescopically-joined parts
  • caps and bodies normally have a side wall, an open end and a closed end. The length of the side wall of each of said parts is generally greater than the capsule diameter.
  • the capsule caps and bodies are telescopically joined together so as to make their side walls partially overlap and obtain a hard capsule shell.
  • Enteric capsule refers to a capsule as define herein above, wherein said capsule can't be dissolved by the gastric juices, but can be dissolved by the intestinal juices, resulting in the delayed release or targeted release of the contents of said capsule in the intestinal tract.
  • enteric capsule are enteric-coated vacant gelatin capsule, or enteric-coated vacant hydroxypropyl methyl cellulose capsule.
  • enteric-coated materials are Cellulose Acetate Phthalate (CAP) , or hydroxypropyl methylcellulose phthalate (HPMC P) , or Polyvinyl alcohol phthalate (PVAP) , or Polyacrylic acid (Eudragit E100, RL/RS, EPO, NE/RD) .
  • a particular example of enteric capsule is a hydroxypropyl methylcellulose phthalate coated vacant hydroxypropyl methyl cellulose capsule.
  • enteric capsule is a hydroxypropyl methylcellulose phthalate coated vacant gelatin capsule.
  • Disintegrant means a substance able to expand and dissolve when in contact with a solvent, causing the breaking down of the solid in small parts, rendering the dissolution of the solids faster.
  • disintegrants are sodium starch glycolate, or crosslinked polymers, such as crosslinked polyvinylpyrrolidone (crospovidone) , crosslinked carboxymethyl cellulose (croscarmellose sodium) , or a combination thereof; in a particular embodiment the disintegrant is croscarmellose sodium.
  • “Glidant” refers to a substance that, when added to a powder, improves the flowability of the powder, such as by reducing inter-particle friction.
  • Exemplary glidants include but are not limited to colloidal silicas, colloidal silicon dioxide (e.g 200) , fumed silica (e.g. ) , magnesium trisilicate, powdered cellulose, talc, starch, magnesium aluminum silicates and combination thereof.
  • a particular example of glidant refers to colloidal silicon dioxide, more particularly the example refers to colloidal silicon dioxide.
  • Lubricant refers to excipients that prevent ingredients from clumping together and from sticking to the capsule filling machine.
  • Lubricants also ensure that formation and ejection can occur with low friction between active ingredient and wall. Examples of lubricants are poloxamer, polyethylene glycol, polyoxyethylene stearate, polyvinyl alcohol, talc, silica stearin, magnesium stearate, sodium stearyl fumarate or mixture thereof. A specific example is magnesium stearate.
  • composition comprising:
  • a particular embodiment relates to a pharmaceutical composition as described herein above comprising:
  • a particular embodiment relates to a pharmaceutical composition as described herein above comprising:
  • a particular embodiment relates to a pharmaceutical composition as described herein above comprising:
  • a particular embodiment relates to a pharmaceutical composition as described herein above comprising:
  • a particular embodiment relates to a pharmaceutical composition as described herein above comprising between 30%and 95%by weight of (R) -N- (4- ( [1, 2, 4] triazolo [1, 5-c] pyrimidin-7-yloxy) -3-methylphenyl) -5- ( (3, 3-difluoro-1-methylpiperidin-4-yl) oxy) -6-methoxyquinazolin-4-amine or an equivalent amount of in the form of a pharmaceutically acceptable salt thereof, more particularly between 50%and 85%by weight of (R) -N- (4- ( [1, 2, 4] triazolo [1, 5-c] pyrimidin-7-yloxy) -3-methylphenyl) -5- ( (3, 3-difluoro-1-methylpiperidin-4-yl) oxy) -6-methoxyquinazolin-4-amine or an equivalent amount of in the form of a pharmaceutically acceptable salt thereof, most particularly 70% ⁇ 10%by weight of (R) -N- (4- ( [1,
  • a particular embodiment relates to a pharmaceutical composition as described herein above comprising between 30%and 95%by weight of a fumarate salt of (R) -N- (4- ( [1, 2, 4] triazolo [1, 5-c] pyrimidin-7-yloxy) -3-methylphenyl) -5- ( (3, 3-difluoro-1-methylpiperidin-4-yl) oxy) -6-methoxyquinazolin-4-amine, more particularly between 50%and 85%by weight of a fumarate salt of (R) -N- (4- ( [1, 2, 4] triazolo [1, 5-c] pyrimidin-7-yloxy) -3-methylphenyl) -5- ( (3, 3-difluoro-1-methylpiperidin-4-yl) oxy) -6-methoxyquinazolin-4-amine, most particularly 70% ⁇ 10%by weight of a fumarate salt of (R) -N- (4- ( [1, 2, 4] triazolo [1, 5-c
  • a particular embodiment relates to a pharmaceutical composition as described herein above, wherein the filler is between 4%and 69%by weight of the filler, more particularly between 10%and 50%by weight of the filler, most particularly 20% ⁇ 10%by weight of the filler.
  • a particular embodiment relates to a pharmaceutical composition as described herein above, wherein the filler is between 4%and 69%by weight of the filler, more particularly between 10%and 50%by weight of the filler, most particularly 12% ⁇ 2%by weight of the filler.
  • a particular embodiment relates to a pharmaceutical composition as described herein above, wherein the binder is between 1%and 5%by weight of the binder, more particularly between 2%and 4%by weight of the binder, most particularly 3% ⁇ 0.5%by weight of the binder.
  • a particular embodiment relates to a pharmaceutical composition as described herein above, comprising between 1%and 5%by weight of the binder, more particularly between 2%and 4%by weight of the binder, most particularly 3% ⁇ 0.5%by weight of the binder.
  • a particular embodiment relates to a pharmaceutical composition as described herein above, wherein the disintegrant is between 0.5%and 15%by weight of the disintegrant, more particularly between 3%and 10%by weight of the disintegrant, most particularly 6% ⁇ 2%by weight of the disintegrant.
  • a particular embodiment relates to a pharmaceutical composition as described herein above, comprising between 0.5%and 15%by weight of the disintegrant, more particularly between 3%and 10%by weight of the disintegrant, most particularly 8% ⁇ 2%by weight of the disintegrant.
  • a particular embodiment relates to a pharmaceutical composition as described herein above, wherein the lubricant is between 0.25%and 5%by weight of the lubricant, more particularly between 0.5%and 2.5%by weight of the lubricant, most particularly 1.5% ⁇ 0.5%by weight of the lubricant.
  • a particular embodiment relates to a pharmaceutical composition as described herein above comprising:
  • a particular embodiment relates to a pharmaceutical composition as described herein above comprising:
  • a particular embodiment relates to a pharmaceutical composition as described herein above comprising:
  • a particular embodiment relates to a pharmaceutical composition as described herein above comprising:
  • a particular embodiment relates to a pharmaceutical composition as described herein above comprising:
  • a particular embodiment relates to a pharmaceutical composition as described herein above comprising:
  • a particular embodiment relates to a pharmaceutical composition as described herein above comprising:
  • a particular embodiment relates to a pharmaceutical composition as described herein above comprising:
  • a particular embodiment relates to a pharmaceutical composition as described herein above comprising:
  • an intragranular component comprising:
  • a particular embodiment relates to a pharmaceutical composition as described herein above comprising:
  • a particular embodiment relates to a pharmaceutical composition as described herein above comprising:
  • a particular embodiment relates to a pharmaceutical composition as described herein above, consisting of:
  • a particular embodiment relates to a pharmaceutical composition as described herein above, wherein the pharmaceutical composition comprises 50 mg of (R) -N- (4- ( [1, 2, 4] triazolo [1, 5-c] pyrimidin-7-yloxy) -3-methylphenyl) -5- ( (3, 3-difluoro-1-methylpiperidin-4-yl) oxy) -6-methoxyquinazolin-4-amine.
