WO2017187336A1 - Complexes d'ivacaftor et de ses sels et dérivés, leur procédé de préparation et compositions pharmaceutiques en contenant - Google Patents

Complexes d'ivacaftor et de ses sels et dérivés, leur procédé de préparation et compositions pharmaceutiques en contenant Download PDF

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WO2017187336A1
WO2017187336A1 PCT/IB2017/052370 IB2017052370W WO2017187336A1 WO 2017187336 A1 WO2017187336 A1 WO 2017187336A1 IB 2017052370 W IB2017052370 W IB 2017052370W WO 2017187336 A1 WO2017187336 A1 WO 2017187336A1
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Prior art keywords
complex
ivacaftor
recited
disease
vinylpyrrolidone
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PCT/IB2017/052370
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English (en)
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WO2017187336A4 (fr
Inventor
Richard Balázs Kárpáti
Gergö PATYI
Orsolya Basa-Dénes
Erzsébet Réka ANGI
Tamás Jordán
Tamás SOLYMOSI
Hristos Glavinas
Genovéva FILIPCSEI
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Druggability Technologies Ip Holdco Limited
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Priority to EP17726697.0A priority Critical patent/EP3448383A1/fr
Priority to AU2017256180A priority patent/AU2017256180A1/en
Priority to CN201780039667.4A priority patent/CN109475548A/zh
Priority to JP2019506560A priority patent/JP2019515029A/ja
Priority to CA3021944A priority patent/CA3021944A1/fr
Publication of WO2017187336A1 publication Critical patent/WO2017187336A1/fr
Publication of WO2017187336A4 publication Critical patent/WO2017187336A4/fr
Priority to IL262489A priority patent/IL262489A/en

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Definitions

  • the invention is directed to a stable complexes with controlled particle size, increased apparent solubility and increased dissolution rate comprising as active compound Ivacaftor, or its salts, or derivatives thereof, which is useful in the treatment of cystic fibrosis transmembrane conductance regulator (CFTR) mediated disease. More specifically, the complexes of the present invention possess instantaneous redispersibility, increased apparent solubility and permeability, no observable food effect which deliver the opportunity of precise dosing and ease of administration of the reconstituted complex in solution form.
  • the invention also relates to methods of formulating and manufacturing complexes according to the invention, pharmaceutical compositions containing it, its uses and methods of treatment using the complex and its compositions.
  • Ivacaftor The active ingredient in KALYDECO tablets is Ivacaftor, which has the following chemical name: N-(2,4-di-tert-butyl-5-hydroxyphenyl)-l,4-dihydro-4-oxoquinoline-3- carboxamide. Its molecular formula is C 24 H 28 N 2 0 3 and its molecular weight is 392.49. Ivacaftor has the following structural formula:
  • Ivacaftor is a white to off-white powder that is practically insoluble in water ( ⁇ 0.05 microgram/mL). Due to poor aqueous solubility, extensive formulation efforts were required and resulted in a spray-dried dispersion of Ivacaftor suitable for oral administration.
  • KALYDECO containing the spray-dried dispersion of Ivacaftor is available as a light blue capsule-shaped, film- coated tablet for oral administration containing 150 mg of Ivacaftor.
  • Each tablet contains the inactive ingredients colloidal silicon dioxide, croscarmellose sodium, hypromellose acetate succinate, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and sodium lauryl sulfate.
  • the tablet film coat contains carnauba wax, FD&C Blue #2, PEG 3350, polyvinyl alcohol, talc, and titanium dioxide.
  • the printing ink contains ammonium hydroxide, iron oxide black, propylene glycol, and shellac.
  • Ivacaftor is a potentiator of the CFTR protein.
  • the CFTR protein is a chloride channel present at the surface of epithelial cells in multiple organs. Ivacaftor facilitates increased chloride transport by potentiating the channel-open probability (or gating) of the CFTR protein.
  • KALYDECO should be administered with fat-containing food.
  • fat-containing foods include eggs, butter, peanut butter, and cheese pizza.
  • the median (range) t max is approximately 4.0 (3.0; 6.0) hours in the fed state.
  • Vz/F The mean apparent volume of distribution (Vz/F) of Ivacaftor after a single dose of 275 mg of KALYDECO in the fed state was similar for healthy subjects and patients with CF. After oral administration of 150 mg every 12 hours for 7 days to healthy volunteers in a fed state, the mean (+SD) for apparent volume of distribution was 353 (122) L.
  • Ivacaftor is extensively metabolized in humans. In-vitro and clinical studies indicate that Ivacaftor is primarily metabolized by CYP3A. Ml and M6 are the two major metabolites of Ivacaftor in humans. Ml has approximately one-sixth the potency of Ivacaftor and is considered pharmacologically active.
  • M6 has less than one-fiftieth the potency of Ivacaftor and is not considered pharmacologically active.
  • the major metabolites Ml and M6 accounted for approximately 65% of the total dose eliminated with 22% as Ml and 43% as M6.
  • the apparent terminal half-life was approximately 12 hours following a single dose.
  • the mean apparent clearance (CL/F) of Ivacaftor was similar for healthy subjects and patients with CF.
  • the CL/F (SD) for the 150 mg dose was 17.3 (8.4) L/hr in healthy subjects.
  • novel complex formulations of Ivacaftor or its salts or its derivatives thereof and complexation agents and pharmaceutically acceptable excipients were prepared.
  • the novel complexes of the present invention possess instantaneous redispersibility, increased apparent solubility and permeability, no observable food effect which deliver the opportunity of precise dosing and ease of administration of the reconstituted complex in solution form.
