NZ624942B2 - Solid dispersions of a erb2 (her2) inhibitor - Google Patents

Solid dispersions of a erb2 (her2) inhibitor Download PDF

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NZ624942B2
NZ624942B2 NZ624942A NZ62494212A NZ624942B2 NZ 624942 B2 NZ624942 B2 NZ 624942B2 NZ 624942 A NZ624942 A NZ 624942A NZ 62494212 A NZ62494212 A NZ 62494212A NZ 624942 B2 NZ624942 B2 NZ 624942B2
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weight
solid dispersion
dispersion
triazolo
quinazoline
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NZ624942A
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NZ624942A (en
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Corey Jay Bloom
Christopher Donovan Craig
Devon Brevard Dubose
David Shank Fry
Jeff Gautschi
Christopher M Lindemann
Michael Preigh
Dan Smithey
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Array Biopharma Inc
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Priority claimed from PCT/US2012/060044 external-priority patent/WO2013056108A2/en
Publication of NZ624942A publication Critical patent/NZ624942A/en
Publication of NZ624942B2 publication Critical patent/NZ624942B2/en

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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
    • A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • 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
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • 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
    • A61K9/10—Dispersions; Emulsions
    • 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
    • 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
    • A61K9/1605—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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds
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    • 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
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • 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
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Abstract

Disclosed is a solid dispersion of the selective ErbB2 (HER2) inhibitor N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine (ARRY -380) and processes for preparing the solid dispersion. Also disclosed are pharmaceutical compositions comprising a solid dispersion of N4-(4-([1,2,4]triazolo[1,5-?]pyridin-7-yloxy)-3- methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine for treating cancer. itions comprising a solid dispersion of N4-(4-([1,2,4]triazolo[1,5-?]pyridin-7-yloxy)-3- methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine for treating cancer.

Description

Solid Dispersion of ErbBZ Inhibitor BACKGROUND OF THE INVENTION FIELD OF THE INVENTION A solid dispersion of N4-(4-([l,2,4]triazolo[l,5-a]pyridinyloxy) methylphenyl)—N6-(4,4-dimethyl-4,5-dihydrooxazolyl)quinazoline-4,6-diamine is provided . Also, a pharmaceutical composition comprising a solid dispersion of N4-(4- ([1 ,2,4]triazolo[l ,5 -a]pyridinyloxy)-3 -mcthylphcnyl)—N6-(4,4-dimcthyl-4,5 -dihydrooxazol yl)quinazoline-4,6-diamine is provided herein.
DESCRIPTION OF THE STATE OF THE ART ([1,2,4]Triazolo[1,5 -a]pyridinyloxy)-3 -methylphenyl)—N6-(4,4- dimethyl-4,5—dihydrooxazol-2—yl)quinazoline-4,6—diamine (also called “ARRY-380”), which has the structure: X70” is a selective ErbB2 (HER2) inhibitor described in , which is incorporated by reference in its entirety. ([1,2,4]Triazolo[1,5-a]pyridinyloxy)methylphenyl)- N6—(4,4-dimethyl-4,S-dihydrooxazolyl)quinazoline-4,6-diamine has been tested in human clinical trials for hyperproliferative diseases, particularly cancer (see Koch, Kevin. “ARRY- 380: A Selective, Oral HERZ Inhibitor for the Treatment of Solid Tumors.” American Association of Cancer Research 10211d Annual Meeting, April 3, 2011; which may also be found at: http://www.arraybiopharma.com/idocuments/Publication/PubAttachment462.pdf).
A powder—in—capsule ) ition of N4—(4—([1,2,4]triazolo[1,5— a]pyridinyloxy)—3-methylphenyl)-N6-(4,4-dimethyl-4,5—dihydrooxazol-Z-yl)quinazoline- 4,6-diamine was prepared and administered to patients with cancer, and the overall inter- patient variability for area under the plasma concentration-time curve (“AUC”) and maximum concentration (“Cmax”) was moderate to high.
There remains a need to prepare a ceutical composition containing N4- (4—([1 riazolo[1 ,5—a]pyridinyloxy)-3—methylphenyl)-N6-(4,4—dimethyl-4,5 - dihydrooxazol-Z-yl)quinazoline-4,6-diamine that minimizes inter-patient variability of pharmacokinetics.
PCT/U52012/060044 SUMMARY OF THE INVENTION A solid dispersion comprising N4-(4-([l,2,4]triazolo[l ,5-a]pyridinyloxy) methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazolyl)quinazoline-4,6-diamine is described herein.
A pharmaceutical composition comprising N4-(4-([l,2,4]triazolo[l,5- a]pyridinyloxy)—3-methylphenyl)—N6-(4,4-dimethyl-4,5—dihydrooxazolyl)quinazoline- aminc is described herein.
A ceutical composition comprising a solid sion of N4-(4- ([1 ,2,4]triazolo[l ,5 -a]pyridinyloxy)-3 lphenyl)—N6-(4,4-dimethyl-4,5- dihydrooxazol-Z-yl)quinazoline-4,6-diamine is described herein.
A pharmaceutical composition comprising a solid dispersion of spray dried N4-(4-([ l ,2,4]triazolo[ l ,5 -a]pyridinyloxy)-3 -methylphenyl)-N6-(4,4-dimethyl-4,5- dihydrooxazolyl)quinazoline-4,6-diamine is described herein.
Processes for preparing the solid dispersion and pharmaceutical composition and methods of using the pharmaceutical composition are also bed herein.
BRIEF DESCRIPTION OF THE FIGURES Figure 1 shows a comparison of XRPD scans of amorphous 30% solid dispersions and crystalline N4-(4-([l,2,4]triazolo[l,5-a]pyridinyloxy)—3-methylphenyl)— N6-(4,4-dimethyl-4,5-dihydrooxazol-2—yl)quinazoline-4,6-diamine, with a close up of the amorphous solid dispersions.
Figure 2 shows a dissolution profile of a 30% solid dispersion of N4-(4- ([1 ,2,4]triazolo[l ,5 -a]pyridinyloxy)-3 -methylphenyl)—N6-(4,4-dimethyl—4,5— dihydrooxazol-Z-yl)quinazolinc-4,6-diaminc.
] Figure 3 shows a dissolution profile of a 30% solid dispersion of N4-(4- ([1 ,2,4]triazolo[l ,5 -a]pyridinyloxy)-3 -methylphenyl)—N6-(4,4-dimethyl-4,5- dihydrooxazol-Z-yl)quinazoline-4,6-diamine.
Figure 4 shows a dissolution profile of a 30% solid dispersion of N4-(4— ([ l riazolo[l ,5 -a]pyridinyloxy)-3 -methylphenyl)-N6-(4,4-dimethyl-4,5- dihydrooxazolyl)quinazoline-4,6-diamine.
Figure 5 shows a dissolution profile of a 30% solid sion of N4-(4- ([1 ,2,4]triazolo[l ,5 -a]pyridinyloxy)-3 -methylphenyl)—N6-(4,4-dimethyl-4,5- dihydrooxazol—Z-yl)quinazoline-4,6-diamine.
Figure 6 shows a dissolution profile of a 30% solid dispersion of N4-(4— ([1 ,2,4]triazolo[l ,5 -a]pyridinyloxy)-3 lphenyl)-N6-(4,4-dimethyl-4,5- dihydrooxazolyl)quinazoline-4,6-diamine.
Figure 7 shows a comparison of XRPD scans of amorphous 60% solid dispersions and crystalline N4-(4-([l,2,4]triazolo[l,5-a]pyridinyloxy)—3-methylphenyl)- N6—(4,4-dimethyl-4,5-dihydrooxazolyl)quinazoline-4,6-diamine, with a close up of the amorphous solid dispersions.
Figure 8 shows a ution profile of a 60% solid dispersion of N4-(4- ([1 ,2,4]triazolo[l ,5 idinyloxy)-3 -methylphenyl)—N6-(4,4-dimethyl-4,5- dihydrooxazol-Z-yl)quinazoline-4,6-diamine.
Figure 9 shows a dissolution profile of a 60% solid dispersion of N4-(4— ([1 ,2,4]triazolo[l ,5 idinyloxy)-3 -methylphenyl)—N6-(4,4-dimethyl-4,5- dihydrooxazolyl)quinazoline-4,6-diamine.
Figure 10 shows a dissolution profile of a 60% solid sion of N4-(4- ([1 ,2,4]triazolo[l ,5 -a]pyridinyloxy)-3 -methylphenyl)—N6-(4,4-dimethyl-4,5- dihydrooxazol—Z-yl)quinazoline-4,6-diamine.
Figure 11 shows a dissolution profile of a 60% solid dispersion of N4—(4— ([1 ,2,4]triazolo[l ,5 idinyloxy)-3 -methylphenyl)—N 6-(4,4-dimethyl-4,5- dihydrooxazolyl)quinazoline-4,6-diamine.
Figure 12 shows a dissolution profile of a 60% solid dispersion of N4-(4- ([1 ,2,4]triazolo[l ,5 -a]pyridinyloxy)-3 -methylphenyl)—N6-(4,4-dimethyl-4,5- ooxazol—Z-yl)quinazoline-4,6-diamine.
Figure 13 shows a dissolution comparison of a solid dispersion tablet and a crystalline PIC composition.
DETAILED DESCRIPTION OF THE INVENTION Reference will now be made in detail to certain embodiments, examples of which are illustrated . While enumerated embodiments will be described, it will be understood that they are not intended to limit the ion to those embodiments. On the contrary, the invention is intended to cover all alternatives, modifications, and equivalents, which may be included Within the scope of the t invention as defined by the claims.
One skilled in the art will recognize many methods and materials similar or equivalent to those described herein, which could be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described. In the event that one or more of the incorporated literature and similar materials differs from or PCT/U52012/060044 contradicts this application, including but not limited to defined terms, term usage, bed techniques, or the like, this application controls.
DEFINITIONS The term "abou " is used herein to mean imately, in the region of, roughly, or around. When the term "abou " is used in conjunction with a cal range, it modifies that range by extending the boundaries above and below the numerical values set forth. In general, the term ”abou ” is used herein to modify a numerical value above and below the stated value by a variance of 20%.
As used herein, the recitation of a numerical range for a variable is ed to convey that the invention may be ced with the variable equal to any of the values within that range. Thus, for a variable that is inherently discrete, the variable can be equal to any integer value of the numerical range, including the end-points of the range. Similarly, for a variable that is inherently continuous, the variable can be equal to any real value of the numerical range, including the end-points of the range. As an example, a variable that is described as having values between 0 and 2, can be 0, l or 2 for variables that are inherently discrete, and can be 0.0, 0.1, 0.01, 0.001, or any other real value for variables that are inherently uous.
The term “amorphous” means a solid in a solid state that is a non-crystalline state. Amorphous solids generally possess crystal-like short range molecular ement, but no long range order of molecular packing as found in crystalline . The solid state form of a solid may be determined by polarized light microscopy, x-ray powder diffraction (“XRPD”), differential scanning calorimetry (“DSC”), or other rd techniques known to those of skill in the art.