  • a particular embodiment relates to a pharmaceutical composition as described herein above, wherein (R) -N- (4- ( [1, 2, 4] triazolo [1, 5-c] pyrimidin-7-yloxy) -3-methylphenyl) -5- ( (3, 3-difluoro-1-methylpiperidin-4-yl) oxy) -6-methoxyquinazolin-4-amine is 50 mg.
  • a particular embodiment relates to a pharmaceutical composition as described herein above comprising:
  • a particular embodiment relates to a pharmaceutical composition as described herein above comprising:
  • a particular embodiment relates to a pharmaceutical composition as described herein above, wherein the pharmaceutical composition comprises 200 mg of (R) -N- (4- ( [1, 2, 4] triazolo [1, 5-c] pyrimidin-7-yloxy) -3-methylphenyl) -5- ( (3, 3-difluoro-1-methylpiperidin-4-yl) oxy) -6-methoxyquinazolin-4-amine.
  • a particular embodiment relates to a pharmaceutical composition as described herein above comprising:
  • a particular embodiment relates to a pharmaceutical composition as described herein above comprising:
  • a particular embodiment relates to a pharmaceutical composition as described herein above comprising a compound of formula (II)
  • a particular embodiment relates to a pharmaceutical composition as described herein above, wherein (R) -N- (4- ( [1, 2, 4] triazolo [1, 5-c] pyrimidin-7-yloxy) -3-methylphenyl) -5- ( (3, 3-difluoro-1-methylpiperidin-4-yl) oxy) -6-methoxyquinazolin-4-amine is a fumarate salt of (R)-N- (4- ( [1, 2, 4] triazolo [1, 5-c] pyrimidin-7-yloxy) -3-methylphenyl) -5- ( (3, 3-difluoro-1-methylpiperidin-4-yl) oxy) -6-methoxyquinazolin-4-amine, in particular a fumarate salt of (R) -N- (4- ( [1, 2, 4] triazolo [1, 5-c] pyrimidin-7-yloxy) -3-methylphenyl) -5- ( (3, 3-difluoro-1
  • a particular embodiment relates to a pharmaceutical composition as described herein above comprising only one active pharmaceutical ingredient (API) , particularly wherein the only API is (R) -N- (4- ( [1, 2, 4] triazolo [1, 5-c] pyrimidin-7-yloxy) -3-methylphenyl) -5- ( (3, 3-difluoro-1-methylpiperidin-4-yl) oxy) -6-methoxyquinazolin-4-amine, more particularly wherein the only API is (R) -N- (4- ( [1, 2, 4] triazolo [1, 5-c] pyrimidin-7-yloxy) -3-methylphenyl) -5- ( (3, 3-difluoro-1-methylpiperidin-4-yl) oxy) -6-methoxyquinazolin-4-amine fumarate.
  • API active pharmaceutical ingredient
  • a particular embodiment relates to a pharmaceutical composition as described herein above wherein the pharmaceutical ingredient (API) has a particle size of less than 95.5 ⁇ m (Dv(90) ) .
  • a particular embodiment relates to a pharmaceutical composition as described herein above comprising between 30%and 95%by weight of (R) -N- (4- ( [1, 2, 4] triazolo [1, 5-c] pyrimidin-7-yloxy) -3-methylphenyl) -5- ( (3, 3-difluoro-1-methylpiperidin-4-yl) oxy) -6-methoxyquinazolin-4-amine fumarate, more particularly between 50%and 85%by weight of (R) -N- (4- ( [1, 2, 4] triazolo [1, 5-c] pyrimidin-7-yloxy) -3-methylphenyl) -5- ( (3, 3-difluoro-1-methylpiperidin-4-yl) oxy) -6-methoxyquinazolin-4-amine fumarate, most particularly 70% ⁇ 10%by weight of (R) -N- (4- ( [1, 2, 4] triazolo [1, 5-c] pyrimidin-7-yloxy) -3-methyl
  • a particular embodiment relates to a pharmaceutical composition as described herein above wherein the pharmaceutical composition comprises 70% ⁇ 10%by weight of (R) -N- (4- ( [1, 2, 4] triazolo [1, 5-c] pyrimidin-7-yloxy) -3-methylphenyl) -5- ( (3, 3-difluoro-1-methylpiperidin-4-yl) oxy) -6-methoxyquinazolin-4-amine fumarate.
  • a particular embodiment relates to a pharmaceutical composition as described herein above wherein the pharmaceutical composition comprises 70% ⁇ 10%by weight of a fumarate salt of (R) -N- (4- ( [1, 2, 4] triazolo [1, 5-c] pyrimidin-7-yloxy) -3-methylphenyl) -5- ( (3, 3-difluoro-1-methylpiperidin-4-yl) oxy) -6-methoxyquinazolin-4-amine, wherein the fumarate salt of (R) -N- (4- ( [1, 2, 4] triazolo [1, 5-c] pyrimidin-7-yloxy) -3-methylphenyl) -5- ( (3, 3-difluoro-1-methylpiperidin-4-yl) oxy) -6-methoxyquinazolin-4-amine has a (R) -N- (4- ( [1, 2, 4] triazolo [1, 5-c] pyrimidin-7-yloxy) -3-methylphenyl)
  • a particular embodiment relates to a pharmaceutical composition as described herein above wherein the pharmaceutical composition comprises 70% ⁇ 10%by weight of Fumarate Type A.
  • a particular embodiment relates to a pharmaceutical composition as described herein above wherein the pharmaceutical composition comprises 65 ⁇ 5 mg of a fumarate salt of (R) -N- (4- ( [1, 2, 4] triazolo [1, 5-c] pyrimidin-7-yloxy) -3-methylphenyl) -5- ( (3, 3-difluoro-1-methylpiperidin-4-yl) oxy) -6-methoxyquinazolin-4-amine, wherein the fumarate salt of (R) -N- (4- ( [1, 2, 4] triazolo [1, 5-c] pyrimidin-7-yloxy) -3-methylphenyl) -5- ( (3, 3-difluoro-1-methylpiperidin-4-yl) oxy) -6-methoxyquinazolin-4-amine has a (R) -N- (4- ( [1, 2, 4] triazolo [1, 5-c] pyrimidin-7-yloxy) -3-methylphenyl) -5
  • a particular embodiment relates to a pharmaceutical composition as described herein above wherein the pharmaceutical composition comprises 260 ⁇ 20 mg of a fumarate salt of (R) -N- (4- ( [1, 2, 4] triazolo [1, 5-c] pyrimidin-7-yloxy) -3-methylphenyl) -5- ( (3, 3-difluoro-1-methylpiperidin-4-yl) oxy) -6-methoxyquinazolin-4-amine, wherein the fumarate salt of (R) -N- (4- ( [1, 2, 4] triazolo [1, 5-c] pyrimidin-7-yloxy) -3-methylphenyl) -5- ( (3, 3-difluoro-1-methylpiperidin-4-yl) oxy) -6-methoxyquinazolin-4-amine has a (R) -N- (4- ( [1, 2, 4] triazolo [1, 5-c] pyrimidin-7-yloxy) -3-methylphenyl)
  • a particular embodiment relates to a pharmaceutical composition as described herein above wherein the pharmaceutical composition comprises 260 ⁇ 20 mg of Fumarate Type A.
  • a particular embodiment relates to a pharmaceutical composition as described herein above, wherein the filler is selected from microcrystalline cellulose (e.g. ) , microcrystalline cellulose coated with colloidal silica, cellulose powder, Isomalt, lactose, lactose spray-dried, lactose anhydrous, lactose monohydrate, maltodextrin, mannitol, dibasic calcium phosphate, sorbitol, sugars, sucrose, dextrose, sugar alcohols, hydrolyzed starch, corn starch, starch, pregelatinized starch, polysaccharides, dibasic calcium phosphate (i.e. Fujicalin) , calcium sulfate and combination thereof.
  • the filler is selected from microcrystalline cellulose (e.g. ) , microcrystalline cellulose coated with colloidal silica, cellulose powder, Isomalt, lactose, lactose spray-dried, lactose anhydrous, lactose monohydrate, mal
  • a particular embodiment relates to a pharmaceutical composition as described herein above, wherein the filler is anhydrous dibasic calcium phosphate, particularly wherein anhydrous dibasic calcium phosphate has an average particle size 115 ⁇ m, most particularly the anhydrous dibasic calcium phosphate is SG.