  • a stable complex with improved physicochemical characteristics and enhanced biological performance comprising i. Ivacaftor, or a salt or derivatives thereof; ii. at least one complexation agent chosen from polyethylene glycol glycerides composed of mono-, di- and triglycerides and mono- and diesters of polyethylene glycol, hydroxypropylcellulose, poloxamers (copolymers of ethylene oxide and propylene oxide blocks), copolymers of vinylpyrrolidone and vinyl acetate, poly(2-ethyl-2-oxazoline), polyvinylpyrrolidone, poly(maleic acid/methyl vinyl ether), polyvinyl caprolactam- polyvinyl acetate -polyethylene glycol graft copolymer, ethylene oxide/propylene oxide tetra functional block copolymer, and d-alpha tocopheryl polyethylene glycol 1000 succinate; and iii.
  • said complex has a particle size is between 10 nm and 600 nm, and possesses one or more among the following features: a) is instantaneously redispersible in physiological relevant media; b) is stable in solid form and in colloid solution and/ or dispersion; c) has an apparent solubility in water is of at least 1 mg/ mL; d) has a PAMPA permeability of at least 0.4xl0 ⁇ 6 cm/s when dispersed in distilled water, which does not decrease in time at least for 6 months; e) exhibits no observable food effect.
  • the complex according to Point 6 wherein said complex possesses instantaneous redispersibility, has an apparent solubility in water of at least 1 mg/ mL, exhibits no observable food effect which deliver the opportunity of precise dosing and ease of administration of the reconstituted complex Ivacaftor in solution form.
  • the complex according to Point 6 wherein said complex possesses instantaneous redispersibility, has a PAMPA permeability of at least 0.4xlCT 6 cm/s when dispersed in water, FaSSIF or FeSSIF biorelevant media, which does not decrease in time at least for 6 month, exhibits no observable food effect which deliver the opportunity of precise dosing and ease of administration of the reconstituted complex Ivacaftor in solution form.
  • the complex according to Point 1 comprising a) Ivacaftor; b) as complexation agent a copolymer of vinylpyrrolidone and vinylacetate, and optionally a poloxamer; c) as an excipient sodium lauryl sulfate; wherein said complex is characterized by infrared (ATR) spectrum having characteristic peaks at 588 cm 1 , 628 cm 1 , 767 cm 1 , 842 cm 1 , 962 cm 1 , 1019 cm 1 , 1108 cm 1 , 1148 cm 1 , 1240 cm 1 , 1343 cm 1 , 1370 cm 1 , 1425 cm 1 , 1465 cm 1 , 1525 cm 1 , 1567 cm 1 , 1666 cm 1 and 1732 cm 1 ; and is characterized by Raman shifts at 552 cm 1 , 648 cm 1 , 826 cm 1 ,845 cm 4 , 888 cm 1 , 932 cm 4 , 1026 cm 1 , 1062 cm 1 , 1082
  • a complex according to either of Point 1 or Point 14 comprising a complexing agent which is selected from the group of copolymer of vinylpyrrolidone and vinylacetate and optionally poloxamers and pharmaceutically acceptable excipient which is sodium lauryl sulfate, in a total amount ranging from about 1.0 weight % to about 95.0 weight % based on the total weight of the complex.
  • a complex according to either of Point 1 or Point 14 comprising a complexation agent which is selected from the group of copolymer of vinylpyrrolidone and vinylacetate and optionally poloxamers and pharmaceutically acceptable excipient which is sodium lauryl sulfate, in a total amount ranging from about 50 weight % to about 95.0 weight % based on the total weight of the complex.
  • a process for the preparation of a stable complex according to Point 1 comprising the step of mixing a solution of Ivacaftor, and at least one complexation agent chosen from copolymers of vinylpyrrolidone and vinylacetate and optionally poloxamers, in a pharmaceutically acceptable solvent with an aqueous solution containing at least one pharmaceutically accepted excipient selected from the group of sodium deoxycholate, dioctyl sodium sulfosuccinate, sodium acetate, cetylpyridinium chloride, citric acid, meglumine and sodium lauryl sulfate.
  • a pharmaceutical composition comprising the stable complex according to Point 1 together with a pharmaceutically acceptable carrier.
  • the pharmaceutical composition according to Point 25, wherein said composition is suitable for oral, pulmonary, rectal, colonic, parenteral, intracisternal, intravaginal, intraperitoneal, ocular, otic, local, buccal, nasal, or topical administration.
  • composition comprising the complex according to Point 28, wherein said granules are suitable for the preparation of sachet dosage form.
  • CFTR mediated diseases are selected from cystic fibrosis, asthma, smoke induced COPD, chronic bronchitis, rhinosinusitis, constipation, pancreatitis, pancreatic insufficiency, male infertility caused by congenital bilateral absence of the vas deferens (CBAVD), mild pulmonary disease, idiopathic pancreatitis, allergic bronchopulmonary aspergillosis (ABPA), liver disease, hereditary emphysema, hereditary hemochromatosis, coagulation-fibrinolysis deficiencies, such as protein C deficiency, Type 1 hereditary angioedema, lipid processing deficiencies, such as familial hypercholesterolemia, Type 1 chylomicronemia, abetalipoproteinemia, lysosomal storage diseases, such as I-cell disease/pseud
  • a method of treatment of CFTR mediated diseases comprising administration of a therapeutically effective amount of the complex according to Point 1 or the pharmaceutical composition according to Point 25.
  • a stable complex comprising a) 5— 40% by weight of Ivacaftor, or its salt or derivatives thereof; b) 20— 80% by weight of a copolymer of vinylpyrrolidone and vinylacetate; c) 5— 40 % by weight of sodium lauryl sulfate; and d) optionally 0— 50 % by weight of a poloxamer; wherein said complex has a controlled particle size in the range between 10 nm and 600 nm; and wherein said complex is not obtained via a milling process, high pressure homogenization process, encapsulation process or solid dispersion processes.
  • said complex further comprises at least one pharmaceutically acceptable excipient.
  • the complexing agents themselves or together with the pharmaceutically acceptable excipients have the function to form a complex structure with an active pharmaceutical ingredient through non-covalent secondary interactions.
  • the secondary interactions can form through electrostatic interactions such as ionic interactions, H-bonding, dipole-dipole interactions, dipole-induced dipole interactions, London dispersion forces, ⁇ - ⁇ interactions, and hydrophobic interactions.