The phrase “amorphous solid dispersion” means a solid comprising a drug substance and a dispersion r. The amorphous solid dispersion discussed herein comprises amorphous N4-(4-([1,2,4]triazolo[1,5 -a]pyridinyloxy)-3 -methylphenyl)-N6- (4,4-dimethyl—4,5-dihydrooxazolyl)quinazoline—4,6-diamine and a dispersion polymer, wherein the amorphous solid dispersion contains N4-(4-([l,2,4]triazolo[1,5-a]pyridin yloxy)methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazolyl)quinazoline-4,6-diamine in a ntially amorphous solid state form. In certain embodiments, the substantially amorphous solid state form means that the N4-(4-([1,2,4]triazolo[l,5-a]pyridin—7-yloxy) methylphenyl)—N6-(4,4-dimethyl—4,5-dihydrooxazolyl)quinazoline-4,6-diamine component in the ous solid dispersion is at least 80% amorphous N4-(4-([1,2,4]triazolo[1,5- a]pyridinyloxy)—3-methylphenyl)—N6-(4,4-dimethyl-4,5-dihydrooxazolyl)quinazoline- PCT/U52012/060044 4,6-diamine. In certain embodiments, the substantially amorphous solid state form means that the N4-(4-([1,2,4]triazolo[l,5 idinyloxy)—3 -methylphenyl)—N6-(4,4-dimethyl-4,5 - dihydrooxazolyl)quinazoline-4,6-diamine component in the amorphous solid dispersion is at least 85% amorphous N4-(4-([l,2,4]triazolo[l,5-a]pyridinyloxy)methylphenyl)-N6- (4,4-dimethyl-4,5-dihydrooxazolyl)quinazoline-4,6-diamine. In certain embodiments, the substantially amorphous solid state form means that the N4—(4-([1,2,4]triazolo[l,5-a]pyridin— 7-yloxy)methylphcnyl)—N6-(4,4-dimethyl-4,5-dihydrooxazolyl)quinazoline-4,6-diamine component in the ous solid dispersion is at least 90% amorphous N4-(4- ([1 ,2,4]triazolo[l ,5 -a]pyridinyloxy)-3 -methylphenyl)—N6-(4,4-dimethyl-4,5- dihydrooxazolyl)quinazoline-4,6-diamine. In certain ments, the substantially amorphous solid state form means that the N4-(4-([l,2,4]triazolo[l,5-a]pyridin—7-yloxy) methylphenyl)—N6-(4,4-dimethyl-4,5-dihydrooxazol-Z-yl)quinazoline-4,6-diamine component in the amorphous solid dispersion is at least 95% amorphous N4-(4-([l,2,4]triazolo[l,5- a]pyridinyloxy)—3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazolyl)quinazoline- 4,6-diamine.
The terms r" and "cancerous" refer to or describe the physiological condition in mammals that is typically characterized by abnormal or unregulated cell .
A "tumor" ses one or more cancerous cells. Examples of cancer include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia or lymphoid malignancies. More particular es of such s include squamous cell cancer (e.g., epithelial squamous cell cancer), lung cancer including small cell lung cancer, non-small cell lung cancer ("NSCLC"), adenocarcinoma of the lung and squamous carcinoma of the lung, cancer of the peritoneum, hepatoccllular , gastric or stomach cancer including gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer, rectal cancer, colorectal cancer, brain, endometrial or uterine carcinoma, salivary gland carcinoma, kidney or renal cancer, prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma, anal carcinoma, penile carcinoma, skin cancer, including melanoma, as well as head and neck cancer.
The phrase “dispersion polymer” means a r that allows for N4-(4- ([1 ,2,4]triazolo[l ,5 -a]pyridinyloxy)-3 -methylphenyl)—N6-(4,4-dimethyl-4,5- dihydrooxazolyl)quinazoline-4,6-diamine to be dispersed throughout such that a solid sion may form. The dispersion polymer is preferably neutral or basic. The dispersion polymer may contain a e of two or more polymers. Examples of dispersion polymers e, but are not d to, vinyl polymers and eopolymers, vinylpyrrolidine vinylacetate PCT/U52012/060044 copolymer (“PVP—VA”), nyl alcohols, polyvinyl alcohol polyvinyl acetate copolymers, polyvinyl pyrrolidine (“PVP”), acrylate and methacrylate copolymers, methylacrylic acid methyl methacrylate copolymer (such as Eudragit®), polyethylene polyvinyl alcohol copolymers, polyoxyethylene-polyoxypropylene block copolymers (also ed to as poloxamers), graft copolymer comprised of polyethylene glycol, nyl actam and polyvinyl acetate (such as Soluplus®), cellulosic polymers, such as hydroxypropyl methyl cellulose acetate (“HPMCA”), hydroxypropyl methyl cellulose (“HPMC”), ypropyl cellulose (“HPC”), methyl cellulose, hydroxyethyl methyl cellulose, hydroxyethyl cellulose, hydroxyethyl ose acetate, and hydroxyethyl ethyl cellulose, hydroxypropyl methyl cellulose acetate succinate (“HPMCAS”), hydroxypropyl methyl cellulose phthalate (“HPMCP”), carboxymethylethyl cellulose (“CMEC”), cellulose acetate ate (“CAP”), cellulose acetate succinate (“CAS”), hydroxypropyl methyl cellulose acetate phthalate (“HPMCAP”), cellulose acetate trimellitate (“CAT”), hydroxypropyl methyl ose acetate trimellitate (“HPMCAT”), and ymethylcellulose acetate butyrate (“CMCAB”), and the like.
The term "mammal" means a warm-blooded animal that has or is at risk of developing a disease described herein and includes, but is not limited to, guinea pigs, dogs, cats, rats, mice, hamsters, and primates, including humans.
The phrase "pharmaceutically acceptable" indicates that the nce or ition is compatible chemically and/or toxicologically, with the other ingredients comprising a composition, and/or the mammal being treated therewith.
The phrase "pharmaceutically acceptable salt," as used herein, refers to pharmaceutically acceptable organic or inorganic salts of a compound described herein.
The phrase “solid dispersion” means a system in a solid state comprising at least two components, n one component is dispersed throughout the other component.
The solid dispersion sed herein comprises one component of ([l,2,4]triazolo[l ,5- a]pyridinyloxy)—3-methylphenyl)—N6-(4,4-dimethyl-4,5—dihydrooxazolyl)quinazoline- 4,6-diamine dispersed throughout another component, particularly a dispersion polymer.
The phrase “spray drying” means processes involved in breaking up liquid mixtures into small droplets zation) and rapidly removing solvent from the e in a spray drying apparatus where there is a strong g force for evaporation of solvent from the droplets. The phrase spray drying is used conventionally and broadly. Spray drying processes and spray drying equipment are described generally in Perry, Robert H., and Don PCT/U52012/060044 W. Green (eds.). Pem’s Chemical Engineers’ Handbook. New York: McGraw—Hill, 2007 (8th edition).
The phrases "therapeutically effective amount" or tive amount” mean an amount of a compound described herein that, when administered to a mammal in need of such treatment, ent to (i) treat or prevent the particular disease, condition, or disorder, (ii) ate, ameliorate, or eliminate one or more ms of the particular e, condition, or disorder, or (iii) prevent or delay the onset of one or more symptoms of the particular disease, condition, or disorder described herein. The amount of a compound that will correspond to such an amount will vary depending upon factors such as the particular compound, disease condition and its severity, the identity (e.g., weight) of the mammal in need of treatment, but can nevertheless be routinely determined by one skilled in the art.
The terms "treat" or "treatment" refer to therapeutic, lactic, palliative or preventative measures. cial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or ctable. ment" can also mean prolonging survival as compared to expected survival if not receiving ent. Those in need of treatment include those already with the condition or disorder, as well as those prone to have the condition or disorder or those in which the condition or disorder is to be prevented.
SOLID SIONS AND PHARMACEUTICAL COMPOSITIONS Provided herein is a solid dispersion comprising N4—(4-([l,2,4]triazolo[l,5— a]pyridinyloxy)—3-mcthylphcnyl)—N6-(4,4-dimcthyl-4,5-dihydrooxazolyl)quinazolinc- 4,6-diamine.
The solid dispersions are generally prepared by dissolving the drug substance and the dispersion polymer in a le solvent to form a feed solution, and then the feed solution may be spray dried to form the solid dispersion (and remove the solvent). Spray drying is a known process. Spray drying is generally performed by dissolving N4-(4- ([1 ,2,4]triazolo[l ,5 -a]pyridinyloxy)-3 -methylphenyl)—N6-(4,4-dimethyl-4,5- dihydrooxazol-Z-yl)quinazoline-4,6-diamine and the dispersion polymer in a le solvent to prepare a feed solution. The feed on may be pumped through an atomizer into a drying chamber. The feed solution can be atomized by conventional means known in the art, such as a two-fluid sonicating nozzle, a pressure nozzle, a rotating nozzle and a two—fluid nicating nozzle. Then, the solvent is removed in the drying chamber to form the solid 2012/060044 dispersion. A typical drying chamber uses hot gases, such as forced air, nitrogen, en— enriched air, or argon to dry particles. The size of the drying chamber may be adjusted to e particle properties or throughput.
Although the solid dispersion are preferably prepared by conventional spray drying techniques, other techniques known in the art may be used, such as melt extrusion, freeze drying, rotary evaporation, drum drying or other solvent removal ses.
In one embodiment, a process of preparing a solid dispersion is provided, comprising: (a) dissolving N4-(4-([ l ,2,4]triazolo[l ,5-a]pyridinyloxy)-3 lphenyl)-N6- (4,4-dimethyl-4,5-dihydrooxazolyl)quinazoline-4,6-diamine and a dispersion polymer in a suitable solvent; and (b) evaporating the t to form the solid dispersion.
In a further embodiment, the evaporation of the t in step (b) is performed by spray drying, melt extrusion, freeze drying, rotary evaporation, drum drying or other solvent removal processes.
In certain embodiments, the sion polymer is selected from PVP-VA, acrylic acid methyl methacrylate copolymer, HPMCP, CAP, HPMCAS and HPMC and es thereof. In certain ments, the dispersion polymer is selected from PVP- VA, methylacrylic acid methyl methacrylate copolymer, HPMCP, CAP, HPMCAS and HPMC. In certain embodiments, the dispersion polymer is selected from PVP-VA, Eudragit® L100, HPMCP H-55, CAP, HPMCAS Grade M, HPMC and es thereof. In certain embodiments, the dispersion polymer is selected from PVP—VA, Eudragit® L100, HPMCP H—SS, CAP, HPMCAS Grade M and HPMC.
In certain embodiments, the dispersion polymer is selected from , methylacrylic acid methyl methacrylate copolymer, HPMCP, CAP and HPMCAS, and mixtures thereof. In certain embodiments, the dispersion polymer is ed from PVP-VA, methylacrylic acid methyl methacrylate copolymer, HPMCP, CAP and HPMCAS. In certain embodiments, the dispersion polymer is ed from PVP-VA, Eudragit® L100, HPMCP H—55, CAP and HPMCAS Grade M, and mixtures thereof. In certain embodiments, the dispersion polymer is selected from PVP-VA, Eudragit® L100, HPMCP H-55, CAP and HPMCAS Grade M.