  • a particular embodiment relates to a pharmaceutical composition as described herein above, wherein the binder is selected from hydroxypropyl methylcellulose (e.g METHOCEL TM E5) , hydroxypropyl cellulose (e.g. KlucelTM hydroxypropylcellulose) , polyvinylpyrrolidone (PVP, such as Povidone K30) , carboxymethylcellulose sodium, carboxymethylcellulose calcium, and proteins like gelatin or mixture thereof.
  • hydroxypropyl methylcellulose e.g METHOCEL TM E5
  • hydroxypropyl cellulose e.g. KlucelTM hydroxypropylcellulose
  • PVP polyvinylpyrrolidone
  • a particular embodiment relates to a pharmaceutical composition as described herein above, wherein the binder is hydroxypropyl cellulose (CAS: 9004-64-20) , particularly wherein hydroxypropyl cellulose with low viscosity of 100-1000 mpa. s (e.g. KlucelTM hydroxypropyl cellulose E) .
  • the binder is hydroxypropyl cellulose (CAS: 9004-64-20) , particularly wherein hydroxypropyl cellulose with low viscosity of 100-1000 mpa. s (e.g. KlucelTM hydroxypropyl cellulose E) .
  • a particular embodiment relates to a pharmaceutical composition as described herein above, wherein the disintegrant is selected from sodium starch glycolate, or crosslinked polymers, such as crosslinked polyvinylpyrrolidone (crospovidone) , crosslinked carboxymethyl cellulose (e.g. croscarmellose sodium) and or mixture thereof.
  • the disintegrant is selected from sodium starch glycolate, or crosslinked polymers, such as crosslinked polyvinylpyrrolidone (crospovidone) , crosslinked carboxymethyl cellulose (e.g. croscarmellose sodium) and or mixture thereof.
  • a particular embodiment relates to a pharmaceutical composition as described herein above, wherein the disintegrant is croscarmellose sodium present at 8 ⁇ 2 wt%.
  • a particular embodiment relates to a pharmaceutical composition as described herein above, wherein the glidant is selected from colloidal silicas, colloidal silicon dioxide (e.g 200) , fumed silica (e.g ) , talc, starch, magnesium aluminum silicates Hydrophilic Fumed Silica and mixture thereof.
  • a particular embodiment relates to a pharmaceutical composition as described herein above, wherein the glidant is Colloidal Silicon Dioxide, particularly wherein Colloidal Silicon Dioxide is hydrophilic fumed silica with surface area of 200m 2 /g (e.g. CAS 7631-86-9) , more particularly the colloidal silicon dioxide is 200 Pharma.
  • the glidant is Colloidal Silicon Dioxide, particularly wherein Colloidal Silicon Dioxide is hydrophilic fumed silica with surface area of 200m 2 /g (e.g. CAS 7631-86-9) , more particularly the colloidal silicon dioxide is 200 Pharma.
  • a particular embodiment relates to a pharmaceutical composition as described herein above, wherein the lubricant is selected from poloxamer, polyethylene Glycol, polyoxyethylene stearate, polyvinyl alcohol, talc, silica stearin, magnesium stearate, sodium stearyl fumarate or mixture thereof.
  • the lubricant is selected from poloxamer, polyethylene Glycol, polyoxyethylene stearate, polyvinyl alcohol, talc, silica stearin, magnesium stearate, sodium stearyl fumarate or mixture thereof.
  • a particular embodiment relates to a pharmaceutical composition as described herein above, wherein the lubricant is magnesium stearate.
  • a particular embodiment relates to a pharmaceutical composition as described herein above, wherein the lubricant is magnesium stearate with bulk density 0.05g/cm 3 to 0.30g/cm 3 (e.g. CAS 557-04-0) , wherein the magnesium stearate is based on vegetable sources for the pharmaceutical product.
  • the lubricant is magnesium stearate with bulk density 0.05g/cm 3 to 0.30g/cm 3 (e.g. CAS 557-04-0) , wherein the magnesium stearate is based on vegetable sources for the pharmaceutical product.
  • a particular embodiment relates to a pharmaceutical composition as described herein above, wherein:
  • the disintegrant is croscarmellose sodium
  • the glidant is colloidal silicon dioxide (e.g. 200) .
  • the binder is hydroxypropyl cellulose (e.g. Type EXF) ,
  • the lubricant is magnesium stearate.
  • a particular embodiment relates to a pharmaceutical composition as described herein above, comprising:
  • filler 12% ⁇ 2%by weight of the filler, wherein the filler is anhydrous dibasic calcium phosphate (e.g. Fujicalin SG) ,
  • glidant 2% ⁇ 0.5%by weight of the glidant, wherein the glidant is colloidal silicon dioxide (e.g. 200) ,
  • binder hydroxypropyl cellulose (e.g. Type EXF) , and
  • a particular embodiment relates to a pharmaceutical composition as described herein above, wherein the pharmaceutical composition is prepared by a process including a wet granulation step (e.g. Manufacturing Process C) .
  • a wet granulation step e.g. Manufacturing Process C
  • a particular embodiment relates to a pharmaceutical composition as described herein above, wherein the pharmaceutical composition is prepared by a process including a wet granulation step, wherein the process comprises the following steps:
  • step (f) milling the dried granules from step (e) .
  • step (g) optionally blending the granules from step (f) with the lubricant, when present.
  • a particular embodiment relates to a pharmaceutical composition as described herein above, wherein:
  • a fumarate salt) thereof is a fumarate salt of (R) -N- (4- ( [1, 2, 4] triazolo [1, 5-c] pyrimidin-7-yloxy) -3-methylphenyl) -5- ( (3, 3-difluoro-1-methylpiperidin-4-yl) oxy) -6-methoxyquinazolin-4-amine, more particularly wherein the fumarate salt of (R) -N- (4- ( [1, 2, 4] triazolo [1, 5-c] pyrimidin-7-yloxy) -3-methylphenyl) -5- ( (3, 3-difluoro-1-methylpiperidin-4-yl) oxy) -6-methoxyquinazolin-4-amine has a (R) -N- (4- ( [1, 2, 4] triazolo [1, 5-c] pyrimidin-7-yloxy) -3-methylphenyl) -5- ( (3, 3-difluoro-1-methylpiperidin
  • the filler is as defined herein, for example anhydrous dibasic calcium phosphate (e.g. Fujicalin SG) ,
  • the disintegrant is as defined herein, for example croscarmellose sodium,
  • the glidant is as defined herein, for example colloidal silicon dioxide (e.g. 200) ,
  • the binder is as defined herein, for example hydroxypropyl cellulose (e.g. Type EXF) , and
  • the lubricant is as defined herein, for example magnesium stearate.
  • a particular embodiment relates to a pharmaceutical composition as described herein above, wherein the (R) -N- (4- ( [1, 2, 4] triazolo [1, 5-c] pyrimidin-7-yloxy) -3-methylphenyl) -5- ( (3, 3-difluoro-1-methylpiperidin-4-yl) oxy) -6-methoxyquinazolin-4-amine or the pharmaceutically acceptable salt (e.g. a fumarate salt) thereof is processed by using a jet milling process or a recrystallization process.
  • the pharmaceutically acceptable salt e.g. a fumarate salt
  • a particular embodiment relates to a pharmaceutical composition as described herein above, wherein the (R) -N- (4- ( [1, 2, 4] triazolo [1, 5-c] pyrimidin-7-yloxy) -3-methylphenyl) -5- ( (3, 3-difluoro-1-methylpiperidin-4-yl) oxy) -6-methoxyquinazolin-4-amine or the pharmaceutically acceptable salt (e.g. a fumarate salt) thereof has a particle size of not more than 95.5 ⁇ m (Dv (90) ) .