  • said stable complex with improved physicochemical characteristics and enhanced biological performance comprising i. Ivacaftor, or a salt thereof or derivatives thereof; ii. at least one complexation agent chosen from polyethylene glycol glycerides composed of mono-, di- and triglycerides and mono- and diesters of polyethylene glycol, hydroxypropylcellulose, poloxamers (copolymers of ethylene oxide and propylene oxide blocks), copolymers of vinylpyrrolidone and vinyl acetate, poly(2- ethyl-2-oxazoline), polyvinylpyrrolidone, poly(maleic acid/methyl vinyl ether), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, ethylene oxide/propylene oxide tetra functional block copolymer, and d-alpha tocopheryl polyethylene glycol 1000 succinate; and iii.
  • said complex has a particle size is between 10 nm and 600 nm, and possesses one or more among the following features: a) is instantaneously redispersible in physiological relevant media; b) is stable in solid form and in colloid solution and/ or dispersion; c) has an apparent solubility in water is of at least 1 mg/ mL; d) has a PAMPA permeability of at least 0.4xlCT 6 cm/s when dispersed in distilled water, which does not decrease in time at least for 6 months; and e) exhibits no observable food effect.
  • said complexing agent is chosen from polyethylene glycol glycerides composed of mono-, di- and triglycerides and mono- and diesters of polyethylene glycol, hydroxypropylcellulose, poloxamers (copolymers of ethylene oxide and propylene oxide blocks), copolymer of vinylpyrrolidone and vinyl acetate, poly(2-ethyl-2-oxazoline), polyvinylpyrrolidone, poly(maleic acid/methyl vinyl ether), (polyvinyl caprolactam-polyvinyl acetate -polyethylene glycol graft copolymer (e.g; Soluplus), polyoxyl 15 hydroxystearate, ethylene oxide/propylene oxide tetra functional block copolymer, and d-alpha tocopheryl polyethylene glycol 1000 succinate.
  • polyethylene glycol glycerides composed of mono-, di- and triglycerides and mono- and diesters of polyethylene glycol, hydroxypropyl
  • said complexation agent is chosen from copolymers of vinylpyrrolidone and vinyl acetate and poloxamers. [0019] In an embodiment, said complexation agent is copolymer of vinylpyrrolidone and vinyl acetate.
  • said copolymer of vinylpyrrolidone and vinyl acetate has a 60:40 weight ratio of vinylpyrrolidone:vinyl acetate monomers.
  • said poloxamer is poloxamer 338. [0022] In an embodiment, said poloxamer is poloxamer 407.
  • said pharmaceutically acceptable excipient is chosen from sodium lauryl sulfate (SDS), dioctyl sodium sulfosuccinate (DSS), cetylpyridinium chloride (CPC), sodium acetate (NaOAC), sodium deoxycolate (SDC), meglumine, D-mannitol, Kollicoat-IR, citric acid, and lactose.
  • SDS sodium lauryl sulfate
  • DSS dioctyl sodium sulfosuccinate
  • CPC cetylpyridinium chloride
  • NaOAC sodium acetate
  • SDC sodium deoxycolate
  • meglumine D-mannitol
  • Kollicoat-IR citric acid
  • lactose lactose
  • said pharmaceutically acceptable excipient is chosen from sodium deoxycolate, dioctyl sodium sulfosuccinate, sodium acetate, cetylpyridinium chloride, citric acid, meglumine and sodium la
  • compositions may additionally include one or more pharmaceutically acceptable excipients, auxiliary materials, carriers, active agents or combinations thereof.
  • said complex has a particle size between 10 nm and 600 nm.
  • said complex has a particle size in the range between 10 nm and 400 nm.
  • said complex is instantaneously redispersible in physiological relevant media.
  • said complex has increased dissolution rate compared to the commercially available form of Ivacaftor (KALYDECO®).
  • said complex is stable in solid form and in colloid solution and/or dispersion.
  • said complex has apparent solubility in water is at least 1 mg/ mL.
  • said complex exhibits X-ray amorphous character in the solid form.
  • said complex has a PAMPA permeability of at least 0.4xl0 ⁇ 6 cm/s when dispersed in distilled water, which does not decrease in time at least for 6 months.
  • the variability of exposure of the complex is significantly reduced compared to the commercially available form (KALYDECO®) .
  • said complex has no observable food effect, which allows the opportunity of precise dosing and ease of administration of the reconstituted complex in solution form.
  • said complex containing copolymer of vinylpyrrolidone and vinylacetate and poloxamer and sodium lauryl sulfate or its pharmaceutical composition according to the invention characterized by the Raman spectrum shown in Figure 11 and ATR spectrum shown in Figure 12.
  • said complex is characterized by characteristic Raman shifts at 552 cm 1 , 648 cm 1 , 826 cm 1 ,845 cm 1 , 888 cm 1 , 932 cm 1 , 1026 cm 1 , 1062 cm 1 , 1082 cm 1 , 1129 cm 1 , 1140 cm 1 , 1208 cm 1 , 1233 cm 1 , 1262 cm 1 , 1284 cm 1 , 1295 cm 1 , 1361 cm 1 , 1450 cm 1 , 1528 cm 1 , 1573 cm 1 , 1618 cm 1 , 1677 cm 1 , 1738 cm 1 , 746 cm 4 , 2884 cm 4 and 2936 cm 4 .
  • said complex is characterized by ATR spectrum having characteristic peaks at 588 cm 1 , 628 cm 1 , 767 cm 1 , 842 cm 1 , 962 cm 1 , 1019 cm 1 , 1108 cm 1 , 1148 cm 1 , 1240 cm 1 , 1343 cm 1 , 1370 cm 1 , 1425 cm 1 , 1465 cm 1 , 1525 cm 1 , 1567 cm 1 , 1666 cm 1 and 1732 cm .