In certain embodiments, the dispersion polymer is selected from PVP—VA, methylacrylic acid methyl methacrylate copolymer, HPMCP, CAP and HPMC, and mixtures thereof. In certain embodiments, the dispersion polymer is selected from PVP-VA, PCT/U52012/060044 methylacrylic acid methyl methacrylate copolymer, HPMCP, CAP and HPMC. In certain embodiments, the dispersion polymer is selected from PVP-VA, Eudragit® L100, HPMCP H—55, CAP and HPMC, and mixtures thereof. In certain embodiments, the dispersion polymer is selected from PVP-VA, Eudragit® L100, HPMCP H-55, CAP and HPMC.
In n embodiments, the dispersion r is selected from PVP-VA, methylacrylic acid methyl methacrylate copolymer, HPMCP and CAP, and mixtures thereof.
In certain cmbodimcnts, the dispersion polymer is selected from , methylacrylic acid methyl methacrylate mer, HPMCP and CAP. In certain embodiments, the dispersion polymer is selected from , it® L100, HPMCP H-SS and CAP, and mixtures thereof. In certain embodiments, the dispersion polymer is ed from PVP-VA, it® L100, HPMCP H—55 and CAP.
In certain embodiments, the dispersion polymer is PVP-VA.
In certain embodiments, the dispersion polymer is methylacrylic acid methyl methacrylate copolymer. In certain embodiments, the dispersion polymer is Eudragit®. In certain embodiments, the dispersion polymer is Eudragit® L100.
In certain embodiments, the dispersion polymer is HPMCP. In certain ments, the dispersion polymer is HPMCP H—55.
In certain embodiments, the dispersion polymer is CAP.
In certain embodiments, the dispersion polymer is HPMCAS. In certain embodiments, the dispersion polymer is HPMCAS Grade M.
In certain embodiments, the dispersion polymer is preferably neutral or basic.
In certain embodiments, the dispersion polymer is selected from PVP-VA and HPMC. In n mcnts, the sion polymer is HPMC. le solvents are a solvent or mixture of solvents in which both N4-(4- ([1 riazolo[l ,5 -a]pyridinyloxy)-3 -methylphenyl)—N6-(4,4-dimethyl-4,5- dihydrooxazolyl)quinazoline-4,6-diamine and the dispersion polymer have adequate solubility (solubility greater than 1 mg/mL). A mixture of solvents may be used if each component of the solid dispersion (z'.e., N4-(4-([l,2,4]triazolo[l,5-a]pyridinyloxy) methylphenyl)—N6-(4,4-dimethyl-4,5-dihydrooxazolyl)quinazoline-4,6-diamine and dispersion polymer) require different solvents to obtain the desired solubility. The solvent may be volatile with a boiling point of 150°C or less. In on, the solvent should have vely low toxicity and be removed from the dispersion to a level that is acceptable to The International Committee on Harmonization (“ICH”) ines. Removal of solvent to this level may require a subsequent processing step, such as tray drying. Examples of suitable PCT/U52012/060044 solvents include, but are not limited to, alcohols, such as methanol ”), l (“EtOH”), n-propanol, isopropanol (“IPA”) and butanol; ketones, such as acetone, methyl ethyl ketone (“MEK”) and methyl isobutyl ketone; esters, such as ethyl acetate (“EA”) and propyl acetate; and s other solvents, such as tetrahydrofuran (“THF”), acetonitrile (“ACN”), methylene chloride, toluene and l,l,l-trichloroethane. Lower volatility solvents, such as dimethyl acetate or dimethylsulfoxide (“DMSO”), may be used. Mixtures of solvents with water may also be used, so long as thc polymcr and N4-(4-([l,2,4]triazolo[l,5-a]pyridin— 7-yloxy)—3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazolyl)quinazoline-4,6-diamine are sufficiently soluble to make the spray drying process practicable. Generally, due to the hydrophobic nature of low solubility drugs, non-aqueous solvents may be used, meaning the solvent comprises less than about 10 weight % water.
In certain embodiments, the suitable solvent is selected from MeOH and THF, and mixtures thereof. In certain ments, the suitable solvent is MeOHITHF solvent system of about 1:3. In certain ments, the le solvent is a 1:3 MeOHzTHF solvent system.
In certain embodiments, the le solvent is selected from MeOH, THF and water, and mixtures thereof. In certain embodiments, the suitable solvent is selected from MeOH, THF and water. In certain embodiments, the suitable solvent is a THF2MeOH2water solvent system of about 80:10:10. In certain ments, the suitable solvent is a 80:10:10 THFzMeOH1water solvent system. In n embodiments, the suitable solvent is a THF:MeOH:water solvent system of about 82:8:10. In certain embodiments, the le solvent is a 82:8:10 Oszater solvent system. In certain embodiments, the suitable solvcnt is a THF:McOH:watcr solvcnt system of about 82.2:8.2:9.6. In certain embodiments, the suitable solvent is a .2:9.6 THF2MeOH2water solvent system.
In certain embodiments, the amount of N4-(4-([l,2,4]triazolo[l,5-a]pyridin yloxy)methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazolyl)quinazoline-4,6-diamine in the solid dispersion ranges from about 0.1% to about 70% by weight relative to the dispersion r. In certain embodiments, the amount of N4-(4-([l,2,4]triazolo[l,5- a]pyridinyloxy)—3-methylphenyl)—N6-(4,4-dimethyl-4,5-dihydrooxazolyl)quinazoline- 4,6-diamine in the solid dispersion ranges from 0.1% to 70% by weight relative to the dispersion polymer.
In certain embodiments, the amount of N4—(4—([1,2,4]triazolo[1,5—a]pyridin—7— yloxy)-3—methylphenyl)-N6—(4,4-dimethyl-4,5-dihydrooxazol-2—yl)quinazoline-4,6-diamine in the solid dispersion ranges from about 1% to about 60% by weight relative to the 2012/060044 dispersion r. In certain embodiments, the amount of ([1,2,4]triazolo[1,5- a]pyridinyloxy)—3-methylphenyl)—N6-(4,4-dimethyl-4,5-dihydrooxazolyl)quinazoline- 4,6-diamine in the solid sion ranges from 1% to 60% by weight relative to the dispersion polymer.
] In n embodiments, the amount of N4-(4-([1,2,4]triazolo[1,5-a]pyridin yloxy)-3—methylphenyl)-N6—(4,4-dimethyl-4,5-dihydrooxazol-2—yl)quinazoline-4,6-diamine in the solid dispersion ranges from about 5% to about 60% by weight relative to the dispersion polymer. In certain embodiments, the amount of N4-(4-([l,2,4]triazolo[l,5- a]pyridinyloxy)—3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazolyl)quinazoline- 4,6-diamine in the solid dispersion ranges from 5% to 60% by weight relative to the dispersion polymer.
In certain embodiments, the amount of N4-(4-([1,2,4]triazolo[1,5-a]pyridin yloxy)methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazolyl)quinazoline-4,6-diamine in the solid dispersion ranges from about 55% to about 65% by weight relative to the dispersion polymer. In certain embodiments, the amount of N4-(4-([l,2,4]triazolo[l,5- a]pyridinyloxy)—3-methylphenyl)—N6-(4,4-dimethyl-4,5—dihydrooxazolyl)quinazoline- 4,6-diamine in the solid dispersion ranges from 55% to 65% by weight relative to the dispersion polymer. In certain embodiments, the amount of N4-(4-([l,2,4]triazolo[l,5- a]pyridinyloxy)—3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazolyl)quinazoline- 4,6-diamine in the solid dispersion is about 60% by weight relative to the dispersion polymer.
In certain embodiments, the amount of N4-(4-([l,2,4]triazolo[l,5-a]pyridinyloxy) methylphenyl)—N6-(4,4-dimethyl—4,5-dihydrooxazol-Z-yl)quinazoline-4,6-diamine in the solid dispersion is 60% by weight relative to the dispersion polymer.
] In certain embodiments, the amount of N4-(4-([l,2,4]triazolo[l,5-a]pyridin yloxy)methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazolyl)quinazoline-4,6-diamine in the solid dispersion ranges from about 25% to about 35% by weight relative to the dispersion polymer. In certain ments, the amount of N4-(4-([l,2,4]triazolo[l,5- a]pyridinyloxy)methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-Z-yl)quinazoline- 4,6-diamine in the solid dispersion ranges from 25% to 3500 by weight relative to the dispersion polymer. In certain embodiments, the amount of N4-(4-([l,2,4]triazolo[l,5- dinyloxy)—3-methylphenyl)—N6-(4,4-dimethyl-4,5-dihydrooxazolyl)quinazoline- 4,6-diamine in the solid dispersion is about 30% by weight relative to the dispersion polymer.
In certain embodiments, the amount of N4-(4-([1,2,4]triazolo[1,5-a]pyridinyloxy) PCT/U52012/060044 methylphenyl)—N6-(4,4-dimethyl—4,5-dihydrooxazolyl)quinazoline-4,6-diamine in the solid sion is 30% by weight relative to the dispersion polymer.
In certain embodiments, the amount of ([l,2,4]triazolo[l,5-a]pyridin yloxy)methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazolyl)quinazoline-4,6-diamine in the solid dispersion ranges from about 45% to about 55% by weight relative to the dispersion r. In certain embodiments, the amount of N4-(4-([l,2,4]triazolo[l,5- a]pyridinyloxy)—3-mcthylphcnyl)—N6-(4,4-dimcthyl-4,5-dihydrooxazolyl)quinazolinc- 4,6-diamine in the solid dispersion ranges from 45% to 55% by weight relative to the dispersion polymer. In certain embodiments, the amount of N4-(4-([l,2,4]triazolo[l,5- a]pyridinyloxy)—3-methylphenyl)—N6-(4,4-dimethyl-4,5-dihydrooxazolyl)quinazoline- 4,6-diamine in the solid dispersion is about 50% by weight relative to the dispersion polymer.
In certain embodiments, the amount of N4-(4-([1,2,4]triazolo[1,5-a]pyridinyloxy) methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazolyl)quinazoline-4,6-diamine in the solid dispersion is 50% by weight relative to the dispersion polymer.
In certain embodiments, the solid dispersion is an ous solid dispersion.
Another embodiment provides a pharmaceutical composition comprising a solid dispersion of N4-(4-([1,2,4]triazolo[l,5-a]pyridin—7-yloxy)-3—methylphenyl)-N6—(4,4- dimethyl-4,5-dihydrooxazolyl)quinazoline-4,6-diamine and a dispersion r, and a r or excipient.
Suitable carriers and excipients are well known to those d in the art and are described in detail in, e.g., Ansel, Howard C., et al., Ansel’s Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: cott, Williams & s, 2004; Gennaro, Alfonso R., ct al. Remington: The Science and ce of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C. Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005.
The pharmaceutical compositions may also e one or more additional components, such as buffers, sion , surfactants, g agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents, diluents and other known additives to provide an elegant presentation of the drug, i.e., a compound described herein or pharmaceutical composition thereof, or aid in the manufacturing of the pharmaceutical product, z'.e., medicament (see Ansel; Gennaro; and Rowe above). The components of the pharmaceutical composition should be pharmaceutically acceptable.
Certain embodiments provide a pharmaceutical composition comprising: PCT/U52012/060044 (a) about 1 to about 70 weight % of a solid dispersion of N4—(4— ([1 ,2,4]triazolo[l ,5 -a]pyridinyloxy)-3 -methylphenyl)—N6-(4,4-dimethyl-4,5- dihydrooxazolyl)quinazoline-4,6-diamine; (b) about 0.1 to about 20 weight % of a disintegrant; (0) about 0.1 to about 25 weight % of an osmogen; (d) about 0.1 to about 10 weight % of a glidant; (c) about 0.1 to about 10 weight % of a lubricant; and (1‘) about 0.1 to about 25 weight % of a binder / diluent.