  • a particular embodiment relates to a pharmaceutical composition as described herein above, wherein:
  • step (g) optionally blending the granules from step (f) with an extragranular part (e.g., a lubricant) .
  • an extragranular part e.g., a lubricant
  • a particular embodiment relates to a process for the manufacture of granules comprising (R) -N- (4- ( [1, 2, 4] triazolo [1, 5-c] pyrimidin-7-yloxy) -3-methylphenyl) -5- ( (3, 3-difluoro-1-methylpiperidin-4-yl) oxy) -6-methoxyquinazolin-4-amine or a pharmaceutically acceptable salt (e.g. a fumarate salt) thereof, a filler, a binder, a disintegrant and a glidant, the process comprising the following steps:
  • step (f) milling the dried granules from step (e) .
  • step (g) optionally blending the granules from step (f) with an extragranular part (e.g., a lubricant) .
  • an extragranular part e.g., a lubricant
  • a particular embodiment relates to a process as described herein above, wherein:
  • a fumarate salt) thereof is a fumarate salt of (R) -N- (4- ( [1, 2, 4] triazolo [1, 5-c] pyrimidin-7-yloxy) -3-methylphenyl) -5- ( (3, 3-difluoro-1-methylpiperidin-4-yl) oxy) -6-methoxyquinazolin-4-amine, more particularly wherein the fumarate salt of (R) -N- (4- ( [1, 2, 4] triazolo [1, 5-c] pyrimidin-7-yloxy) -3-methylphenyl) -5- ( (3, 3-difluoro-1-methylpiperidin-4-yl) oxy) -6-methoxyquinazolin-4-amine has a (R) -N- (4- ( [1, 2, 4] triazolo [1, 5-c] pyrimidin-7-yloxy) -3-methylphenyl) -5- ( (3, 3-difluoro-1-methylpiperidin
  • the filler is as defined herein, for example anhydrous dibasic calcium phosphate (e.g. Fujicalin SG) ,
  • the disintegrant is as defined herein, for example croscarmellose sodium,
  • the glidant is as defined herein, for example colloidal silicon dioxide (e.g. 200) ,
  • the binder is as defined herein, for example hydroxypropyl cellulose (e.g. Type EXF) , and
  • the lubricant is as defined herein, for example magnesium stearate.
  • a particular embodiment relates to a process as described herein above further comprising filling the mixture obtained in step g) , as described herein above, into capsules, wherein the capsules are as defined herein above.
  • a particular embodiment relates to a process as described herein above further comprising packaging the said capsules in bottles.
  • a particular embodiment relates to a process as described herein above wherein the (R) -N- (4- ( [1, 2, 4] triazolo [1, 5-c] pyrimidin-7-yloxy) -3-methylphenyl) -5- ( (3, 3-difluoro-1-methylpiperidin-4-yl) oxy) -6-methoxyquinazolin-4-amine or the pharmaceutically acceptable salt (e.g. a fumarate salt) thereof is processed by using a jet milling process or a recrystallization process.
  • the pharmaceutically acceptable salt e.g. a fumarate salt
  • a particular embodiment relates to a process as described herein above wherein the (R) -N- (4- ( [1, 2, 4] triazolo [1, 5-c] pyrimidin-7-yloxy) -3-methylphenyl) -5- ( (3, 3-difluoro-1-methylpiperidin-4-yl) oxy) -6-methoxyquinazolin-4-amine or the pharmaceutically acceptable salt (e.g. a fumarate salt) thereof has a particle size of not more than 95.5 ⁇ m (Dv (90) ) .
  • a particular embodiment relates to a pharmaceutical composition as described herein above, comprising (R) -N- (4- ( [1, 2, 4] triazolo [1, 5-c] pyrimidin-7-yloxy) -3-methylphenyl) -5- ( (3, 3-difluoro-1-methylpiperidin-4-yl) oxy) -6-methoxyquinazolin-4-amine that can be administered to an individual at any suitable dosage (e.g. to achieve a therapeutically effective amount) , particularly a suitable dose of a therapeutically effective amount of about 200 mg to 2000 mg per day (the daily dose is calculated based on the free base) , more particularly 200 mg to 1800 mg per day, most particularly about 400 mg to 1600 mg per day.
  • the pharmaceutical composition as described herein above is for the treatment of cancers comprising but not limited to cancers of the: circulatory system, for example, heart (sarcoma [angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma] , myxoma, rhabdomyoma, fibroma, lipoma and teratoma) , mediastinum and pleura, and other intrathoracic organs, vascular tumors and tumor-associated vascular tissue; respiratory tract, for example, nasal cavity and middle ear, accessory sinuses, larynx, trachea, bronchus and lung such as small cell lung cancer (SCLC) , non-small cell lung cancer (NSCLC) , bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma) , alveolar (bronchiolar) carcinoma, bronchial adenoma, s
  • a particular embodiment relates to a pharmaceutical composition as described herein above for use in the treatment of cancers comprising but not limited to cancers of the: circulatory system, for example, heart (sarcoma [angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma] , myxoma, rhabdomyoma, fibroma, lipoma and teratoma) , mediastinum and pleura, and other intrathoracic organs, vascular tumors and tumor-associated vascular tissue; respiratory tract, for example, nasal cavity and middle ear, accessory sinuses, larynx, trachea, bronchus and lung such as small cell lung cancer (SCLC) , non-small cell lung cancer (NSCLC) , bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma) , alveolar (bronchiolar) carcinoma, bronchial ade
  • a particular embodiment relates to a pharmaceutical composition as described herein above for use in the treatment of a HER2-associated cancer.
  • a particular embodiment relates to a pharmaceutical composition as described herein above for use in the treatment of cancer, or a pharmaceutical composition as described herein above for use in a method of treatment as described herein above, wherein the cancer is selected from a HER2-expressing cancer, a HER2-positive cancer, or a HER-ligand overexpressing cancer.
  • a particular embodiment relates to a pharmaceutical composition as described herein above for use in a method of treatment as described herein above wherein the cancer is a HER2-positive cancer.
  • a particular embodiment relates to a pharmaceutical composition as described herein above for use in the treatment of cancer, or a pharmaceutical composition as described herein above for use in a method of treatment as described herein above, wherein the cancer is selected from breast, gastric, biliary, colorectal, brain, lung, NSCLC, pancreatic, head and neck, ovarian and uterine cancer, more particularly wherein the cancer is selected from breast, gastric, colorectal, or NSCLC cancer.
  • a particular embodiment relates to a pharmaceutical composition as described herein above for use in a method of treatment as described herein above wherein the cancer is metastases of a cancer specified in any of the previous embodiments.
  • a particular embodiment relates to a pharmaceutical composition as described herein above for use in a method of treatment as described herein above wherein the metastases are brain metastases.
  • a particular embodiment relates to a pharmaceutical composition as described herein above for use in the treatment of cancer, or a pharmaceutical composition as described herein above for use in a method of treatment as described herein above, wherein the cancer is breast cancer brain metastases.
  • a particular embodiment relates to a method for the treatment of a HER2-associated cancer, the method comprising administering a pharmaceutical composition as described herein above.
  • a particular embodiment relates to a method of treatment as described herein above, wherein the cancer is metastases of a cancer specified in any of the previous embodiments.
  • a particular embodiment relates to a method of treatment as described herein above, wherein the metastases are brain metastases.
  • a particular embodiment relates to a method for the treatment of cancer, the method comprising administering a pharmaceutical composition as described herein above, or a method of treatment as described herein above, wherein the cancer is breast cancer brain metastases.
  • the pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof optionally further comprises a diluent, such as lactose, starch, hydrolyzed starch, microcrystalline cellulose, mannitol, sorbitol, sucrose, dextrose, dibasic calcium phosphate, calcium sulfate, or combinations thereof.
  • a diluent such as lactose, starch, hydrolyzed starch, microcrystalline cellulose, mannitol, sorbitol, sucrose, dextrose, dibasic calcium phosphate, calcium sulfate, or combinations thereof.
