WO2011130500A1 - Formulations d'une pyridazine bipyrazinyl - Google Patents

Formulations d'une pyridazine bipyrazinyl Download PDF

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Publication number
WO2011130500A1
WO2011130500A1 PCT/US2011/032470 US2011032470W WO2011130500A1 WO 2011130500 A1 WO2011130500 A1 WO 2011130500A1 US 2011032470 W US2011032470 W US 2011032470W WO 2011130500 A1 WO2011130500 A1 WO 2011130500A1
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WO
WIPO (PCT)
Prior art keywords
formulation
compound
pharmaceutical formulation
bipyrazinyl
binders
Prior art date
Application number
PCT/US2011/032470
Other languages
English (en)
Inventor
Sundeep Sundish Dhareshwar
K. Bal Reddy
Zongqin Ruan
Original Assignee
Novartis Ag
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 Novartis Ag filed Critical Novartis Ag
Publication of WO2011130500A1 publication Critical patent/WO2011130500A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • This invention relates to formulations and methods of preparation of 2-[(R)-4-(6-benzyl- 4,5-dimethyl-pyridazin-3-yl)-2-methyl-3,4,5,6-tetrahydro-2H-[l ,2']bipyrazinyl-5'-yl]- propan-2-ol, as well as methods of treatment using the same.
  • the present invention is directed to formulations and their methods of preparation for 2- [(R)-4-(6-benzyl-4,5-dimethyl-pyridazin-3-yl)-2-methyl-3,4,5,6-tetrahydro-2H- [l,2']bipyrazinyl-5'-yl]-propan-2-ol and analogs thereof.
  • Figure 1 is a dissolution profile of the formulation of Example 2 showing a dissolution profile after 3 months.
  • Figure 2 is a dissolution profile of the formulation of Example 3 showing a dissolution profile after 3 months.
  • Figure 3 shows an X-ray diffraction pattern of one the Formulation of
  • Example 2 at initial an three months time.
  • the lack of crystalline peaks indicates that this formulation can prevent recrystallization of amorphous to crystalline Compound A in the given time frame.
  • Figure 4 shows a dissolution profile of the crystalline compound A, as well as the formulation of Example 2 (Variant III) and the formulation of Example 3 (Variant IV).
  • Dissolution time profiles are for the 10, 50 and 100 mg clinical formulation batches in pH 2, 37°C, USP Type 1 dissolution method.
  • Figure 6 is a powder X-ray diffraction (XPRD) scan comparing 10, 50 and 100 mg formulation batches (the formulation of Example 2), PEG3350 and the crystalline form Compound A.
  • XPRD powder X-ray diffraction
  • Figure 7 is a differential scanning calorimeter (DSC) thermogram analysis of a formulation of the present invention.
  • Compound A is a compound with a very low solubility of less than (0.005 mg/mL). Administering Compound A in a solid oral conventional dosage formulation to achieve high bioavailability is challenging given its low solubility.
  • the crystalline Compound A is converted to amorphous form using melt extrusion, and the amorphous form is then stabilized using hydrophilic polymers. This results in a formulation that is stable with an enhanced dissolution rate in basic pH. The present formulation prevents thermal degradation of Compound A and showed good chemical and physical stability in a 3 month stability program.
  • a process to form a solid dispersion for Compound A can use a melt extrusion process in presence of hydrophilic polymers, which function as binders and a low melting crystalline surfactant (for example 51°C), which functions as a plasticizer.
  • the current invention avoids chemical modification of drug substance, salt formation, size reduction, and is capable of enhancing drug dissolution rate.
  • the invented formulation composition is superior to previously attempted strategies to enhance dissolution rate or solubility such as, formulating using co-solvents, which limited drug solubility, particle size reduction, which resulted in poor flow of drug particles in drug-excipient blend and segregation of blend, and complexation with cyclodextrins, which resulted in low aqueous solubility of complex.
  • the present invention is formulated as a capsule, such as hard gelatin capsule or a soft elastic capsule.
  • the present invention is in the form of a tablet or a pill.
  • the amount of (2-[(R)-4-(6- benzyl-4,5-dimethyl-pyridazin-3-yl)-2-methyl-3,4,5,6-tetrahydro-2H-[ 1 ,2']bipyrazinyl-5 '- yl]-propan-2-ol can be present in the ranges of 1-1500 mg, 2.5-800 mg, or 5-400 mg, with preferred examples including 1 mg, 2.5 mg, 5 mg, 10 mg, 20 mg, 25 mg, 50 mg , 100 mg, 200 mg, 400 mg and 500 mg.
  • %w/w of active agent in different embodiments of the present invention, various ranges of %w/w of active agent, first and second binder, plasticizer and diluent are preferred. For instance, 5-30% Compound A, 25-45% first binder, 10-25% second binder, 5-30% plasticizer, and 10-25% diluent. In addition to Compound A, other very low solubility active agents can be used with the present invention.
  • the solid oral formulations of the present invention can be administered to treat diseases related to the inhibition of the Hedgehog pathway and Smoothened, including cancer and cancer tumors.
  • Crystalline Compound A was placed in a ceramic crucible, heated (135-140 °C) to above its melting point (133 °C) and held at that temperature for about 2 minutes, then rapidly cooled to a molten mass by placing the crucible in liquid nitrogen. Confirmation of an amorphous form of Compound A was obtained using mDSC and X-ray diffraction. The presence of a glass transition temperature Tg (59.6 °C) and the absence of a melting temperature in mDSC thermogram indicates the presence of an amorphous form. Absence of characteristic peaks in an X-ray diffraction pattern also confirmed the lack of crystallinity.
  • a formulation was prepared in accordance with the following Table 1, for 10 mg, 50 mg and 100 mg gelatin capsules.
  • a physical mixture of crystalline Compound A, polyvinylpyrrolidone (K30), vinylpyrrolidone/vinylacetate copolymer (VA64) and Macrogol 3350 (PEG with a molecular weight of 3350 daltons) is blended to generate a uniformly mixed powder blend.
  • This powder blend is then added at a fixed rate (gm/min) to a melt extruder preset to temperature range of 25-170°C.
  • the molten material, as output from the melt extruder is collected, cooled to room temperature, then milled to a fine powder.
  • the milled material is thereafter blended with microcrystalline cellulose, silica, crospovidone and magnesium stearate to make a blend suitable for filling into hard gelatin capsule using conventional capsule filling equipment.
  • Table 1 Table 1
  • a formulation was prepared in accordance with the following Table 2 for a 100 mg gelatin capsule, following the process of Example 2, except that Polyvinylpyrrolidone (K 30) is substituted with microcrystalline cellulose.
  • Hard gelatin capsules were prepared in accordance as disclosed in below Table 3. Table 3
  • Total capsule weight (mg) 98.00 326.00 618.00
  • the amorphous character of the Formulation I was further confirmed by differential scanning calorimeter (DSC) thermogram analysis (Fig 7). A clear absence of the melting point of the active (135°C) and a single glass transition temperature (Tg) (1 1 1.47°C) confirmed the formulation to be a true one-phase solid dispersion with an expected increased Tg due to the presence of polymers.
  • DSC differential scanning calorimeter