In a further ment, the pharmaceutical composition comprises: (a) l to 70 weight % of a solid dispersion of N4-(4-([l,2,4]triazolo[l,5- a]pyridinyloxy)—3-methylphenyl)—N6-(4,4-dimethyl-4,5—dihydrooxazolyl)quinazoline- 4,6-diamine; (b) 0.1 to 20 weight % of a disintegrant; (c) 0.1 to 25 weight % of an osmogen; (d) 0.1 to 10 weight % ofa glidant; (e) 0.1 to 10 weight % of a lubricant; and (l) 0.1 to 25 weight % of a binder / diluent.
Certain embodiments provide a pharmaceutical composition comprising: (a) about 25 to about 60 weight % of a solid sion of N4-(4- ([1 ,2 ,4]triazolo[l ,5 -a]pyridinyloxy)-3 -methylphenyl)—N6-(4,4-dimethyl-4,5- dihydrooxazolyl)quinazoline-4,6-diamine; (b) about 5 to about 15 weight % of a disintegrant; (0) about 15 to about 25 weight % of an osmogcn; (d) about 0.1 to about 3 weight % of a t; (6) about 0.1 to about 3 weight % of a lubricant; and (1) about 10 to about 25 weight % of a binder / diluent.
In a further embodiment, the ceutical composition comprises: (a) 25 to 60 weight % of a solid dispersion of N4-(4-([l,2,4]triazolo[l,5- a]pyridinyloxy)—3-methylphenyl)—N6-(4,4-dimethyl-4,5-dihydrooxazolyl)quinazoline- amine; (b) 5 to 15 weight % of a disintegrant; (c) 15 to 25 weight % of an osmogen; (d) 0.1 to 3 weight % of a glidant; (e) 0.1 to 3 weight % of a lubricant; and PCT/U52012/060044 (f) 10 to 25 weight % of a binder/ diluent.
Certain embodiments provide a pharmaceutical composition comprising: (a) about 40 to about 60 weight % of a solid dispersion of N4-(4- ([1 ,2,4]triazolo[l ,5 -a]pyridinyloxy)-3 -methylphenyl)—N6-(4,4-dimethyl-4,5- dihydrooxazolyl)quinazoline-4,6-diamine; (b) about 5 to about 15 weight % of a disintegrant; (0) about 15 to about 25 weight % of an osmogcn; (d) about O.l to about 3 weight % of a glidant; (6) about 0.1 to about 3 weight % of a lubricant; and (f) about 10 to about 25 weight % of a binder / diluent.
In a further embodiment, the pharmaceutical composition comprises: (a) 40 to 60 weight % of a solid dispersion of N4-(4-([l,2,4]triazolo[l,5- a]pyridinyloxy)—3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazolyl)quinazoline- 4,6-diamine; (b) 5 to 15 weight % of a disintegrant; (c) 15 to 25 weight % of an osmogen; (d) 0.1 to 3 weight % of a glidant; (e) 0.1 to 3 weight % of a lubricant; and (f) 10 to 25 weight % of a binder/ t. n embodiments provide a pharmaceutical composition comprising: (a) about 1 to about 70 weight % of a solid dispersion of N4-(4- ([1 riazolo[l ,5 -a]pyridinyloxy)-3 -methylphenyl)—N6-(4,4-dimethyl—4,5— dihydrooxazolyl)quinazolinc-4,6-diaminc; (b) about 0.1 to about 20 weight % of a disintegrant; (0) about 0.1 to about 25 weight % of an osmogen; (d) about 0.1 to about 10 weight % of a glidant; (e) about 0.1 to about 10 weight % of a lubricant; and (l) about 0.1 to about 25 weight % of a filler.
In a r embodiment, the pharmaceutical composition comprises: (a) l to 70 weight % of a solid dispersion of N4-(4-([l,2,4]triazolo[l,5- dinyloxy)—3-methylphenyl)—N6-(4,4-dimethyl-4,5-dihydrooxazolyl)quinazoline- 4,6-diamine; (b) 0.1 to 20 weight % of a disintegrant; (c) 0.1 to 25 weight % of an osmogen; PCT/U52012/060044 (d) 0.1 to 10 weight % of a glidant; (e) 0.1 to 10 weight % of a lubricant; and (f) 0.1 to 25 weight % ofa filler.
Certain embodiments provide a pharmaceutical composition comprising: (a) about 25 to about 60 weight % of a solid dispersion of N4-(4- ([1 ,2,4]triazolo[l ,5 -a]pyridinyloxy)-3 lphenyl)—N6-(4,4-dimethyl—4,5— dihydrooxazolyl)quinazolinc-4,6-diaminc; (b) about 1 to about 10 weight % of a disintegrant; (0) about 15 to about 25 weight % of an osmogen; (d) about 0.1 to about 3 weight % of a glidant; (e) about 0.1 to about 3 weight % of a lubricant; and (l) about 10 to about 25 weight % of a filler.
In a further embodiment, the pharmaceutical ition ses: (a) 25 to 60 weight % of a solid dispersion of N4-(4-([1,2,4]triazolo[1,5- a]pyridinyloxy)—3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazolyl)quinazoline- 4,6-diamine; (b) l to 10 weight % of a disintegrant; (c) 15 to 25 weight % of an osmogen; (d) 0.1 to 3 weight % of a glidant; (e) 0.1 to 3 weight % of a lubricant; and (f) 10 to 25 weight % of a filler.
Certain embodiments provide a ceutical composition comprising: (a) about 40 to about 60 weight % of a solid dispersion of N4-(4- ([1 ,2,4]triazolo[l ,5 -a]pyridinyloxy)-3 lphenyl)—N6-(4,4-dimethyl-4,5- dihydrooxazolyl)quinazoline-4,6-diamine; (b) about 1 to about 10 weight % of a disintegrant; (0) about 15 to about 25 weight % of an osmogen; (d) about 0.1 to about 3 weight % of a glidant; (e) about 0.1 to about 3 weight % of a lubricant; and (f) about 10 to about 25 weight % of a filler.
In a further embodiment, the pharmaceutical composition comprises: (a) 40 to 60 weight % of a solid dispersion of N4-(4-([l,2,4]triazolo[l,5- a]pyridinyloxy)—3-methylphenyl)-N6-(4,4-dimethyl-4,5—dihydrooxazolyl)quinazoline- 4,6-diamine; PCT/U52012/060044 (b) l to 10 weight % of a disintegrant; (c) 15 to 25 weight % of an osmogen; (d) 0.1 to 3 weight % of a glidant; (e) 0.1 to 3 weight % of a ant; and (f) 10 to 25 weight % of a filler.
In certain embodiments, the osmogen is selected from NaCl and KCl, and mixtures thereof.
] In certain embodiments, the lubricant is magnesium stearate.
In certain embodiments, the glidant is colloidal silicon dioxide.
In certain embodiments, the binder / diluent is microcrystalline cellulose. In certain embodiments, the binder / diluent acts as both a binder and a diluent.
In n embodiments, the binder is microcrystalline cellulose.
In n embodiments, the diluent is microcrystalline cellulose.
In certain embodiments, the filler is lactose.
In certain embodiments, the disintegrant is selected from crospovidone and sodium bicarbonate (NaHC03), and mixtures f. In certain ments, the disintegrant is ed from crospovidone and sodium bicarbonate. In certain embodiments, the disintegrant is sodium bicarbonate. In certain ments, the disintegrant is crospovidone.
In certain embodiments, the ition contains sodium bicarbonate. N4-(4- ([1 ,2,4]Triazolo[l ,5 -a]pyridinyloxy)—3 -methylphenyl)-N6-(4,4-dimethyl-4,5 - dihydrooxazol—Z-yl)quinazoline-4,6-diamine may slowly e, through hydrolysis or other means, to a carbamatc impurity: Sodium bicarbonate helps to slow the degradation to the carbamate impurity. Sodium onate also helps to provide consistent tablet disintegration when the tablets are exposed to different humidities.
] Certain embodiments provide a pharmaceutical composition comprising: (a) N4-(4-([1,2,4]triazolo[l ,5 -a]pyridinyloxy)-3 -methylphenyl)-N6— (4,4-dimethyl—4,5-dihydrooxazol-Z-yl)quinazoline—4,6-diamine; and PCT/U52012/060044 (b) sodium bicarbonate.
Certain embodiments provide a pharmaceutical composition comprising: (a) about 1 to about 70 weight % of a solid dispersion of N4-(4- ([1 ,2,4]triazolo[l ,5 -a]pyridinyloxy)-3 -methylphenyl)—N6-(4,4-dimethyl-4,5- dihydrooxazol-Z-yl)quinazoline-4,6-diamine; and (b) about 0.1 to about 30 weight % sodium bicarbonate.
In a further embodiment, the pharmaceutical composition ses: (a) l to 70 weight % of a solid dispersion of ([l,2,4]triazolo[l,5- a]pyridinyloxy)—3-methylphenyl)—N6-(4,4-dimethyl-4,5-dihydrooxazolyl)quinazoline- 4,6-diamine; and (b) 0.1 to 30 weight % sodium onate.
Certain ments provide a pharmaceutical composition comprising: (a) about I to about 70 weight % of a solid sion of N4-(4- ([1 ,2,4]triazolo[l ,5 -a]pyridinyloxy)-3 -methylphenyl)—N6-(4,4-dimethyl-4,5- dihydrooxazol-Z-yl)quinazoline-4,6-diamine; (b) about 0.1 to about 30 weight % sodium bicarbonate; and (c) the remaining weight is other pharmaceutically acceptable excipients and carriers.
In a further embodiment, the ceutical composition comprises: (a) 1 to 70 weight % of a solid dispersion of N4-(4-([l,2,4]triazolo[l,5- a]pyridinyloxy)—3-methylphenyl)—N6-(4,4-dimethyl-4,5-dihydrooxazolyl)quinazoline- 4,6-diamine; (b) 0.1 to 30 weight % sodium bicarbonate; and (c) the remaining weight is other pharmaceutically acceptable excipients and rs.
Certain embodiments provide a pharmaceutical composition comprising: (a) about 25 to about 60 weight % of a solid dispersion of N4—(4— ([ l ,2,4]triazolo[l ,5 -a]pyridinyloxy)-3 -methylphenyl)—N6-(4,4-dimethyl-4,5- dihydrooxazol-Z-yl)quinazoline-4,6-diamine; and (b) about 1 to about 15 weight % of sodium bicarbonate.
In a further embodiment, the pharmaceutical composition ses: (a) 25 to 60 weight % of a solid dispersion of N4-(4-([l,2,4]triazolo[l,5- a]pyridinyloxy)—3-methylphenyl)—N6-(4,4-dimethyl-4,5—dihydrooxazol-Z-yl)quinazoline- 4,6-diamine; and PCT/U52012/060044 (b) 1 to 15 weight % of sodium bicarbonate.