  • compositions comprising (R) -N- (4- ( [1, 2, 4] triazolo [1, 5-c] pyrimidin-7-yloxy) -3-methylphenyl) -5- ( (3, 3-difluoro-1-methylpiperidin-4-yl) oxy) -6-methoxyquinazolin-4-amine fumarate, and are summarized in Table 2 below.
  • the net API as directly filled into the size 0 enteric gelatin hard capsule shell by manual filling.
  • Blending speed 20rpm, Time: 10 minutes.
  • Manufacturing process C is a wet granulation process, steps as described below:
  • Manufacturing process D is a dry granulation for D, steps as described below:
  • Blending speed 20 rpm, Time: 10 minutes.
  • the capsules prepared by different manufacturing process were evaluated in the dissolution testing to evaluate the effective of the wet granulation process on the dissolution, using FaSSIF as the dissolution medium.
  • the results are described in Table 3.
  • the capsules manufactured by wet granulation process showed comparable dissolution profile to that of capsules made by direct dry blend and neat API encapsulation.
  • the dissolution profiles were found to be acceptable.
  • the pharmaceutical compositions comprising (R) -N- (4- ( [1, 2, 4] triazolo [1, 5-c] pyrimidin-7-yloxy) -3-methylphenyl) -5- ( (3, 3-difluoro-1-methylpiperidin-4-yl) oxy) -6-methoxyquinazolin-4-amine fumarate with four different particle size distributions (PSD) were prepared.
  • Table 4 Formulation Components by Using Different PSD API a
  • the strength is equal to free base ( (R) -N- (4- ( [1, 2, 4] triazolo [1, 5-c] pyrimidin-7-yloxy) -3- methylphenyl) -5- ( (3, 3-difluoro-1-methylpiperidin-4-yl) oxy) -6-methoxyquinazolin-4-amine) 200.0 mg.
  • the API used for E is processed by using jet milling process. And the API used for F, G and H are obtained by common recrystallization process.
  • the enteric capsule product was prepared by using wet granulation process then encapsulation using an automatic capsule filling machine.
  • compositions comprising (R) -N- (4- ( [1, 2, 4] triazolo [1, 5-c] pyrimidin-7-yloxy) -3-methylphenyl) -5- ( (3, 3-difluoro-1-methylpiperidin-4-yl) oxy) -6-methoxyquinazolin-4-amine fumarate with different disintegrant levels of croscarmellose sodium (0.0%, 2.0%, 5.0%and 8.0%) were prepared to investigate the impact of disintegrant level on drug release according to the following Table 6.
  • Table 6 Formulation Components for Different Disintegrant Level a
  • the strength is equal to free base ( (R) -N- (4- ( [1, 2, 4] triazolo [1, 5-c] pyrimidin-7-yloxy) -3- methylphenyl) -5- ( (3, 3-difluoro-1-methylpiperidin-4-yl) oxy) -6-methoxyquinazolin-4-amine) 200.0 mg.
  • the enteric capsule products were prepared with high shear wet granulation process followed by automatic capsule filling into the enteric gelatin hard capsule.
  • the dissolution testing results are summarized in Table 7.
  • the capsule product containing a higher disintegrant level showed faster release.
  • the capsule product with no disintegrant did not meet the dissolution quality criteria.
  • more than 2%of croscarmellose sodium as the disintegrant was selected for the capsule product.
  • a pharmaceutical composition comprising (R) -N- (4- ( [1, 2, 4] triazolo [1, 5-c] pyrimidin-7-yloxy) -3-methylphenyl) -5- ( (3, 3-difluoro-1-methylpiperidin-4-yl) oxy) -6-methoxyquinazolin-4-amine fumarate with commonly used filler of microcrystalline cellulose, lactose monohydrate and calcium phosphate dibasic were used to assess the formulation and high shear wet granulation process feasibility.
  • the formulation composition is described in the Table 8.
  • Table 8 Composition of Formulation with Different Filler a
  • the strength is equal to free base ( (R) -N- (4- ( [1, 2, 4] triazolo [1, 5-c] pyrimidin-7-yloxy) -3- methylphenyl) -5- ( (3, 3-difluoro-1-methylpiperidin-4-yl) oxy) -6-methoxyquinazolin-4-amine) 200.0 mg.
  • the enteric capsules were prepared with the different fillers of microcrystalline cellulose, lactose monohydrate and calcium phosphate dibasic by using high shear wet granulation process.
  • the granule properties are summarized in following Table 9.
  • the wet granulation process shows robust for all the formulations with the filler of microcrystalline cellulose, lactose monohydrate and calcium phosphate dibasic.
  • Example 6 Manufacturing of 50mg and 200 mg Strength Enteric Capsules
  • Table 10 illustrates the capsules in different strengths 50 mg and 200 mg based on the salt of (R) -N- (4- ( [1, 2, 4] triazolo [1, 5-c] pyrimidin-7-yloxy) -3-methylphenyl) -5- ( (3, 3-difluoro-1-methylpiperidin -4-yl) oxy) -6-methoxyquinazolin-4-amine fumarate.
  • the 10’ 200g common granule was produced with high shear wet granulation process following with automatic capsule filling process.
  • the particle size for API is: Dv (10) : 4.47 ⁇ m, Dv (50) : 15.44 ⁇ m and Dv (90) : 40.27 ⁇ m.
  • the high shear wet granulation manufacturing process is summarized as below:
  • the lubricated blend is filled into enteric capsules of size 0 and size 2 to obtain 200mg and 50mg strength capsule product separately.
  • enteric capsules are packaged in 75 ml high-density polyethylene (HDPE) bottles for solid preparation sealed with an aluminum foil induction seal liner and 33 mm medicinal safe caps (oral solid preparation polypropylene (PP) child-resistant closure) .
  • HDPE high-density polyethylene
  • the 50mg and 200mg strength enteric capsules were tested for drug release in acid stage and buffer stage using the USP Apparatus Type II paddle Method under the conditions described below with a bath temperature of 37°C and with a qualified high performance liquid chromatography method. These formulations were tested using the conditions described herein.
  • the dissolution is provided below in Table 11 that represent the average percent drug release ( (R) -N- (4- ( [1, 2, 4] triazolo [1, 5-c] pyrimidin-7-yloxy) -3-methylphenyl) -5- ( (3, 3-difluoro-1-methylpiperidin-4-yl) oxy) -6-methoxyquinazolin-4-amine) fumarate in the capsule.
  • the 50mg and 200mg strength enteric capsules show good anti-acid ability in 0.1N HCI solution, no drug release was observed for dissolution testing. And in buffer stage, the products show acceptable release profile and meet the quality criteria.
  • the study design was the following:
  • the enteric capsule shows good pharmacokinetic profile and exposure in male beagle dogs.
  • Table 14 illustrates 200 mg granules in enteric coated capsule.
  • the granules may be prepared by a process including a wet granulation step (e.g. Manufacturing Process C) .
  • the capsules may also have one or more of the following features:
  • Capsule type Gelatine, enteric-coated.
  • Embodiments 1 A pharmaceutical composition comprising:
  • Embodiment 2 The pharmaceutical composition of embodiment 1 comprising:
  • Embodiment 3 The pharmaceutical composition of embodiment 1 or 2, comprising:
  • Embodiment 4 The pharmaceutical composition of any one of embodiments 1 to 3 comprising:
  • Embodiment 5 The pharmaceutical composition of any one of embodiments 1 to 4 comprising:
  • an intragranular component comprising:
  • Embodiment 6 The pharmaceutical composition according to any one of embodiments 1 to 5, comprising between 30%and 95%by weight of (R) -N- (4- ( [1, 2, 4] triazolo [1, 5-c] pyrimidin-7-yloxy) -3-methylphenyl) -5- ( (3, 3-difluoro-1-methylpiperidin-4-yl) oxy) -6-methoxyquinazolin-4-amine or an equivalent amount of in the form of a pharmaceutically acceptable salt thereof, more particularly between 50%and 85%by weight of (R) -N- (4- ( [1, 2, 4] triazolo [1, 5-c] pyrimidin-7-yloxy) -3-methylphenyl) -5- ( (3, 3-difluoro-1-methylpiperidin-4-yl) oxy) -6-methoxyquinazolin-4-amine or an equivalent amount of in the form of a pharmaceutically acceptable salt thereof, most particularly 70% ⁇ 10%by weight of (R) -N- (4-
  • Embodiment 7 The pharmaceutical composition according to any one of embodiments 1 to 6, wherein the filler is between 4%and 69%by weight of the filler, more particularly between 10%and 50%by weight of the filler, most particularly 20% ⁇ 10%by weight of the filler.