  • said complex comprises a) Ivacaftor; or a combination of active compounds including Ivacaftor; b) a complexing agent which is a copolymer of vinylpyrrolidone and vinyl acetate; c) and optionally poloxamers as a complexing agent; and d) sodium lauryl sulfate as an excipient.
  • said complex comprises a complexation agent chosen from copolymer of vinylpyrrolidone and vinyl acetate and poloxamer 407 or poloxamer 338 and a pharmaceutically acceptable excipient which is sodium lauryl sulfate, in a total amount comprising from about 1.0 weight % to about 95.0 weight % based on the total weight of the complex.
  • said complex comprises a complexation agent chosen from copolymer of vinylpyrrolidone and vinyl acetate and poloxamer 407 or poloxamer 338 and a pharmaceutically acceptable excipient which is sodium lauryl sulfate, in a total amount comprising from about 50 weight % to about 95 weight % of the total weight of the complex.
  • said complex comprises a complexation agent which is copolymer of vinylpyrrolidone and vinyl acetate and a pharmaceutically acceptable excipient which is sodium lauryl sulfate, in a total amount comprising from about 1.0 weight % to about 95.0 weight % based on the total weight of the complex.
  • said complex comprises complexation agent which is a copolymer of vinylpyrrolidone and vinyl acetate and pharmaceutically acceptable excipient which is sodium lauryl sulfate in a total amount comprising from about 50 weight% to about 95 weight% of the total weight of the complex.
  • a stable complex comprising i. 5— 40% by weight of Ivacaftor, or a salt or derivative thereof; ii. 20— 80% by weight of a copolymer of vinylpyrrolidone and vinyl acetate; iii. 5— 40 % by weight of sodium lauryl sulfate; and optionally iv. 0— 50 % by weight of a poloxamer.
  • a process for the preparation of a stable complex of Ivacaftor comprising the step of mixing a solution of the active agent and at least one complexing agent and optionally one or more pharmaceutically acceptable excipient in a pharmaceutically acceptable solvent with an aqueous solution containing optionally at least one pharmaceutically acceptable excipient.
  • said process comprises the step of mixing a solution of Ivacaftor, and at least one complexation agent chosen from copolymers of vinylpyrrolidone and vinylacetate and poloxamers, in a pharmaceutically acceptable solvent with an aqueous solution containing at least one pharmaceutically accepted excipient selected from the group of sodium deoxycolate, dioctyl sodium sulfosuccinate, sodium acetate, cetylpyridinium chloride, citric acid, meglumine and sodium lauryl sulfate.
  • a pharmaceutically accepted excipient selected from the group of sodium deoxycolate, dioctyl sodium sulfosuccinate, sodium acetate, cetylpyridinium chloride, citric acid, meglumine and sodium lauryl sulfate.
  • said complex is obtained via a mixing process.
  • said complex is obtained via a continuous flow mixing process.
  • said process is performed in a continuous flow instrument.
  • said continuous flow instrument is a micro flui die flow instrument.
  • said complex is not obtained via a milling process, high pressure homogenization process, encapsulation process and solid dispersion processes.
  • said pharmaceutically acceptable solvent is chosen from water, methanol, ethanol, 1-propanol, 2-propanol, acetone, acetonitrile, dimethyl-sulfoxide, tetrahydrofuran, methyl-ethyl ketone or combinations thereof.
  • said pharmaceutically acceptable solvent is tetrahydrofuran.
  • said pharmaceutically acceptable solvent and said aqueous solvent are miscible with each other.
  • said aqueous solvent comprises 0.1 to 99.9% weight of the final solution.
  • said aqueous solvent comprises 50 to 90% weight of the final solution.
  • said aqueous solvent comprises 50 to 80% weight of the final solution. [0059] In an embodiment, said aqueous solvent comprises 50 to 70% weight of the final solution.
  • said aqueous solvent comprises 50 to 60% weight of the final solution.
  • said aqueous solvent comprises 45 to 55% weight of the final solution.
  • said aqueous solvent comprises 50 % weight of the final solution.
  • said aqueous solvent comprises 35 to 45 % weight of the final solution.
  • said aqueous solvent comprises 25 to 35 % weight of the final solution.
  • said aqueous solvent comprises 15 to 25 % weight of the final solution.
  • said aqueous solvent comprises 5 to 15 % weight of the final solution.
  • a pharmaceutical composition comprising the complex together with pharmaceutically acceptable carriers.
  • said composition is suitable for oral, pulmonary, rectal, colonic, parenteral, intracisternal, intravaginal, intraperitoneal, ocular, otic, local, buccal, nasal, or topical administration.
  • compositions are suitable for oral administration.
  • composition comprises fast dissolving granules of the complex Ivacaftor formulation.
  • said granules are suitable for the preparation of sachet dosage form.
  • said complexes are for use in the manufacture of a medicament for the treatment of CFTR mediated diseases.
  • said complexes are used for the treatment of CFTR mediated diseases.
  • CFTR mediated disease is selected from cystic fibrosis, asthma, smoke induced COPD, chronic bronchitis, rhinosinusitis, constipation, pancreatitis, pancreatic insufficiency, male infertility caused by congenital bilateral absence of the vas deferens (CBAVD), mild pulmonary disease, idiopathic pancreatitis, allergic bronchopulmonary aspergillosis (ABPA), liver disease, hereditary emphysema, hereditary hemochromatosis, coagulation-fibrinolysis deficiencies, such as protein C deficiency, Type 1 hereditary angioedema, lipid processing deficiencies, such as familial hypercholesterolemia, Type 1 chylomicronemia, abetalipoproteinemia, lysosomal storage diseases, such as I-cell disease/pseudo-Hurler, mucopolysaccharidoses, Sandhof/Tay-Sachs,
  • a method of treatment of CFTR mediated diseases comprises administration of a therapeutically effective amount of complexes or pharmaceutical compositions as described herein.
  • a method for reducing the therapeutically effective dosage of Ivacaftor compared to commercially available KALYDECO® comprises oral administration of a pharmaceutical composition as described herein.