Certain embodiments e a pharmaceutical composition comprising: (a) about 25 to about 60 weight % of a solid dispersion of N4-(4- ([1 ,2,4]triazolo[1 ,5 idinyloxy)-3 -methylphenyl)—N6-(4,4-dimethyl-4,5- dihydrooxazol-Z-yl)quinazoline-4,6-diamine; (b) about 1 to about 15 weight % of sodium bicarbonate; and (c) the remaining weight is other pharmaceutically acceptable excipients and carriers.
In a further embodiment, the pharmaceutical composition comprises: (a) 25 to 60 weight % of a solid dispersion of N4-(4-([1,2,4]triazolo[1,5- a]pyridinyloxy)—3-methylphenyl)—N6-(4,4-dimethyl-4,5—dihydrooxazolyl)quinazoline- 4,6-diamine; (b) 1 to 15 weight % of sodium bicarbonate; and (c) the remaining weight is other pharmaceutically acceptable excipients and carriers. n embodiments provide a pharmaceutical ition comprising: (a) about 40 to about 60 weight % of a solid dispersion of N4—(4— ([1 ,2,4]triazolo[1 ,5 -a]pyridinyloxy)-3 -methylphenyl)—N6-(4,4-dimethyl-4,5- ooxazol-2—yl)quinazoline-4,6-diamine; and (b) about 1 to about 15 weight % of sodium bicarbonate.
In a further embodiment, the ceutical composition comprises: (a) 40 to 60 weight % of a solid dispersion of ([1,2,4]triazolo[1,5- a]pyridinyloxy)—3-mcthylphcnyl)—N6-(4,4-dimethyl-4,5-dihydrooxazolyl)quinazoline- 4,6-diamine; and (b) 1 to 15 weight % of sodium bicarbonate.
Certain embodiments provide a pharmaceutical composition comprising: (a) about 40 to about 60 weight % of a solid dispersion of N4—(4— ([ l riazolo[l ,5 -a]pyridinyloxy)-3 -methylphenyl)—N6-(4,4-dimethyl-4,5- dihydrooxazol-Z-yl)quinazoline-4,6-diamine; (b) about 1 to about 15 weight % of sodium bicarbonate; (c) the remaining weight is other pharmaceutically acceptable excipients and carriers.
In a further embodiment, the pharmaceutical composition comprises: PCT/U52012/060044 (a) 40 to 60 weight % of a solid dispersion of ([1,2,4]triazolo[1,5- a]pyridinyloxy)—3-methylphenyl)—N6-(4,4-dimethyl-4,5-dihydrooxazolyl)quinazoline- 4,6-diamine; (b) 1 to 15 weight % of sodium bicarbonate; (c) the remaining weight is other pharmaceutically acceptable excipients and carriers.
The pharmaceutical ition preferably contains a therapeutically effective amount of N4-(4-([l,2,4]triazolo[l,5-a]pyridinyloxy)methylphenyl)-N6-(4,4- dimethyl-4,5-dihydrooxazolyl)quinazoline-4,6-diamine. However, in some embodiments, each individual dose contains a portion of a therapeutically effective amount of N4-(4- ([1,2,4]triazolo[l,5 -a]pyridinyloxy)-3 lphenyl)—N6-(4,4-dimethyl—4,5— dihydrooxazolyl)quinazoline-4,6-diamine, such that multiple doses of the composition may be required (for example, two or more tablets are required for a therapeutically effective ). Thus, in this application when it states that the pharmaceutical composition contains a therapeutically effective amount it means that the ition may be one dose (for example, one tablet) or multiple doses (for example, two tablets). In certain embodiments, the ceutical composition contains between 1 and 500 mg of ([l,2,4]triazolo[1,5- a]pyridin-7—yloxy)—3-methylphenyl)—N6-(4,4-dimethyl-4,5-dihydrooxazolyl)quinazoline- 4,6-diamine.
In certain embodiments, the pharmaceutical composition contains between 25 and 400 mg of N4-(4-([l,2,4]triazolo[l,5-a]pyridinyloxy)methylphenyl)-N6-(4,4- dimethyl-4,5—dihydrooxazol-Z—yl)quinazoline-4,6—diamine.
] In certain ments, the pharmaceutical composition contains between 100 and 300 mg of N4-(4-([l,2,4]triazolo[l,5-a]pyridinyloxy)—3-methylphenyl)—N6-(4,4- dimethyl-4,5-dihydrooxazolyl)quinazoline-4,6-diamine.
The pharmaceutical compositions described herein may be administered by any convenient route appropriate to the condition to be treated. Suitable routes include oral, parenteral (including subcutaneous, intramuscular, intravenous, intraarterial, intradermal, intrathecal and epidural), ermal, rectal, nasal, topical (including buccal and sublingual), , vaginal, intraperitoneal, intrapulmonary and intranasal. If parenteral administration is desired, the compositions will be sterile and in a solution or suspension form suitable for injection or infiasion.
PCT/U52012/060044 ] The compounds may be administered in any ient strative form, e.g., tablets, powders, capsules, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc.
The pharmaceutical compositions described herein are typically administered orally. The pharmaceutical compositions described herein are typically stered as a tablet, , hard or soft n capsule, pill, granules or a suspension.
METHODS OF TREATMENT WITH COMPOUNDS OF THE INVENTION Also provided are methods of treating or preventing disease or condition by administering the ceutical composition described herein. In one embodiment, a human patient is treated with a pharmaceutical composition described herein in an amount to inhibit ErbB2 activity. In one embodiment, a human patient is treated with a pharmaceutical composition described herein in an amount to detectably inhibit ErbBZ activity.
In another embodiment, a method of treating a hyperproliferative disease in a mammal comprising administering the pharmaceutical composition described herein, to the mammal is provided.
In certain embodiments, the hyperproliferative disease is cancer.
In another embodiment, a method of treating or preventing cancer in a mammal in need of such treatment, wherein the method comprises administering to said mammal a pharmaceutical composition described herein. The cancer is selected from breast, ovary, cervix, prostate, testis, genitourinary tract, esophagus, larynx, glioblastoma, lastoma, stomach, skin, keratoacanthoma, lung, epidermoid carcinoma, large cell carcinoma, NSCLC, small cell carcinoma, lung adenocarcinoma, bone, colon, adenoma, pancrcas, arcinoma, thyroid, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, r carcinoma, liver carcinoma and biliary es, kidney carcinoma, myeloid disorders, lymphoid disorders, hairy cells, buccal cavity and pharynx (oral), lip, tongue, mouth, pharynx, small intestine, colon-rectum, large intestine, rectum, brain and central nervous system, Hodgkin's and leukemia. Another ment provides the use of a ceutical composition bed , in the manufacture of a medicament for the ent of cancer.
In another embodiment, the cancer is ErbB2 positive.
In another embodiment, the cancer is selected from breast, gastric, biliary, colorectal, lung, NSCLC, pancreatic, head and neck, ovarian, uterine and brain cancer.
In another embodiment, the cancer is selected from breast, gastric, biliary, colorectal, lung, NSCLC, atic, head and neck, n and uterine cancer.
PCT/U52012/060044 In another embodiment, the cancer is selected from breast, gastric, colorectal, lung and ovarian cancer.
In another embodiment, the cancer is selected from , ovarian, gastric and uterine .
In another embodiment, the cancer is selected from breast, gastric, colorectal, NSCLC and ovarian cancer.
In r embodiment, the cancer is sclcctcd from breast, lung, pancreatic, colorectal and head and neck cancers.
In another embodiment, the cancer is breast cancer.
In another embodiment, the cancer is gastric cancer.
In another embodiment, the cancer is biliary cancer.
In r embodiment, the cancer is colorectal cancer.
In another embodiment, the cancer is lung cancer.
In another embodiment, the cancer is NSCLC.
In another embodiment, the cancer is pancreatic cancer. 0] In another embodiment, the cancer is head and neck cancer.
In another embodiment, the cancer is ovarian cancer.
In another embodiment, the cancer is uterine cancer.
In another ment, the cancer is brain cancer.
In another ment, a method of treating or preventing a disease or disorder ted by ErbB2, comprising administering to a mammal in need of such treatment an effective amount of a pharmaceutical composition described herein. Examples of such cs and disorders include, but are not limited to, cancer.
Another embodiment provides the use of a pharmaceutical composition described herein, in the manufacture of a medicament for the treatment of cancer.
Another embodiment provides the solid sions described herein for the treatment of disease. In a further embodiment, the disease is a hyperproliferative disease. In a further embodiment, the hyperproliferative disease is .
Another embodiment provides the pharmaceutical compositions described herein for the treatment of disease. In a further embodiment, the disease is a hyperproliferative disease. In a r embodiment, the roliferative disease is cancer.
EXAMPLES For illustrative purposes, the ing Examples are included. However, it is to be understood that these Examples do not limit the ion and are only meant to suggest PCT/U52012/060044 a method of practicing the invention. Persons skilled in the art will recognize that the chemical reactions described may be readily d to prepare the compounds described herein, and alternative methods for preparing the compounds are deemed to be within the scope of this invention. For example, the synthesis of the compounds described herein may be successfully performed by modifications apparent to those skilled in the art, e.g., by appropriately protecting interfering groups, by utilizing other suitable reagents known in the art other than those described, and/or by making routinc modifications of reaction ions.
Alternatively, other reactions disclosed herein or known in the art will be recognized as having applicability for preparing the compounds described herein. Persons skilled in the art will also recognize that the solid dispersions and compositions described may be readily adapted to prepare other dispersions and compositions, and alternative methods for preparing the sions and compositions, as well as alternative compositions are deemed to be within the scope of this ion.
Example 1 % Solid Dispersion using PVP-VA A solid dispersion was prepared containing 30 weight percent N4-(4— ([1 ,2,4]triazolo[1 ,5 -a]pyridinyloxy)-3 -methylphenyl)-N6-(4,4-dimethyl—4,5— dihydrooxazolyl)quinazoline-4,6-diamine and PVP-VA using a Buchi B-290 mini spray drier. The solid dispersion was spray dried from a MeOH:THF (1:3) solvent system, a 5% spray solution concentration, an inlet temperature of 100°C at a flow rate of 22 mL/minute, drying gas flow rate of 35 mg/hour, nozzle pressure of 80 psig, nozzle gas flow of 0.66 ms/hour, and a 1.5 mm nozzle type. Secondary drying of the dispersion was done at 40°C under vacuum for about 16 hours. The spray drying yicldcd 19.6 g (87.7% yield) of the solid dispersion. ochemical analysis s are in Table 1. The XRPD scan is shown in Figure 1. al solvent analysis showed that the sion had less than 0.5% THF and no detectable MeOH.
Dissolution testing was performed at a pH of 6.5 in phosphate . The solid dispersion was suspended in H20 and added directly to the buffer solution at 37°C. The dissolution profile was collected over a period of about 240 minutes. The results are in Figure 2. The Cmax and AUC for the total drug s (colloidal + free) was 63.46 ug/mL and 245.05 ug/mL*hr, respectively. The Cmax and AUC for the free drug species was 52.50 ug/mL and 204.12 ug/mL*hr, respectively.