  • Embodiment 8 The pharmaceutical composition according to any one of embodiments 1 to 7, wherein the binder is between 1%and 5%by weight of the binder, more particularly between 2%and 4%by weight of the binder, most particularly 3% ⁇ 0.5%by weight of the binder.
  • Embodiment 9 The pharmaceutical composition according to any one of embodiments 1 to 8, wherein the disintegrant is between 0.5%and 15%by weight of the disintegrant, more particularly between 3%and 10%by weight of the disintegrant, most particularly 8% ⁇ 2%by weight of the disintegrant.
  • Embodiment 10 The pharmaceutical composition according to any one of embodiments 1 to 9, wherein the glidant is between 0.5%and 10%by weight of the glidant, more particularly between 1%and 3%by weight of the glidant, most particularly 2% ⁇ 0.5%by weight of the glidant.
  • Embodiment 11 The pharmaceutical composition according to any one of embodiments 1 to 10, wherein the lubricant is between 0.25%and 5%by weight of the lubricant, more particularly between 0.5%and 2.5%by weight of the lubricant, most particularly 1.5% ⁇ 0.5%by weight of the lubricant.
  • Embodiment 12 A pharmaceutical composition according to any one of embodiments 1 to 11 comprising:
  • Embodiment 13 A pharmaceutical composition according to any one of embodiments 1 to 12 comprising:
  • Embodiment 14 A pharmaceutical composition according to any one of embodiments 1 to 13 comprising:
  • Embodiment 15 A pharmaceutical composition according to any one of embodiments 1 to 14 comprising:
  • Embodiment 16 A pharmaceutical composition according to any one of embodiments 1 to 15 comprising:
  • an intragranular component comprising:
  • Embodiment 17 The pharmaceutical composition according to any one of embodiments 1 to 16, comprising:
  • Embodiment 18 The pharmaceutical composition according to any one of embodiments 1 to 17, wherein the pharmaceutical composition comprises 50 mg of (R) -N- (4- ( [1, 2, 4] triazolo [1, 5-c] pyrimidin-7-yloxy) -3-methylphenyl) -5- ( (3, 3-difluoro-1-methylpiperidin-4-yl) oxy) -6-methoxyquinazolin-4-amine.
  • Embodiment 19 The pharmaceutical composition according to any one of embodiments 1 to 18, comprising:
  • Embodiment 20 The pharmaceutical composition according to any one of embodiments 1 to 17, wherein the pharmaceutical composition comprises 200 mg of (R) -N- (4- ( [1, 2, 4] triazolo [1, 5-c] pyrimidin-7-yloxy) -3-methylphenyl) -5- ( (3, 3-difluoro-1-methylpiperidin-4-yl) oxy) -6-methoxyquinazolin-4-amine.
  • Embodiment 21 The pharmaceutical composition according to any one of embodiments 1 to 17, and 20, comprising:
  • Embodiment 22 The pharmaceutical composition of any one of embodiments 1 to 21, further comprising a compound of formula (II)
  • Embodiment 23 The pharmaceutical composition of any one of embodiments 1 to 22, wherein (R) -N- (4- ( [1, 2, 4] triazolo [1, 5-c] pyrimidin-7-yloxy) -3-methylphenyl) -5- ( (3, 3-difluoro-1-methylpiperidin-4-yl) oxy) -6-methoxyquinazolin-4-amine is a fumarate salt of (R) -N- (4- ( [1, 2, 4] triazolo [1, 5-c] pyrimidin-7-yloxy) -3-methylphenyl) -5- ( (3, 3-difluoro-1-methylpiperidin-4-yl) oxy) -6-methoxyquinazolin-4-amine, in particular a fumarate salt of (R) -N- (4- ( [1, 2, 4] triazolo [1, 5-c] pyrimidin-7-yloxy) -3-methylphenyl) -5- ( (3, 3-difluor
  • Embodiment 24 The pharmaceutical composition of any one of embodiments 1 to 23, comprises only one active pharmaceutical ingredient (API) , particularly wherein the only API is the compound of (R) -N- (4- ( [1, 2, 4] triazolo [1, 5-c] pyrimidin-7-yloxy) -3-methylphenyl) -5- ( (3, 3-difluoro-1-methylpiperidin-4-yl) oxy) -6-methoxyquinazolin-4-amine, more particularly wherein the only API (R) -N- (4- ( [1, 2, 4] triazolo [1, 5-c] pyrimidin-7-yloxy) -3-methylphenyl) -5- ( (3, 3-difluoro-1-methylpiperidin-4-yl) oxy) -6-methoxyquinazolin-4-amine fumarate.
  • API active pharmaceutical ingredient
  • Embodiment 25 The pharmaceutical composition according to any one of embodiments 1 to 24, comprises between 30%and 95%by weight of (R) -N- (4- ( [1, 2, 4] triazolo [1, 5-c] pyrimidin-7-yloxy) -3-methylphenyl) -5- ( (3, 3-difluoro-1-methylpiperidin-4-yl) oxy) -6-methoxyquinazolin-4-amine fumarate, more particularly between 50%and 85%by weight of (R) -N- (4- ( [1, 2, 4] triazolo [1, 5-c] pyrimidin-7-yloxy) -3-methylphenyl) -5- ( (3, 3-difluoro-1-methylpiperidin-4-yl) oxy) -6-methoxyquinazolin-4-amine fumarate, most particularly 70% ⁇ 10%by weight of (R)-N- (4- ( [1, 2, 4] triazolo [1, 5-c] pyrimidin-7-yloxy) -3-
  • Embodiment 26 The pharmaceutical composition according to any one of embodiments 1 to 25, wherein the filler is selected from microcrystalline cellulose (e.g., ) , microcrystalline cellulose coated with colloidal silica, cellulose powder, Isomalt, lactose, lactose spray-dried, lactose anhydrous, lactose monohydrate, maltodextrin, mannitol, dibasic calcium phosphate, sorbitol, sugars, sucrose, dextrose, sugar alcohols, hydrolyzed starch, corn starch, starch, pregelatinized starch, polysaccharides, dibasic calcium phosphate (i.e., Fujicalin) , calcium sulfate and combination thereof.
  • the filler is selected from microcrystalline cellulose (e.g., ) , microcrystalline cellulose coated with colloidal silica, cellulose powder, Isomalt, lactose, lactose spray-dried, lactose anhydrous, lactos
  • Embodiment 27 The pharmaceutical composition according to any one of embodiments 1 to 26, wherein the filler is anhydrous dibasic calcium phosphate, particularly wherein anhydrous dibasic calcium phosphate has an average particle size of 115 ⁇ m, most particularly the anhydrous dibasic calcium phosphate is SG.
  • Embodiment 28 The pharmaceutical composition according to any one of embodiments 1 to 27, wherein the binder is selected from hydroxypropyl methylcellulose (e.g., METHOCEL TM E5) , hydroxypropyl cellulose (e.g., Klucel TM hydroxypropylcellulose) , polyvinylpyrrolidone (PVP, such as Povidone K30) , carboxymethylcellulose sodium, carboxymethylcellulose calcium, and proteins like gelatin or mixture thereof.