  • said complexes further comprise one or more additional active agents.
  • said additional active agent is Lumacaftor, Tezacaftor or chosen from agents used for the treatment of CFTR mediated diseases.
  • said complex comprises Ivacaftor; or a combination of active compounds including Ivacaftor; a complexing agent chosen from copolymers of vinylpyrrolidone and vinyl acetate and sodium lauryl sulfate as an excipient; said complex characterized in that they possess at least one of the following properties: a) is instantaneously redispersable in physiological relevant media; b) is stable in solid form and in colloid solution and/ or dispersion; c) has an apparent solubility in water of at least 1 mg/ mL; d) has a PAMPA permeability of at least 0.4xl0 ⁇ 6 cm/ s when dispersed in FaSSIF or FeSSIF biorelevant media, which does not decrease in time at least for 6 month; e) exhibits no observable food effect.
  • novel complexes of the present invention possess instantaneous redispersibility, increased apparent solubility and permeability, no observable food effect which deliver the opportunity of precise dosing and ease of administration of the reconstituted complex in solution form.
  • Ivacaftor is generally used for Ivacaftor, or its salts or its derivatives.
  • said complexation agent is chosen from polyethylene glycol glycerides composed of mono-, di- and triglycerides and mono- and diesters of polyethylene glycol, hydroxypropylcellulose, poloxamers (copolymers of ethylene oxide and propylene oxide blocks), copolymer of vinylpyrrolidone and vinyl acetate, poly(2-ethyl-2-oxazoline), polyvinylpyrrolidone, poly(maleic acid/methyl vinyl ether), (polyvinyl caprolactam-polyvinyl acetate -polyethylene glycol graft copolymer, polyoxyl 15 hydroxystearate, ethylene oxide/propylene oxide tetra functional block copolymer, and d-alpha tocopheryl polyethylene glycol 1000 succinate.
  • polyethylene glycol glycerides composed of mono-, di- and triglycerides and mono- and diesters of polyethylene glycol, hydroxypropylcellulose, poloxamers (cop
  • said complexation agents are copolymer of vinylpyrrolidone and vinyl acetate and poloxamer and said pharmaceutically acceptable excipient is sodium lauryl sulfate
  • a) is characterized by infrared (ATR) spectrum having characteristic absorption peaks at 588 cm 4 , 628 cm 1 , 767 cm 1 , 842 cm 1 , 962 cm 1 , 1019 cm 1 , 1108 cm 1 , 1148 cm 1 , 1240 cm 1 , 1343 cm 1 , 1370 cm 4 , 1425 cm 4 , 1465 cm 1 , 1525 cm 1 , 1567 cm 1 , 1666 cm 1 and 1732 cm 1 ; and b) has characteristic Raman shifts at 552 cm 4 , 648 cm 4 , 826 cm 4 ,845 cm 4 , 888 cm 4 , 932 cm 4 , 1026 cm 4 , 1062 cm 4 , 1082 cm 4 , 1129 cm 4 , 1140 cm 4 ,
  • Another aspect of the invention is the complex formulations of the Ivacaftor with complexation agents and pharmaceutically acceptable excipients in which the complexation agents and pharmaceutically acceptable excipients preferably are associated or interacted with the Ivacaftor, such as the results of a mixing process or a continuous flow mixing process.
  • the structure of the complex Ivacaftor formulations is different from the core-shell type milled particle, precipitated encapsulated particles, micelles and solid dispersions.
  • the pharmaceutical composition of the invention can be formulated: (a) for administration selected from the group consisting of oral, pulmonary, rectal, colonic, parenteral, intracisternal, intravaginal, intraperitoneal, ocular, otic, local, buccal, nasal, and topical administration; (b) into a dosage form selected from the group consisting of liquid dispersions, gels, aerosols, ointments, creams, lyophilized formulations, tablets, capsules; (c) into a dosage form selected from the group consisting of controlled release formulations, fast melt formulations, delayed release formulations, extended release formulations, pulsatile release formulations, and mixed immediate release and controlled release formulations; or (d) any combination of (a), (b), and (c).
  • compositions can be formulated by adding different types of pharmaceutically acceptable excipients for oral administration in solid, liquid, local (powders, ointments or drops), or topical administration, and the like.
  • the dosage form of the invention is a solid dosage form, although any pharmaceutically acceptable dosage form can be utilized.
  • Solid dosage forms for oral administration include, but are not limited to, capsules, tablets, pills, powders (sachet), and granules.
  • the complex formula of Ivacaftor is admixed with at least one of the following: one or more inert excipients (or carriers): (a) fillers or extenders, such as, lactose, sucrose, glucose, mannitol, sorbitol, dextrose, dextrates, dextrin, erythritol, fructose, isomalt, lactitol, maltitol, maltose, maltodextrin, trehalose, xylitol, starches, microcrystalline cellulose, dicalcium phosphate, calcium carbonate, magnesium carbonate, magnesium oxide; (b) sweetening, flavoring, aromatizing and perfuming agents such as saccharin, saccharin sodium, acesulfame potassium, alitam
  • the dosage form of the invention is a liquid dispersible granules in a sachet form.
  • said liquid dispersible granules comprise the complex formulation of Ivacaftor of the present invention together with pharmaceutically acceptable excipients selected from the group of fillers or extenders, such as, lactose, sucrose, glucose, mannitol, sorbitol, dextrose, dextrates, dextrin, erythritol, fructose, isomalt, lactitol, maltitol, maltose, maltodextrin, trehalose, xylitol, starches, microcrystalline cellulose, dicalcium phosphate, calcium carbonate, magnesium carbonate, magnesium oxide.