WO 56108 PCT/U52012/060044 Example 2 % Solid Dispersion using Eudragit A solid dispersion was prepared containing 30 weight percent N4-(4- ([1 ,2,4]triazolo[1 ,5 -a]pyridinyloxy)-3 -methylphenyl)—N6-(4,4-dimethyl-4,5- dihydrooxazolyl)quinazoline-4,6-diamine and Eudragit L100 using a Buchi B-290 mini spray drier. The solid dispersion was spray dried from a MeOHzTHF (1:3) t system, a % spray solution concentration, an inlet temperature of 100°C at a flow rate of 22 ute, drying gas flow rate of 35 m3,/hour, nozzle pressure of 80 psi g, nozzle gas flow of 0.66 mS/hour, and a 1.5 mm nozzle type. Secondary drying of the dispersion was done at 40°C under vacuum for about 16 hours. The spray drying d 18.6 g (82.7% yield) of the solid dispersion. Physicochemical analysis results are in Table 1. The XRPD scan is shown in Figure 1. Residual solvent analysis showed that the dispersion had about 4.5% THF and no detectable MeOH.
Dissolution testing was performed at a pH of 6.5 in ate buffer. The solid dispersion was suspended in H20 and added directly to the buffer on at 37°C. The dissolution profile was collected over a period of about 240 minutes. The results are in Figure 3. The Cmax and AUC for the total drug species (colloidal + free) was 22.70 ug/mL and 71.06 hr, respectively. The Cmax and AUC for the free drug species was 9.26 ug/mL and 35.49 ug/mL*hr, respectively.
Example 3 % Solid Dispersion using HPMCP A solid dispersion was ed containing 30 weight percent N4-(4— ([1 ,2,4]triazolo[1 ,5 -a]pyridinyloxy)-3 -methylphcnyl)-N6-(4,4-dimcthyl-4,5- dihydrooxazolyl)quinazoline-4,6-diamine and HPMCP H-55 using a Buchi B-290 mini spray drier. The solid dispersion was spray dried from a MeOHzTHF (1 :3) solvent system, a % spray solution concentration, an inlet temperature of 100°C at a flow rate of 22 mL/minute, drying gas flow rate of 35 n13/hour, nozzle pressure of 80 psig, nozzle gas flow of 0.66 m3/hour, and a 1.5 mm nozzle type. Secondary drying of the dispersion was done at 40°C under vacuum for about 16 hours. The spray drying yielded 20.3 g (90.3% yield) of the solid dispersion. Physicochemical analysis results are in Table 1. The XRPD scan is shown in Figure 1. al solvent analysis showed that the dispersion had less than 0.5% THF and no detectable MeOH.
Dissolution testing was performed at a pH of 6.5 in phosphate buffer. The solid dispersion was suspended in H20 and added directly to the buffer solution at 37°C. The PCT/U52012/060044 dissolution profile was collected over a period of about 240 minutes. The results are in Figure 4. The Cmax and AUC for the total drug species (colloidal + free) was 25.00 ug/mL and 96.66 itg/mL*hr, respectively. The CmaX and AUC for the free drug species was 16.15 ug/mL and 56.81 ug/mL*hr, respectively.
Example 4 % Solid Dispersion using CAP A solid sion was prepared containing 30 weight percent N4-(4- ([l ,2,4]triazolo[1 ,5-a]pyridinyloxy)-3 lphenyl)—N6-(4,4-dimethyl-4,5- dihydrooxazolyl)quinazoline-4,6-diamine and CAP using a Buchi B—290 mini spray drier.
The solid dispersion was spray dried from a MeOH:THF (1:3) solvent system, a 5% spray on concentration, an inlet temperature of 100°C at a flow rate of 22 mL/minute, drying gas flow rate of 35 n13/hour, nozzle pressure of 80 psig, nozzle gas flow of 0.66 ur, and a 1.5 mm nozzle type. Secondary drying of the dispersion was done at 40°C under vacuum for about 16 hours. The spray drying yielded 20.0 g (90.4% yield) of the solid dispersion.
Physieochemical analysis results are in Table l. The XRPD scan is shown in Figure 1.
Residual solvent analysis showed that the dispersion had less than 0.5% THF and no able MeOH.
Dissolution testing was performed at a pH of 6.5 in phosphate buffer. The solid dispersion was suspended in H20 and added directly to the buffer on at 37°C. The dissolution profile was ted over a period of about 240 minutes. The results are in Figure . The Cmax and AUC for the total drug species (colloidal + free) was 11.62 ug/mL and 36.69 ug/mL*hr, respectively. The CmaX and AUC for the free drug species was 5.64 ug/mL and 20.58 ug/mL*hr, respectively.
Example 5 % Solid Dispersion using HPMCAS A solid dispersion was prepared containing 30 weight percent N4-(4- ([1 ,2,4]triazolo[1 ,5 -a]pyridinyloxy)-3 lphenyl)—N6-(4,4-dimethyl—4,5— dihydrooxazolyl)quinazoline-4,6-diamine and HPMCAS Grade M using a Buchi B-290 mini spray drier. The solid dispersion was spray dried from a MeOH:THF (1:3) solvent system, a 5% spray solution concentration, an inlet temperature of 80°C at a flow rate of 35 mL/minute, drying gas flow rate of 40 m3,/hour, nozzle pressure of 80 psig, nozzle gas flow of 0.66 m3/hour, and a 1.5 mm nozzle type. Secondary drying of the dispersion was done at 40°C under vacuum for about 16 hours. The spray drying d 163.19 mg (48.3% yield) of the solid dispersion. Physieoehemieal analysis results are in Table 1. The XRPD scan is PCT/U52012/060044 shown in Figure 1. Residual t analysis showed that the dispersion had less than 0.5% THF and no detectable MeOH.
Dissolution g was performed at a pH of 6.5 in phosphate . The solid dispersion was suspended in H20 and added directly to the buffer on at 37°C. The dissolution profile was collected over a period of about 240 minutes. The results are in Figure 6. The Cmax and AUC for the total drug species (colloidal + free) was 19.04 ug/mL and 68.09 ug/mL*hr, respectively. The Cmax and AUC for the free drug species was 13.50 ug/mL and 51 .74 ug/mL*hr, tively.
Table 1 Example Polymer API: HPLC Tg TGA % copicity Polymer (area%) (°C) wt loss THF (% wt change (%) (w/w) at 80% RH) 1 PVP—VA 3:7 99.45 117 2.3 0.5 14.4 3 HPMCP 3:7 97.30 149 1.7 0.3 7.5 HPMCAS 3:7 113 NA NA NA Example 6 60% Solid Dispersion using PVP—VA A solid dispersion was prepared containing 60 weight percent N4-(4— ([1 ,2,4]triazolo[l ,5-a]pyridinyloxy)-3 -methylphenyl)—N6-(4,4-dimethyl-4,5- dihydrooxazolyl)quinazoline-4,6-diamine and PVP-VA using a Buchi B-290 mini spray drier. The solid dispersion was spray dried from a MeOHzTHF (1:3) solvent system, a 5% spray solution concentration, an inlet temperature of 80°C at a flow rate of 35 mL/rninute, drying gas flow rate of 40 mg/hour, nozzle pressure of 80 psig, nozzle gas flow of 0.66 m3/hour, and a 1.5 mm nozzle type. Secondary drying of the dispersion was done at 40°C under vacuum for about 16 hours. The spray drying yielded 135.0 mg (88.2% yield) of the solid dispersion. The XRPD scan is shown in Figure 7.
Dissolution testing was performed at a pH of 6.5 in phosphate . The solid dispersion was suspended in H20 and added directly to the buffer solution at 37°C. The dissolution profile was collected over a period of about 240 minutes. The results are in Figure 8. The Cmax and AUC for the total drug species (colloidal + free) was 34.80 ug/mL and 133.76 ug/mL*hr, respectively. The Cmax and AUC for the free drug s was 21.88 ug/mL and 84.43 ug/mL*hr, respectively.
PCT/U52012/060044 Example 7 60% Solid Dispersion using Eudragit A solid dispersion was prepared ning 60 weight percent N4-(4- ([1 ,2,4]triazolo[l ,5 -a]pyridinyloxy)-3 -methylphenyl)—N6-(4,4-dimethyl-4,5- dihydrooxazolyl)quinazoline-4,6-diamine and it L100 using a Buchi B-290 mini spray drier. The solid dispersion was spray dried from a MeOHzTHF (1 :3) solvent system, a % spray solution concentration, an inlet temperature of 80°C at a flow rate of 35 mL/minute, drying gas flow rate of 40 m3/hour, nozzle pressure of 80 psig, nozzle gas flow of 0.66 r, and a 1.5 mm nozzle type. Secondary drying of the dispersion was done at 40°C under vacuum for about 16 hours. The spray drying yielded 88.1 mg (52.4% yield) of the solid dispersion. The XRPD scan is shown in Figure 7.
Dissolution testing was performed at a pH of 6.5 in phosphate buffer. The solid dispersion was suspended in H20 and added directly to the buffer solution at 37°C. The dissolution profile was collected over a period of about 240 minutes. The results are in Figure 9. The Cmax and AUC for the total drug species (colloidal + free) was 26.82 ug/mL and 84.49 ug/mL*hr, respectively. The CmaX and AUC for the free drug s was 9.85 ug/mL and 34.89 ug/mL*hr, tively.
Example 8 60% Solid Dispersion using HPMCP A solid dispersion was prepared containing 60 weight percent N4-(4- ([1 ,2,4]triazolo[l ,5 -a]pyridinyloxy)-3 -methylphenyl)—N6-(4,4-dimethyl-4,5- dihydrooxazol—2-yl)quinazoline-4,6-diamine and HPMCP H—55 using a Buchi B-290 mini spray drier. The solid dispersion was spray dried from a MeOHzTHF (1:3) solvent system, a % spray solution concentration, an inlet temperature of 80°C at a flow rate of 35 mL/minute, drying gas flow rate of 40 r, nozzle pressure of 80 psig, nozzle gas flow of 0.66 mS/hour, and a 1.5 mm nozzle type. Secondary drying of the dispersion was done at 40°C under vacuum for about 16 hours. The spray drying yielded 98.0 mg (58.0% yield) of the solid dispersion. The XRPD scan is shown in Figure 7.
Dissolution testing was performed at a pH of 6.5 in phosphate buffer. The solid dispersion was suspended in H20 and added directly to the buffer on at 37°C. The ution profile was collected over a period of about 240 s. The results are in Figure . The Cmax and AUC for the total drug species (colloidal + free) was 32.21 ug/mL and 38.28 ug/mL*hr, respectively. The Cmax and AUC for the free drug species was 9.96 ug/mL and 38.28 ug/mL*hr, respectively.
PCT/U52012/060044 Example 9 60% Solid Dispersion using CAP A solid dispersion was prepared containing 60 weight t N4-(4- ([1 ,2,4]triazolo[1 ,5 -a]pyridinyloxy)-3 -methylphenyl)—N6-(4,4-dimethyl-4,5- dihydrooxazolyl)quinazoline-4,6-diamine and CAP using a Buchi B—290 mini spray drier.
The solid dispersion was spray dried from a MeOH:THF (1:3) solvent system, a 5% spray solution concentration, an inlet ature of 80°C at a flow rate of 35 mL/minute, drying gas flow rate of 40 mS/hour, nozzle pressure of 80 psig, nozzle gas flow of0.66 mS/hour, and a 1.5 mm nozzle type. Secondary drying of the dispersion was done at 400C under vacuum for about 16 hours. The spray drying yielded 74.9 mg (44.6% yield) of the solid dispersion.
The XRPD scan is shown in Figure 7.