  • hydroxypropyl methylcellulose e.g., METHOCEL TM E5
  • hydroxypropyl cellulose e.g., Klucel TM hydroxypropylcellulose
  • PVP polyvinylpyrrolidone
  • Embodiment 29 The pharmaceutical composition according to any one of embodiments 1 to 28, wherein the binder is hydroxypropyl cellulose (CAS: 9004-64-20) , particularly wherein hydroxypropyl cellulose with low viscosity of 100-1000 mpa. s (e.g., Klucel TM hydroxypropyl cellulose E) .
  • the binder is hydroxypropyl cellulose (CAS: 9004-64-20) , particularly wherein hydroxypropyl cellulose with low viscosity of 100-1000 mpa. s (e.g., Klucel TM hydroxypropyl cellulose E) .
  • Embodiment 30 The pharmaceutical composition according to any one of embodiments 1 to 29, wherein the disintegrant is sodium starch glycolate or crosslinked polymers, such as crosslinked polyvinylpyrrolidone (crospovidone) , crosslinked carboxymethyl cellulose (e.g., croscarmellose sodium) or a mixture thereof.
  • the disintegrant is sodium starch glycolate or crosslinked polymers, such as crosslinked polyvinylpyrrolidone (crospovidone) , crosslinked carboxymethyl cellulose (e.g., croscarmellose sodium) or a mixture thereof.
  • crosslinked polymers such as crosslinked polyvinylpyrrolidone (crospovidone) , crosslinked carboxymethyl cellulose (e.g., croscarmellose sodium) or a mixture thereof.
  • crospovidone crosslinked polyvinylpyrrolidone
  • carboxymethyl cellulose e.g., croscarmellose sodium
  • Embodiment 31 The pharmaceutical composition according to any one of embodiments 1 to 30, wherein the disintegrant is croscarmellose sodium, particularly wherein croscarmellose sodium has a loss on dry of ⁇ 10%.
  • Embodiment 32 The pharmaceutical composition according to any one of embodiments 1 to 31, wherein the glidant is selected from colloidal silicas, colloidal silicon dioxide (e.g., 200) , fumed silica (e.g., ) , talc, starch, magnesium aluminum silicates Hydrophilic Fumed Silica and mixture thereof.
  • colloidal silicas colloidal silicon dioxide (e.g., 200)
  • fumed silica e.g., )
  • talc e.g., starch
  • magnesium aluminum silicates Hydrophilic Fumed Silica e.g., magnesium aluminum silicates Hydrophilic Fumed Silica and mixture thereof.
  • Embodiment 33 The pharmaceutical composition according to any one of embodiments 1 to 32, wherein the glidant is Colloidal Silicon Dioxide, particularly wherein Colloidal Silicon Dioxide is hydrophilic fumed silica with surface area of 200 m 2 /g (e.g., CAS 7631-86-9) , more particularly the colloidal silicon dioxide is 200 Pharma.
  • the glidant is Colloidal Silicon Dioxide, particularly wherein Colloidal Silicon Dioxide is hydrophilic fumed silica with surface area of 200 m 2 /g (e.g., CAS 7631-86-9) , more particularly the colloidal silicon dioxide is 200 Pharma.
  • Embodiment 34 The pharmaceutical composition according to any one of embodiments 1 to 33, wherein the lubricant is selected from poloxamer, polyethylene Glycol, polyoxyethylene stearate, polyvinyl alcohol, talc, silica stearin, magnesium stearate, sodium stearyl fumarate or mixture thereof.
  • the lubricant is selected from poloxamer, polyethylene Glycol, polyoxyethylene stearate, polyvinyl alcohol, talc, silica stearin, magnesium stearate, sodium stearyl fumarate or mixture thereof.
  • Embodiment 35 The pharmaceutical composition according to any one of embodiments 1 to 34, wherein the lubricant is magnesium stearate with bulk density 0.05 g/cm 3 to 0.30 g/cm 3 (e.g., CAS 557-04-0) , wherein the magnesium stearate is based on vegetable sources for the pharmaceutical product.
  • the lubricant is magnesium stearate with bulk density 0.05 g/cm 3 to 0.30 g/cm 3 (e.g., CAS 557-04-0) , wherein the magnesium stearate is based on vegetable sources for the pharmaceutical product.
  • Embodiment 36 A capsule comprising the pharmaceutical composition according to any one of embodiments 1 to 35.
  • Embodiment 37 The capsule according to embodiment 36, wherein the capsule is an enteric capsule, particularly wherein the capsule is an oral enteric capsule.
  • Embodiment 38 The capsule according to embodiments 36 or 37, wherein the capsule is a pH-dependent enteric-coated vacant gelatin capsule, most particularly comprising gelatin and hydroxypropyl methylcellulose phthalate.
  • Embodiment 39 The capsule according to embodiments 36 or 37, wherein the capsule is pH-dependent enteric-coated vacant hydroxypropyl methyl cellulose capsule comprising hydroxypropyl methyl cellulose and hypromellose acetate succinate.
  • Embodiment 40 A kit comprising the pharmaceutical composition according to any one of embodiments 1 to 35, in the form of a capsule, in particular enteric capsule, comprising a therapeutically effective amount of (R) -N- (4- ( [1, 2, 4] triazolo [1, 5-c] pyrimidin-7-yloxy) -3-methylphenyl) -5- ( (3, 3-difluoro-1-methylpiperidin-4-yl) oxy) -6-methoxyquinazolin-4-amine, prescribing information also known as “leaflet” , a blister package or bottle (HDPE or glass) , particularly a moisture protective primary packaging, more particularly Alu/Alu blister or a plastic bottle with desiccant and a container, in particular wherein the prescribing information particularly includes the advice to a patient regarding the administration of the (R) -N- (4- ( [1, 2, 4] triazolo [1, 5-c] pyrimidin-7-yloxy) -3-methylphenyl)
  • Embodiment 41 A process for the manufacture of granules comprising (R) -N- (4- ( [1, 2, 4] triazolo [1, 5-c] pyrimidin-7-yloxy) -3-methylphenyl) -5- ( (3, 3-difluoro-1-methylpiperidin-4-yl) oxy) -6-methoxyquinazolin-4-amine, a filler, a binder, and a glidant, , the process comprising the following steps:
  • step (f) milling the dried granules from step (e) .
  • step (g) optionally blending the granules from step (f) with an extragranular part (e.g., a lubricant) .
  • an extragranular part e.g., a lubricant
  • Embodiment 42 The process according to embodiment 41, further comprising (h) filling the mixture obtained in step g) into capsules.
  • Embodiment 43 The process to embodiment 42, further comprising (i) packaging the said capsules in bottles.
  • Embodiment 44 A pharmaceutical composition according to any one of embodiments 1 to 35, wherein the pharmaceutical composition is administered to an individual at any suitable dosage (e.g., to achieve a therapeutically effective amount) , particularly a suitable dose of a therapeutically effective amount of about 200 mg to 2000 mg per day (the daily dose is calculated based on the free base) , more particularly 200 mg to 1800 mg per day, most particularly about 400 mg to 1600 mg per day.
  • a suitable dosage e.g., to achieve a therapeutically effective amount
  • Embodiment 45 A pharmaceutical composition according to any one of embodiments 1 to 35 for the treatment of cancers comprising but not limited to cancers of the: circulatory system, for example, heart (sarcoma [angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma] , myxoma, rhabdomyoma, fibroma, lipoma and teratoma) , mediastinum and pleura, and other intrathoracic organs, vascular tumors and tumor-associated vascular tissue; respiratory tract, for example, nasal cavity and middle ear, accessory sinuses, larynx, trachea, bronchus and lung such as small cell lung cancer (SCLC) , non-small cell lung cancer (NSCLC) , bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma) , alveolar (bronchiolar) carcinoma, bronchial a
  • a pharmaceutical composition comprising:
  • glidant is between 0.5%and 10%by weight of the glidant, more particularly between 1%and 3%by weight of the glidant, most particularly 2% ⁇ 0.5%by weight of the glidant.