  • pharmaceutically acceptable excipients selected from the group of fillers or extenders, such as, lactose, sucrose, glucose, mannitol, sorbitol, dextrose, dextrates, dextrin, erythritol, fructose, isomalt, lactitol, maltitol
  • said liquid dispersible granules comprise the complex formulation of Ivacaftor of the present invention together with pharmaceutically acceptable excipients selected from the group of sweetening, flavoring, aromatizing and perfuming agents such as saccharin, saccharin sodium, acesulfame potassium, alitame, aspartame, glycine, inulin, neohesperidin dihydrochalcone, neotame, sodium cyclamate, sucralose, tagatose, thaumatin, citric acid, adipic acid, fumaric acid, leucine, malic acid, menthol, propionic acid, tartaric acid.
  • pharmaceutically acceptable excipients selected from the group of sweetening, flavoring, aromatizing and perfuming agents such as saccharin, saccharin sodium, acesulfame potassium, alitame, aspartame, glycine, inulin, neohesperidin di
  • liquid dispersible granules comprising a. 25—95 % stable complex formulation of Ivacaftor of the present invention
  • liquid dispersible granules disperses within 3 min in liquid; and wherein said liquid dispersible granules obtained by wet or dry processes.
  • said dispersion time is between 0.1 min and 10 min.
  • said dispersion time is between 0.1 min and 5 min. [0098] In an embodiment, said dispersion time is between 0.1 min and 3 min.
  • said dispersion time is between 0.1 min and 1 min.
  • Hausner-ratio of the said liquid dispersible granules of complex Ivacaftor formulations is less than 1.25 more preferably 1.00-1.18 [00101] In an embodiment, Hausner-ratio of the said liquid dispersible granules of complex Ivacaftor formulations is between 1.00 and 1.18.
  • the particle size (D(90)) of said solid aggregates of complex Ivacaftor formulations is less than 2000 micrometers.
  • 60-99 % of the said solid aggregates of complex Ivacaftor formulations are in the size range of 160-1200 micrometers
  • said liquid is water, saliva, other physiologically or biologically acceptable fluid.
  • the dosage form is chosen from a tablet and a capsule.
  • Advantages of the complex Ivacaftor formulations of the invention include, but are not limited to (1) physical and chemical stability, (2) instantaneous redispersibility, (3) stability in colloid solution or dispersion in the therapeutic time window, (4) increased apparent solubility and permeability compared to the conventional Ivacaftor formulation, (5) no observable food effect which deliver the opportunity of precise dosing and ease of administration of the reconstituted complex formulation in solution form, (6) good processability.
  • Beneficial features of the present invention are as follows: the good/instantaneous redispersibility of solid complex formulations of Ivacaftor in water, biologically relevant media, e.g.
  • the complex Ivacaftor formulations of the present invention has increased apparent solubility and permeability.
  • the apparent solubility and permeability of the complex Ivacaftor formulae is at least 1 mg/mL and 0.5xl0 ⁇ 6 cm/s, respectively.
  • said complex possesses instantaneous redispersibility, has an apparent solubility in water of at least 1 mg/mL, and has a PAMPA permeability of at least 0.5xl0 ⁇ 6 cm/s.
  • the complexes of the present invention possess instantaneous redispersibility, increased apparent solubility and permeability, no observable food effect which deliver the opportunity of precise dosing and ease of administration of the reconstituted solid.
  • the complexes of the present invention possess instantaneous redispersibility, has a PAMPA permeability of at least 0.4xl0 ⁇ 6 cm/s when dispersed in water, FaSSIF or FeSSIF biorelevant media, which does not decrease in time at least for 6 month, exhibits no observable food effect which deliver the opportunity of precise dosing and ease of administration of the reconstituted complex Ivacaftor in solution form.
  • Figure 2. Redispersibility and PAMPA permeability of complex Ivacaftor compositions.
  • Figure 3. Redispersibility and PAMPA permeability of complex Ivacaftor compositions containing vinylpyrrolidone and vinylacetate copolymer (Kollidon VA 64) and poloxamer in different ratios.
  • Figure 6. Physical appearance and stability of the produced complex Ivacaftor formula during the flow optimization.
  • Figure 7. Ivacaftor dissolution from granulated complex Ivacaftor formulation.
  • Figure 9 PAMPA permeability of complex Ivacaftor formulations stored at different condition and measured at different time points.
  • FIG. 13 XRD diffractogram of amorphous Ivacaftor and complex Ivacaftor.
  • PAMPA permeability of the selected formulations was measured in order to select the complex Ivacaftor formulation having the best in-vitro performance ( Figure 2). PAMPA permeability measurements were performed as described by M. Kansi et al. (Journal of medicinal chemistry, 41, (1998) pp 1007) with modifications based on S. Bendels et al (Pharmaceutical research, 23 (2006) pp 2525) . Permeability was measured in a 96-well plate assay across an artificial membrane composed of dodecane with 20% soy lecithin supported by a PVDF membrane (Millipore, USA) .
  • the receiver compartment was phosphate buffered saline (pH 7.0) supplemented with 1 % sodium dodecyl sulfate.
  • the assay was performed at room temperature; incubation time was 4 hours in ultrapurified water, FaSSIF and FeSSIF, respectively.
  • the concentration in the receiver compartment was determined by UV-VIS spectrophotometry (VWR UV-3100PC Scanning Spectrophotometer).
  • Copolymer of vinylpyrrolidone and vinylacetate (Kollidon VA 64) itself and in combination with poloxamer 338 (Pluronic F108) or poloxamer 407 (Lutrol F127) were selected as complexation agents and sodium lauryl sulfate was selected as pharmaceutically acceptable excipient in order to prepare complex Ivacaftor formulations having improved material characteristics.
  • a solution mixture of Ivacaftor complex formula was prepared.
  • 100 mL Solution 1 was prepared by dissolving 100 mg Ivacaftor and 300 mg copolymer of vinylpyrrolidone and vinylacetate (Kollidon VA 64) and 200 mg poloxamer 338 (Pluronic F108) in 100 mL tetrahydrofurane.
  • the prepared Solution 1 was mixed with Solution 2 containing 25-100 mg sodium lauryl sulfate in 100 mL in order to produce complex Ivacaftor formulation.