Dissolution testing was performed at a pH of 6.5 in phosphate buffer. The solid dispersion was ded in H20 and added directly to the buffer solution at 37°C. The dissolution profile was collected over a period of about 240 minutes. The results are in Figure 11. The Cmax and AUC for the total drug species (colloidal + free) was 51.98 ug/mL and 144.91 ug/mL*hr, respectively. The Cmax and AUC for the free drug species was 15.07 ug/mL and 59.69 ug/mL*hr, respectively.
Example 10 60% Solid Dispersion using HPMCAS A solid dispersion was prepared containing 60 weight percent N4-(4- ([1 riazolo[1 ,5 -a]pyridinyloxy)-3 -methylphenyl)—N6-(4,4-dimethyl-4,5- dihydrooxazol—2-yl)quinazoline-4,6-diamine and HPMCAS Grade M using a Buchi B-290 mini spray drier. The solid dispersion was spray dried from a MeOHiTHF (1:3) t system, a 5% spray solution concentration, an inlet temperature of 80°C at a flow rate of 35 mL/minute, drying gas flow rate of 40 m3/hour, nozzle pressure of 80 psig, nozzle gas flow of 0.66 m3/hour, and a 1.5 mm nozzle type. ary drying of the dispersion was done at 40°C under vacuum for about 16 hours. The spray drying yielded 113.3 mg (67.2% yield) of the solid dispersion. The XRPD scan is shown in Figure 7.
Dissolution g was performed at a pH of 6.5 in phosphate buffer. The solid dispersion was ded in H20 and added directly to the buffer solution at 37°C. The dissolution profile was collected over a period of about 240 minutes. The s are in Figure 12. The Cmax and AUC for the total drug species (colloidal + free) was 26.45 ug/mL and 96.21 ug/mL*hr, respectively. The Cmax and AUC for the free drug species was 10.96 ug/mL and 42.83 ug/mL*hr, respectively.
PCT/U52012/060044 Example 11 50% Solid Dispersion using PVP-PA A solid dispersion was prepared ning 50 weight percent N4-(4- ([1 ,2,4]triazolo[l ,5 -a]pyridinyloxy)-3 -methylphenyl)—N6-(4,4-dimethyl-4,5- dihydrooxazolyl)quinazoline-4,6-diamine and PVP-VA using a Buehi B-290 mini spray drier. The solid dispersion was spray dried from a MeOH:THF (1:3) solvent system, a 3.9% spray solution concentration, an inlet temperature of 100°C at a flow rate of 30 mL/minute, drying gas flow rate of 40 m3/hour, nozzle pressure of 80 psig, nozzle gas flow of 0.66 m3/hour, and a 1.5 mm nozzle type. Secondary drying of the dispersion was done at 50°C under vacuum for about 72 hours. The spray drying yielded 28.7 g (72.7% yield) of the solid dispersion.
Example 12 N4- 4- l 2 4 lo l 5-a - lox meth l,hen 1 -N6- 4 4-dimeth 1-4 5- dihydrooxazol-Z-yl)guinazoline-4,6-diamine freebase hemi-ethanolate Step 1: (E)-N'—(2-Cyano(3-(l-hydroxymethylpropanyl)thioureido) phenyl)- ,N—dimethylformimidamide was coupled with 2,4]triazolo[l,5—a]pyridin yloxy)-3—methylaniline in isopropyl aeetate:acetic acid (65:35 v/v) at 45°C to yield l—(4—((4— ([1 ,2,4]triazolo[l ,5 -a]pyridinyloxy)-3 -methylphenyl)amino)quinazolinyl)-3 -( 1 -hydroxy methylpropanyl)thiourea (91%).
Step 2: 1-(4-((4-([l,2,4]Triazolo[l,5-a]pyridinyloxy)methylphenyl) amino)quinazo1inyl)( l xymethy1propan—2-yl)thiourea was agitated in tetrahydrofuran under basic conditions (2.5N NaOH), followed by the on of p— tolucnesulfonyl chloride. Water was charged to yield N4-(4-([l,2,4]triazolo[l,5-a]pyridin yloxy)methylpheny1)-N6-(4,4-dimethy1-4,5-dihydrooxazoly1)quinazoline-4,6-diamine (96%) as a mixture of polymorphs (generally a e containing one or more of Form C, Form G hemi-THF, Form G mono-THF, Form M or Form P).
Step 3: N4-(4-([ l ,2,4]Triazolo[l ,5 -a]pyridinyloxy)-3 -methylphenyl)-N6- (4,4-dimethyl-4,5-dihydrooxazolyl)quinazoline-4,6-diamine from Step 2 was triturated in ethanol at greater than 65°C to provide ([l,2,4]triazolo[l,5-a]pyridinyloxy) methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazolyl)quinazoline-4,6-diamine Form B Ethanol (89%).
The crystalline hemi-ethanolate (Form B Ethanol) XRPD scans are shown in Figures 1 and 7.
WO 56108 PCT/U52012/060044 Dissolution testing was med at a pH of 6.5 in phosphate buffer. The crystals (particles) were suspended in H20 and added directly to the buffer solution at 370C.
The dissolution profile was collected over a period of about 240 minutes. The Cmax and AUC for the free drug species was 0.44 ug/mL and 5.49 ug/mL*hr, respectively.
Example 13 Pharmaceutical Composition 1 Tablcts containing the solid dispersions of any of es l to 11 may be ed in a conventional manner comprising: Function Incredient % 0f Blend Solid dispersion as preparedin Example Disintegrant Crospovidone — Pol lasdonc® Osmoen NaCl Osmo _en KC] Glidant Colloidal Silicon Dioxide Lubricant Ma-nesium Stearate Bindcr / Dilucnt Microcrystallinc cellulose — ® Osmoen Disinte _rant Glidant Colloidal Silicon Dioxide Lubricant Ma_ In one preparation, tablets were made using OPADRY ll 85F92727 at 3% by weight as a tablet coating. The tablets contained 150 mg of API.
Example 14 Pharmaceutical Composition 2 Tablets containing the solid sions of any of Examples 1 to ll may be ed in a conventional manner comprising: °/» of Blend Solid dispersion as 50 preparedin Example Disintegrant Crospov1done — P01 1 lasdone® 2012/060044 Disintc - rant NaHCO; 3 Osmo-en NaCl Osmo-en KCI Glidant Colloidal Silicon 0.5 Dioxide Lubricant Ma-nesium Stearate Binder / Diluent Microcrystalline cellulose — Avicel® NaCl Osmoen KCl 4.625 Disinte _rant Pol ,lasdone Glidant Colloidal n 0.5 Dioxide Lubricant Manesium Stearate In one preparation, tablets were made using OPADRY II 85F92727 at 3% by weight as a tablet coating. The s contained 150 mg of API.
Example 15 Pharmaceutical Composition 3 Tablets containing the solid dispersions of any of Examples 1 to ll may be prepared in a conventional manner comprising: Function In 1 redient % 0f Blend Solid dispersion as ed in Example Disintegrant Crospovidone — Pol lasdone® Osmo -en NaCl Osmo -_en KCl Filler Lactose t Colloidal Silicon Dioxide Glidant Colloidal Silicon Dioxide Lubricant Manesium Stearate In one ation, tablets were made using OPADRY II 85F92727 at 3% by weight as a tablet coating. The s contained 150 mg ofAH.
PCT/U52012/060044 Example 16 Referential Pharmaceutical Composition — Powder-in-Capsule A PIC composition was prepared containing 25 mg or 100 mg of N4-(4- ([1 ,2,4]triazolo[1 ,5 -a]pyridinyloxy)-3 -methylphenyl)—N6-(4,4-dimethyl-4,5 -dihydrooxazol y1)quinazoline-4,6-diamine as prepared in Example 12. The PIC composition was prepared in size 00 white opaque hard n es.
A dissolution test comparison was performed comparing the lline hemi- ethanolate PIC composition of Example 16 and the 50% PVP-VA solid dispersion (Example 11) tablet of Example 13 in 900 mL of 10 mM citrate buffer at 370C and a pH of 4.5, using USP Apparatus II at 75 rpm. The results are shown in Figure 13.
Example 17 Stability Screen A stability screen of the spray dried sions was completed at 40°C, 75% relative humidity under open conditions, in glass vials, over a period of 8 days. Results are shown in TABLE 2.
TABLE 2 HPLC Area % Time Example 1 Example 2 Example 3 Example 4 Standard 99.39 99.39 99.39 99.39 As received 99.45 98.63 97.30 95.45 4 days 99.21 96.10 93.03 90.89 8 days 99.35 93.16 86.63 87.15 The main degradant observed was the carbamate impurity, likely due to the acidic nature of some of these polymers. XRPD analysis over the course of the study showed no evidence of crystallization for any solid dispersion of Examples 1-4.
Example 18 In vivo Pharmacokinetics in s The solid sion of Example 1 was tested against a crystalline, micronizcd sion formulation (d(v, 0.9) = 3.0um) of Example 12 under normal fasted conditions, as well as with atment using pentagastrin or famotidine. The solid sion of Example 1 was prepared as a suspension in water and administered orally. The micronized suspension of Example 12 was prepared as a suspension with SyrSpend® SF Dry reconstituted with water and administered orally. To reduce variability, beagles were crossed over from pentagastrin 2012/060044 to famotidine after a 5 day washout period. Pentagastrin is a pH modifier to modify c pH to about 2 to 3, and famotidine is a pH modifier to modify gastric pH to about 5 to 7.5 (Zhou, Rong, et a]. “pH-Dependent Dissolution in Vitro and Absorption in Vivo of Weakly Basic Drugs: Development of a Canine Model.” Pharm. Res. Vol. 22, No. 2 (Feb. 2005): pp. 188-192). There were four beagles per group. Group A received pentagastrin pretreatment, the micronized suspension of Example 12, followed by a 5 day washout period, then famotidinc pretreatment, and finally the micronized suspension of Examplc 12. Group B received astrin pretreatment, the solid dispersion of Example 1, followed by a 5 day washout period, then famotidine pretreatment, and finally the solid dispersion of e 1.
Group C received the micronized suspension of Example 12, followed by a 5 day washout , and finally the solid dispersion of Example 1. s are shown in TABLE 3.
TABLE 3 AUCinf atment Dosing Formulatlon. . Cmax (ug/mL) (ug*hr/mL) Micronized Suspension of Example 12 7.43 :: 1.77 None Solid Dispersion of Example 1 10.0 :: 2.7 6 ug/kg Micronized Suspension of Example 12 17.2 :: 2.7 astrin Solid Dispersion of Example 1 40 mg/kg Micronized Suspension of e 12 Famotidine Solid Dispersion ofExample 1 6.32 :: 2.88 1.45 :: 0.54 It will be understood that the enumerated embodiments are not intended to limit the invention to those embodiments. On the contrary, the invention is intended to cover all alternatives, modifications and equivalents, which may be included within the scope of the present invention as defined by the claims. Thus, the foregoing description is considered as illustrative only of the principles of the invention.
The words "comprise," "comprising," "include," "including," and "includes" when used in this specification and in the following claims are intended to specify the ce of stated features, integers, components, or steps, but they do not preclude the presence or addition of one or more other features, integers, ents, steps, or groups thereof.