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne une formulation pharmaceutique de 2 - [ (R) - 4 -(6 -benzyl -4,5- diméthyl -pyridazin -3 -yl) -2 -méthyl -3,4,5, 6- tétrahydro - 2H- [ 1, 21 ] bipyrazinyl - 5' -y1] -propan- 2 -ol amorphe comprenant des liants stabilisants et un plastifiant cristallin.
PCT/US2011/032470 2010-04-16 2011-04-14 Formulations d'une pyridazine bipyrazinyl WO2011130500A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US32498010P 2010-04-16 2010-04-16
US61/324,980 2010-04-16
US36104010P 2010-07-02 2010-07-02
US61/361,040 2010-07-02

Publications (1)

Publication Number Publication Date
WO2011130500A1 true WO2011130500A1 (fr) 2011-10-20

Family

ID=44170469

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2011/032470 WO2011130500A1 (fr) 2010-04-16 2011-04-14 Formulations d'une pyridazine bipyrazinyl

Country Status (3)

Country Link
AR (1) AR080908A1 (fr)
TW (1) TW201202223A (fr)
WO (1) WO2011130500A1 (fr)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5980942A (en) * 1997-01-23 1999-11-09 Yissum Research Development Company Of The Hebrew University Of Jerusalem Zero-order sustained release matrix tablet formulations of carbamazepine
WO2000071098A1 (fr) * 1999-05-24 2000-11-30 Purepac Pharmaceutical Co. Composition pharmaceutique contenant un agent actif maintenu sous une forme amorphe solide et son procede de fabrication
WO2007002308A2 (fr) * 2005-06-22 2007-01-04 Bristol-Myers Squibb Company Procede de preparation de derives de piperazine azaindoleoxoacetique a substitution triazole et nouvelles formes de sels obtenues selon ce procede
WO2010007120A1 (fr) * 2008-07-18 2010-01-21 Novartis Ag Dérivés de pyridazine en tant qu’inhibiteurs de smo

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5980942A (en) * 1997-01-23 1999-11-09 Yissum Research Development Company Of The Hebrew University Of Jerusalem Zero-order sustained release matrix tablet formulations of carbamazepine
WO2000071098A1 (fr) * 1999-05-24 2000-11-30 Purepac Pharmaceutical Co. Composition pharmaceutique contenant un agent actif maintenu sous une forme amorphe solide et son procede de fabrication
WO2007002308A2 (fr) * 2005-06-22 2007-01-04 Bristol-Myers Squibb Company Procede de preparation de derives de piperazine azaindoleoxoacetique a substitution triazole et nouvelles formes de sels obtenues selon ce procede
WO2010007120A1 (fr) * 2008-07-18 2010-01-21 Novartis Ag Dérivés de pyridazine en tant qu’inhibiteurs de smo
US20100041663A1 (en) 2008-07-18 2010-02-18 Novartis Ag Organic Compounds as Smo Inhibitors

Also Published As

Publication number Publication date
AR080908A1 (es) 2012-05-16
TW201202223A (en) 2012-01-16

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