  • the appearance and stability of produced colloid solution were monitored. Based on the physical appearance and stability of the produced complex Ivacaftor formula in colloid solution, the best composition was selected for analytical investigations and further work (Figure 4 and Figure 5) .
  • a solution mixture of Ivacaftor complex formula was prepared.
  • 100 mL Solution 1 was prepared by dissolving 100 mg Ivacaftor and 600 mg copolymer of vinylpyrrolidone and vinylacetate (Kollidon VA 64) in 100 mL tetrahydrofurane.
  • the prepared Solution 1 was mixed with Solution 2 containing 300 mg sodium lauryl sulfate in 100 mL in order to produce complex Ivacaftor formulation.
  • the composition was selected for analytical investigations and further work.
  • a solution mixture of Ivacaftor complex formula was prepared.
  • 100 mL Solution 1 was prepared by dissolving 100 mg Ivacaftor and 300 mg copolymer of vinylpyrrolidone and vinylacetate (Kollidon VA 64) and 60-200 mg poloxamer 407 (Lutrol F127) in 100 mL tetrahydrofurane.
  • the prepared Solution 1 was mixed with Solution 2 containing 60-100 mg sodium lauryl sulfate in 100 mL in order to produce complex Ivacaftor formulation.
  • a colloid solution of complex Ivacaftor formulation of the present invention was prepared by mixing process.
  • Solution 1 containing 500 mg Ivacaftor and 1500 mg copolymer of vinylpyrrolidone and vinylacetate (Kollidon VA 64) and 1000 mg poloxamer 338 (Pluronic F108) in 100 mL tetrahydrofuran was mixed with aqueous Solution 2 containing 500 mg sodium lauryl sulfate in 100 mL ultrapurified water in different flow rates.
  • the colloid solution of the complex Ivacaftor formulation was produced at atmospheric pressure and 20-50 °C temperature. The appearance and stability of the produced colloid solution were monitored. Based on the physical appearance and stability of the produced complex Ivacaftor formulation in colloid solution, the best composition was selected for spray-drying experiments. Figure 6 summarizes the results.
  • the solidification of the colloid solution was performed by spray-drying technique. 5 mg/mL Ivacaftor, 15 mg/mL copolymer of vinylpyrrolidone and vinylacetate (Kollidon VA 64) and 10 mg/mL poloxamer 338 (Pluronic F108) in tetrahydrofurane and 5 mg/mL sodium lauryl sulfate in water were chosen for starting concentrations. The ratio of the solutions was found to be optimal at 1 :1 ratio.
  • the solidification of the colloid solution was performed by spray-drying technique. 5 mg/ mL Ivacaftor, 30 mg/ mL copolymer of vinylpyrrolidone and vinylacetate (Kollidon VA 64) in tetrahydrofurane and 15 mg/mL sodium lauryl sulfate in water were chosen for starting concentrations. The ratio of the solutions was found to be optimal at 1 :1 ratio.
  • the colloid solution of the complex Ivacaftor formulation prepared by the optimal parameter sets was spray- dried (Yamato DL-410 / GAS410) in order to obtain solid powder. The spray-drying process was optimized.
  • the solidification of the colloid solution was performed by spray-drying technique. 5 mg/mL Ivacaftor, 15 mg/mL copolymer of vinylpyrrolidone and vinylacetate (Kollidon VA 64) and 10 mg/mL poloxamer 407 (Lutrol F127) in tetrahydrofurane and 5 mg/mL sodium lauryl sulfate in water were chosen for starting concentrations. The ratio of the solutions was found to be optimal at 1 :1 ratio.
  • the colloid solution of the complex Ivacaftor formulation prepared by the optimal parameter sets was spray-dried (Yamato DL-410 / GAS410) in order to obtain solid powder.
  • the spray-drying process was optimized.
  • the solidification of the colloid solution was performed by spray-drying technique. 5 mg/mL Ivacaftor, 15 mg/mL copolymer of vinylpyrrolidone and vinylacetate (Kollidon VA 64) and 3 mg/mL poloxamer 407 (Lutrol F127) in tetrahydrofurane and 3 mg/mL sodium lauryl sulfate in water were chosen for starting concentrations. The ratio of the solutions was found to be optimal at 1 :1 ratio.
  • Liquid dispersible granules comprising the complex Ivacaftor formulations of the present invention can be obtained by wet or dry granulation processes.
  • [00127]Dry granulation process includes, but not limited to the slugging or roll compaction of the powder formulation of complex Ivacaftor into compacts and breaking of the compacts into granules with appropriate mesh size.
  • the obtained granules can be blended with pharmaceutically acceptable excipients.
  • [00128]Dry granulation technique can be also applied on the powder blend of complex Ivacaftor formulations.
  • Powder blend consists of the powder formulation of complex Ivacaftor and pharmaceutically acceptable excipients and prepared by blending of the powders. Slugging or roll compaction are used to manufacture compacts from the powder blend. Then the compacts are broken into granules with appropriate mesh size.
  • Wet granulation process covers the moisturizing of the powder formulations of complex Ivacaftor (direct granulation) or moisturizing the pharmaceutically acceptable excipients with aqueous solution of pharmaceutically acceptable binders and blending it with the powder formulations of complex Ivacaftor (indirect granulation).
  • the particle size of the granules can be controlled by physical impact before and after the drying step.
  • [00130]Liquid dispersible granules of complex Ivacaftor formulation of the present invention were prepared by compacting appropriate amount of complex Ivacaftor powder blend using 0.5 ton load.
  • the powder blend comprised of the solid formulation of the complex of Ivacaftor and pharmaceutically acceptable excipients selected from the group of sweetening, flavouring, aromatizing and perfuming agents.
  • the height of the compact was found to be optimal between 0.8-1.0 mm.
  • the compacts were broken up by physical impact to form granulates.
  • the particle size of the granules was controlled by sieving with appropriate mesh size to achieve 160-800 micrometres particle size.