Claims (53)

What is claimed is:
1. A solid dispersion comprising N4-(4-([1,2,4]triazolo[1,5-a]pyridin yloxy)methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazolyl)quinazoline-4,6- e and a dispersion polymer.
2. The solid dispersion of Claim 1, comprising amorphous N4-(4- 4]triazolo[1,5-a]pyridinyloxy)methylphenyl)-N6-(4,4-dimethyl-4,5- dihydrooxazolyl)quinazoline-4,6-diamine.
3. The solid dispersion of Claims 1 or 2, wherein the dispersion r is ed from vinyl polymers and copolymers, PVP-VA, polyvinyl alcohols, polyvinyl alcohol polyvinyl acetate copolymers, PVP, acrylate and rylate copolymers, methylacrylic acid methyl methacrylate copolymer, polyethylene polyvinyl alcohol copolymers, polyoxyethylene-polyoxypropylene block copolymers, graft copolymer comprised of polyethylene glycol, polyvinyl caprolactam and polyvinyl acetate, cellulosic polymers, such as HPMCA, HPMC, HPC, methyl cellulose, hydroxyethyl methyl cellulose, hydroxyethyl cellulose, hydroxyethyl cellulose acetate, and yethyl ethyl cellulose, HPMCAS, hydroxypropyl methyl cellulose phthalate, carboxymethylethyl cellulose, ose acetate phthalate, cellulose e succinate, hydroxypropyl methyl cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropyl methyl cellulose acetate trimellitate, and carboxymethylcellulose acetate butyrate.
4. The solid dispersion of any one of Claims 1 to 3, wherein the sion r is selected from vinylpyrrolidine / vinylacetate copolymer, methylacrylic acid / methyl methacrylate copolymer, hydroxypropylmethyl cellulose phthalate, and ose acetate phthalate and hydroxypropyl methyl cellulose.
5. The solid dispersion of any one of Claims 1 to 4, wherein the dispersion polymer is methylacrylic acid / methyl methacrylate copolymer.
6. The solid sion of any one of Claims 1 to 4, wherein the dispersion polymer is hydroxypropylmethyl cellulose phthalate.
7. The solid dispersion of any one of Claims 1 to 4, wherein the dispersion polymer is cellulose acetate phthalate.
8. The solid dispersion of Claims 1 or 2, wherein the dispersion polymer is preferably neutral or basic.
9. The solid sion of any one of Claims 1 to 4 or 8, wherein the dispersion polymer is selected from vinylpyrrolidine / vinylacetate copolymer and hydroxypropyl methyl cellulose, or mixtures thereof.
10. The solid dispersion of any one of Claims 1 to 4, 8 or 9, wherein the dispersion polymer is vinylpyrrolidine / vinylacetate copolymer.
11. The solid dispersion of any one of Claims 1 to 4, 8 or 9, wherein the dispersion polymer is hydroxypropyl methyl cellulose.
12. The solid dispersion of any one of Claims 1 to 11, wherein the N4-(4- 4]triazolo[1,5-a]pyridinyloxy)methylphenyl)-N6-(4,4-dimethyl-4,5- ooxazolyl)quinazoline-4,6-diamine is present in an amount of from about 0.1% to about 50% by weight relative to the dispersion polymer.
13. The solid dispersion of any one of Claims 1 to 12, wherein the N4-(4- ([1,2,4]triazolo[1,5-a]pyridinyloxy)methylphenyl)-N6-(4,4-dimethyl-4,5- dihydrooxazolyl)quinazoline-4,6-diamine is t in an amount of from about 1% to about 40% by weight relative to the sion polymer.
14. The solid dispersion of any one of Claims 1 to 13, wherein the N4-(4- ([1,2,4]triazolo[1,5-a]pyridinyloxy)methylphenyl)-N6-(4,4-dimethyl-4,5- dihydrooxazolyl)quinazoline-4,6-diamine is present in an amount of from about 5% to about 35% by weight relative to the dispersion polymer.
15. The solid dispersion of any one of Claims 1 to 14, wherein the N4-(4- 4]triazolo[1,5-a]pyridinyloxy)methylphenyl)-N6-(4,4-dimethyl-4,5- dihydrooxazolyl)quinazoline-4,6-diamine is present in an amount of from about 25% to about 35% by weight relative to the dispersion polymer.
16. The solid dispersion of any one of Claims 1 to 15, wherein at least 80% of the N4-(4-([1,2,4]triazolo[1,5-a]pyridinyloxy)methylphenyl)-N6-(4,4-dimethyl-4,5- dihydrooxazolyl)quinazoline-4,6-diamine is in amorphous form.
17. The solid dispersion of any one of Claims 1 to 16, n at least 85% of the N4-(4-([1,2,4]triazolo[1,5-a]pyridinyloxy)methylphenyl)-N6-(4,4-dimethyl-4,5- dihydrooxazolyl)quinazoline-4,6-diamine is in amorphous form.
18. The solid dispersion of any one of Claims 1 to 17, wherein at least 90% of the N4-(4-([1,2,4]triazolo[1,5-a]pyridinyloxy)methylphenyl)-N6-(4,4-dimethyl-4,5- dihydrooxazolyl)quinazoline-4,6-diamine is in amorphous form.
19. The solid dispersion of any one of Claims 1 to 18, wherein at least 95% of the ([1,2,4]triazolo[1,5-a]pyridinyloxy)methylphenyl)-N6-(4,4-dimethyl-4,5- dihydrooxazolyl)quinazoline-4,6-diamine is in amorphous form.
20. A pharmaceutical composition comprising a solid dispersion according to any one of Claims 1 to 19 and one or more pharmaceutically acceptable excipients.
21. The pharmaceutical composition of Claim 20, n the composition is a tablet.
22. A pharmaceutical composition comprising: (a) about 1 to about 70 weight % of the solid sion of any one of Claims 1 to 19; (b) about 0.1 to 20 weight % of a disintegrant; (c) about 0.1 to 25 weight % of an osmogen; (d) about 0.1 to 10 weight % of a glidant; (e) about 0.1 to 10 weight % of a lubricant; and (f) about 0.1 to 25 weight % of a binder.
23. A pharmaceutical composition comprising: (a) about 1 to about 70 weight % of the solid dispersion of any one of Claims 1 to 19; (b) about 0.1 to 20 weight % of a egrant; (c) about 0.1 to 25 weight % of an osmogen; (d) about 0.1 to 10 weight % of a glidant; (e) about 0.1 to 10 weight % of a lubricant; and (f) about 0.1 to 25 weight % of a filler.
24. The pharmaceutical composition of Claim 22, wherein the binder is about 10 to 25 weight %.
25. The pharmaceutical composition of Claims 22 or 24, wherein the disintegrant is about 5 to 15 weight %.
26. The pharmaceutical composition of Claim 23, wherein the filler is about 10 to 25 weight %.
27. The pharmaceutical composition of Claims 22 or 24, wherein the disintegrant is about 1 to 10 weight %.
28. The pharmaceutical ition of any one of Claims 22 to 27, wherein the osmogen is about 15 to 25 weight %.
29. The pharmaceutical composition of any one of Claims 22 to 28, wherein the glidant is about 0.1 to 3 weight %.
30. The pharmaceutical composition of any one of Claims 22 to 29, wherein the lubricant is about 0.1 to 3 weight %.
31. A pharmaceutical ition comprising: (a) ([1,2,4]triazolo[1,5-a]pyridinyloxy)methylphenyl)-N6-(4,4- dimethyl-4,5-dihydrooxazolyl)quinazoline-4,6-diamine; and (b) sodium bicarbonate.
32. A pharmaceutical composition comprising: (a) a solid dispersion of any one of Claims 1 to 19; and (b) sodium bicarbonate.
33. A pharmaceutical composition comprising: (a) about 1 to about 70 weight % of the solid dispersion of any one of Claims 1 to 15; and (b) about 0.1 to about 30 weight % sodium bicarbonate.
34. The pharmaceutical composition of any one of Claims 31 to 33, wherein the remaining weight of the composition is other ceutically acceptable excipients and carriers.
35. The pharmaceutical composition of any one of Claims 22 to 30 or 32 to 34, wherein the solid dispersion is about 25 to about 60 weight %.
36. The pharmaceutical composition of any one of Claims 22 to 30 or 32 to 35, wherein the solid dispersion is about 40 to about 60 weight %.
37. The pharmaceutical composition of any one of Claims 22 to 36, wherein the composition is a tablet.
38. Use of a pharmaceutical composition of any one of Claims 1 to 37 in the manufacture of a medicament for the treatment of cancer.
39. The use of Claim 38, wherein the cancer is selected from , gastric, biliary, colorectal, lung, NSCLC, pancreatic, head and neck, n, uterine and brain cancer.
40. The use of Claims 38 or 39, wherein the cancer is ErbB2 positive.
41. The solid dispersion of any one of Claims 1 to 19 for the treatment of disease.
42. The solid dispersion of Claim 41, wherein the disease is a roliferative disease.
43. The solid dispersion of Claim 42, wherein the hyperproliferative disease is cancer.
44. The solid dispersion of Claim 43, wherein the cancer is selected from breast, c, biliary, colorectal, lung, NSCLC, pancreatic, head and neck, n, uterine and brain cancer.
45. The solid dispersion of Claims 43 or 44, wherein the cancer is ErbB2 positive.
46. The pharmaceutical composition of any one of Claims 20 to 37 for the treatment of e.
47. The pharmaceutical composition of Claim 46, n the disease is a hyperproliferative disease.
48. The ceutical composition of Claim 47, wherein the hyperproliferative disease is cancer.
49. The pharmaceutical ition of Claim 48, wherein the cancer is selected from breast, gastric, biliary, colorectal, lung, NSCLC, pancreatic, head and neck, ovarian, uterine and brain cancer.
50. The pharmaceutical composition of Claims 47 or 48, wherein the cancer is ErbB2 positive.
51. A process of preparing a solid dispersion of any one of Claims 1 to 19 comprising the steps of: (a) dissolving N4-(4-([1,2,4]triazolo[1,5-a]pyridinyloxy)methylphenyl)- N6-(4,4-dimethyl-4,5-dihydrooxazolyl)quinazoline-4,6-diamine and a dispersion polymer in a suitable solvent; and (b) evaporating the solvent to form the solid sion.
52. The process of Claim 51, wherein the evaporation of the solvent in step (b) is performed by spray drying, melt extrusion, freeze drying, rotary evaporation, drum drying or other solvent removal processes.
53. The process of Claims 51 or 52, comprising the steps of: (a) dissolving N4-(4-([1,2,4]triazolo[1,5-a]pyridinyloxy)methylphenyl)- N6-(4,4-dimethyl-4,5-dihydrooxazolyl)quinazoline-4,6-diamine and a dispersion r in a le solvent to form a feed solution; and (b) spray drying the feed solution to form the solid dispersion.
NZ624942A 2011-10-14 2012-10-12 Solid dispersions of a erb2 (her2) inhibitor NZ624942B2 (en)

Applications Claiming Priority (5)

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US201161547620P 2011-10-14 2011-10-14
US61/547,620 2011-10-14
US201261606207P 2012-03-02 2012-03-02
US61/606,207 2012-03-02
PCT/US2012/060044 WO2013056108A2 (en) 2011-10-14 2012-10-12 Solid dispersion

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NZ624942B2 true NZ624942B2 (en) 2016-09-27

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