  • a pharmaceutical composition according to any one of clauses 1 to 11 comprising:
  • a pharmaceutical composition according to any one of clauses 1 to 12 comprising:
  • a pharmaceutical composition according to any one of clauses 1 to 13 comprising:
  • a pharmaceutical composition according to any one of clauses 1 to 14 comprising:
  • a pharmaceutical composition according to any one of clauses 1 to 15 comprising: (3) an intragranular component comprising:
  • the pharmaceutical composition of any one of clauses 1 to 23, comprises only one active pharmaceutical ingredient (API) , particularly wherein the only API is the compound of (R) -N- (4- ( [1, 2, 4] triazolo [1, 5-c] pyrimidin-7-yloxy) -3-methylphenyl) -5- ( (3, 3-difluoro-1-methylpiperidin-4-yl) oxy) -6-methoxyquinazolin-4-amine, more particularly wherein the only API (R) -N- (4- ( [1, 2, 4] triazolo [1, 5-c] pyrimidin-7-yloxy) -3-methylphenyl) -5- ( (3, 3-difluoro-1-methylpiperidin-4-yl) oxy) -6-methoxyquinazolin-4-amine fumarate.
  • API active pharmaceutical ingredient
  • the pharmaceutical composition according to any one of clauses 1 to 24, comprises between 30%and 95%by weight of (R) -N- (4- ( [1, 2, 4] triazolo [1, 5-c] pyrimidin-7-yloxy) -3-methylphenyl) -5- ( (3, 3-difluoro-1-methylpiperidin-4-yl) oxy) -6-methoxyquinazolin-4-amine fumarate, more particularly between 50%and 85%by weight of (R) -N- (4- ( [1, 2, 4] triazolo [1, 5-c] pyrimidin-7-yloxy) -3-methylphenyl) -5- ( (3, 3-difluoro-1-methylpiperidin-4-yl) oxy) -6-methoxyquinazolin-4-amine fumarate, most particularly 70% ⁇ 10%by weight of (R) -N- (4- ( [1, 2, 4] triazolo [1, 5-c] pyrimidin-7-yloxy) -3-methylphenyl
  • the filler is selected from microcrystalline cellulose (e.g., ) , microcrystalline cellulose coated with colloidal silica, cellulose powder, Isomalt, lactose, lactose spray-dried, lactose anhydrous, lactose monohydrate, maltodextrin, mannitol, dibasic calcium phosphate, sorbitol, sugars, sucrose, dextrose, sugar alcohols, hydrolyzed starch, corn starch, starch, pregelatinized starch, polysaccharides, dibasic calcium phosphate (i.e., Fujicalin) , calcium sulfate and combination thereof.
  • the filler is selected from microcrystalline cellulose (e.g., ) , microcrystalline cellulose coated with colloidal silica, cellulose powder, Isomalt, lactose, lactose spray-dried, lactose anhydrous, lactose monohydrate, maltodextrin, mannitol, dibasic
  • the binder is selected from hydroxypropyl methylcellulose (e.g., METHOCEL TM E5) , hydroxypropyl cellulose (e.g., Klucel TM hydroxypropylcellulose) , polyvinylpyrrolidone (PVP, such as Povidone K30) , carboxymethylcellulose sodium, carboxymethylcellulose calcium, and proteins like gelatin or mixture thereof.
  • hydroxypropyl methylcellulose e.g., METHOCEL TM E5
  • hydroxypropyl cellulose e.g., Klucel TM hydroxypropylcellulose
  • PVP polyvinylpyrrolidone
  • crosslinked polymers such as crosslinked polyvinylpyrrolidone (crospovidone) , crosslinked carboxymethyl cellulose (e.g., croscarmellose sodium) or a mixture thereof.
  • glidant is selected from colloidal silicas, colloidal silicon dioxide (e.g., 200) , fumed silica (e.g., ) , talc, starch, magnesium aluminum silicates Hydrophilic Fumed Silica and mixture thereof.
  • the glidant is Colloidal Silicon Dioxide, particularly wherein Colloidal Silicon Dioxide is hydrophilic fumed silica with surface area of 200 m 2 /g (e.g., CAS 7631-86-9) , more particularly the colloidal silicon dioxide is 200 Pharma.
  • composition according to any one of clauses 1 to 33, wherein the lubricant is selected from poloxamer, polyethylene Glycol, polyoxyethylene stearate, polyvinyl alcohol, talc, silica stearin, magnesium stearate, sodium stearyl fumarate or mixture thereof.
  • the lubricant is selected from poloxamer, polyethylene Glycol, polyoxyethylene stearate, polyvinyl alcohol, talc, silica stearin, magnesium stearate, sodium stearyl fumarate or mixture thereof.
  • composition according to any one of clauses 1 to 34, wherein the lubricant is magnesium stearate with bulk density 0.05 g/cm 3 to 0.30 g/cm 3 (e.g., CAS 557-04-0) , wherein the magnesium stearate is based on vegetable sources for the pharmaceutical product.
  • the lubricant is magnesium stearate with bulk density 0.05 g/cm 3 to 0.30 g/cm 3 (e.g., CAS 557-04-0) , wherein the magnesium stearate is based on vegetable sources for the pharmaceutical product.
  • a capsule comprising the pharmaceutical composition according to any one of clauses 1 to 35.
  • a kit comprising the pharmaceutical composition according to any one of clauses 1 to 35, in the form of a capsule, in particular enteric capsule, comprising a therapeutically effective amount of (R) -N- (4- ( [1, 2, 4] triazolo [1, 5-c] pyrimidin-7-yloxy) -3-methylphenyl) -5- ( (3, 3-difluoro-1-methylpiperidin-4-yl) oxy) -6-methoxyquinazolin-4-amine, prescribing information also known as “leaflet” , a blister package or bottle (HDPE or glass) , particularly a moisture protective primary packaging, more particularly Alu/Alu blister or a plastic bottle with desiccant and a container, in particular wherein the prescribing information particularly includes the advice to a patient regarding the administration of the (R) -N- (4- ( [1, 2, 4] triazolo [1, 5-c] pyrimidin-7-yloxy) -3-methylphenyl) -5- (
  • a process for the manufacture of granules comprising (R) -N- (4- ( [1, 2, 4] triazolo [1, 5-c] pyrimidin-7-yloxy) -3-methylphenyl) -5- ( (3, 3-difluoro-1-methylpiperidin-4-yl) oxy) -6-methoxyquinazolin-4-amine, a filler, a binder, and a glidant, the process comprising the following steps:
  • step (f) milling the dried granules from step (e) .
  • step (g) optionally blending the granules from step (f) with an extragranular part (e.g., a lubricant) .
  • an extragranular part e.g., a lubricant
  • a suitable dosage e.g., to achieve a therapeutically effective amount
  • a pharmaceutical composition according to any one of clauses 1 to 35 for the treatment of cancers comprising but not limited to cancers of the: circulatory system, for example, heart (sarcoma [angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma] , myxoma, rhabdomyoma, fibroma, lipoma and teratoma) , mediastinum and pleura, and other intrathoracic organs, vascular tumors and tumor-associated vascular tissue; respiratory tract, for example, nasal cavity and middle ear, accessory sinuses, larynx, trachea, bronchus and lung such as small cell lung cancer (SCLC) , non-small cell lung cancer (NSCLC) , bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma) , alveolar (bronchiolar) carcinoma, bronchial adenoma,

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des compositions pharmaceutiques et des formes galéniques comprenant de la (R)-N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-méthylphényl)-5-((3, 3-difluoro-1-méthylpipéridin-4-yl)oxy)-6-méthoxyquinazolin-4-amine qui sont utiles dans le traitement de sujets atteints d'un cancer. La présente invention concerne également des procédés de préparation des compositions pharmaceutiques et des formes galéniques selon l'invention, et des méthodes de traitement de sujets atteints d'un cancer à l'aide des compositions pharmaceutiques et des formes galéniques décrites dans la description.
PCT/CN2025/082972 2024-03-19 2025-03-17 Formulation pharmaceutique d'inhibiteurs d'erbb2 Pending WO2025195333A1 (fr)

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