  • the apparent solubility of complex Ivacaftor formulation containing copolymer of vinylpyrrolidone and vinyl acetate (Kollidon VA 64) and sodium lauryl sulfate and poloxamer 338 of the present invention was 0.991; 2.356; 4.924 and 9.463 mg/mL, when 1; 2.5; 5; and 10 mg/ mL Ivacaftor equivalent formulations were dispersed in ultrapurified water, respectively.
  • Ivacaftor dissolution was measured from the dry granulated formulation of the complex Ivacaftor containing copolymer of vinylpyrrolidone and vinyl acetate (Kollidon VA 64), poloxamer 338 (Pluronic F108) and sodium lauryl sulfate.
  • the dissolution test was performed by dispersing the granulated complex Ivacaftor formulation in purified water at 1 mg/mL concentrations. The dissolved amount was measured with UV-VIS spectrophotometry after filtration with 0.1 ⁇ pore size filter at different time points. Dissolution of Ivacaftor from the granulated complex formulation was instantaneous, within 10 minutes 95 % of the Ivacaftor dissolved from the granulated complex Ivacaftor formulation ( Figure 7).
  • PAMPA permeabilities of complex Ivacaftor formulations were measured in water, FaSSIF and FeSSIF media and were found to be above 0.4xl0 ⁇ 6 cm/s in all tested media (Figure 8).
  • PAMPA permeability of the solid complex Ivacaftor formulations was used to monitor the physical stability of the formulation. PAMPA permeability was measured after storage of the complex Ivacaftor formulation at different conditions. 6 month storage at RT or 40 °C relative humidity showed no significant decrease in the measured PAMPA permeability under any of the conditions tested ( Figure 9).
  • Ivacaftor is marketed in its solid dispersion form under the trade name of KALYDECO®. Manufacturing of solid dispersion of Ivacaftor is described in US 20140221424 Al patent application. Using the manufacturing method described in the patent application, solid dispersion of Ivacaftor was prepared for comparative analytical assays. A solvent system of methyl ethyl ketone (MEK) and water in the ratio of 90 wt % MEK : 10 wt % water was heated to 20-30° C in a reaction vessel equipped with a magnetic stirrer and thermal circuit.
  • MEK methyl ethyl ketone
  • hypromellose acetate succinate polymer HPMCAS
  • sodium lauryl sulfate sodium lauryl sulfate
  • Ivacaftor Into this solvent system, hypromellose acetate succinate polymer (HPMCAS), sodium lauryl sulfate and Ivacaftor were added in the ratio of 19.5 wt % hypromellose acetate succinate : 0.5 wt % SLS:80 wt % Ivacaftor.
  • the resulting mixture was solid formulated by spray-drying method.
  • a beagle dog study using the granulated complex Ivacaftor formulation containing copolymer of vinylpyrrolidone and vinyl acetate (Kollidon VA 64), poloxamer 338 (Pluronic F108) and sodium lauryl sulfate of the present invention at a dose of 3 mg/kg was performed in the fasted and fed state.
  • the granulated complex formulation was administered to the animals orally as reconstituted dispersion.
  • Food effect was only 1.1 -fold (food effect in humans is 2-4- fold higher in the fed state, that is why the drug has to be taken after a high fat meal).
  • Exposure was 1.25-times higher than the reference exposure.
  • C max was somewhat lower for the complex Ivacaftor formulation, however, for the more important parameter, C 24h , the complex Ivacaftor was 1.4-times higher ( Figure 17 and Figure 18).

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Abstract

La présente invention concerne des formulations de complexes de qualité pharmaceutique comprenant des complexes d'ivacaftor, ou d'un sel ou de dérivés de celui-ci, des agents complexants et des excipients de qualité pharmaceutique, leur procédé de préparation et des compositions pharmaceutiques en contenant. Les complexes de la présente invention présentent une redispersibilité instantanée, une solubilité et une perméabilité apparentes accrues, aucun effet des aliments n'est observable, ce qui offre la possibilité d'un dosage précis et d'une grande facilité d'administration du complexe d'ivacaftor reconstitué sous la forme d'une solution.
PCT/IB2017/052370 2016-04-25 2017-04-25 Complexes d'ivacaftor et de ses sels et dérivés, leur procédé de préparation et compositions pharmaceutiques en contenant WO2017187336A1 (fr)

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Application Number Priority Date Filing Date Title
EP17726697.0A EP3448383A1 (fr) 2016-04-25 2017-04-25 Complexes d'ivacaftor et de ses sels et dérivés, leur procédé de préparation et compositions pharmaceutiques en contenant
AU2017256180A AU2017256180A1 (en) 2016-04-25 2017-04-25 Complexes of Ivacaftor and its salts and derivatives, process for the preparation thereof and pharmaceutical compositions containing them
CN201780039667.4A CN109475548A (zh) 2016-04-25 2017-04-25 依伐卡托及其盐和衍生物的复合物、其制备方法以及含有它们的药物组合物
JP2019506560A JP2019515029A (ja) 2016-04-25 2017-04-25 アイバカフトールならびにアイバカフトールの塩及び誘導体の複合剤、その製造方法ならびにこれを含有する医薬組成物
CA3021944A CA3021944A1 (fr) 2016-04-25 2017-04-25 Complexes d'ivacaftor et de ses sels et derives, leur procede de preparation et compositions pharmaceutiques en contenant
IL262489A IL262489A (en) 2016-04-25 2018-10-21 Complexes of ivacaptor and its salts and their history, a process for their preparation and pharmaceutical preparations containing them

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HU1600270A HUP1600270A2 (hu) 2016-04-25 2016-04-25 Ivacaftornak, sóinak és származékainak komplexei, eljárás azok elõállítására és azok gyógyszerészetileg elfogadott készítményei
HUP1600270 2016-04-25

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HUP1600270A2 (hu) 2017-10-30
CN109475548A (zh) 2019-03-15
EP3448383A1 (fr) 2019-03-06
IL262489A (en) 2018-12-31

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