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WO2020055359A2 - Forme posologique orale de tosylate de sorafénib - Google Patents

Forme posologique orale de tosylate de sorafénib Download PDF

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Publication number
WO2020055359A2
WO2020055359A2 PCT/TR2019/050578 TR2019050578W WO2020055359A2 WO 2020055359 A2 WO2020055359 A2 WO 2020055359A2 TR 2019050578 W TR2019050578 W TR 2019050578W WO 2020055359 A2 WO2020055359 A2 WO 2020055359A2
Authority
WO
WIPO (PCT)
Prior art keywords
dosage form
oral dosage
weight
form according
mixtures
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/TR2019/050578
Other languages
English (en)
Other versions
WO2020055359A3 (fr
Inventor
Ali Turkyilmaz
Ali Ihsan SECKIN
Irem Yenice
Yuksel TOPALOGLU
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Arven Ilac Sanayi ve Ticaret AS
Original Assignee
Arven Ilac Sanayi ve Ticaret AS
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 Arven Ilac Sanayi ve Ticaret AS filed Critical Arven Ilac Sanayi ve Ticaret AS
Publication of WO2020055359A2 publication Critical patent/WO2020055359A2/fr
Publication of WO2020055359A3 publication Critical patent/WO2020055359A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to an oral dosage form comprising sorafenib tosylate as an active ingredient, and which has improved properties. Further, the present invention provides a method for the preparation of the said composition.
  • Sorafenib tosylate a multi-kinase inhibitor targeting several serine/threonine and receptor tyrosine kinases, is the tosylate salt of sorafenib.
  • Sorafenib tosylate has the chemical name 4-(4-(3-(4-chloro- 3- (trifluoromethyl) phenyl) ureido) phenoxy)-N-methylpicolinamide tosylate and its chemical structure is shown in the formula I.
  • Sorafenib tosylate is marketed by Bayer Pharmaceutical under the trademark NEXAVAR ® which is film-coated tablet consisting sorafenib tosylate (274 mg) equivalent to 200 mg of sorafenib and the following excipients: croscarmellose sodium, microcrystalline cellulose, hypromellose, sodium lauryl sulphate, magnesium stearate, polyethylene glycol, titanium dioxide and ferric oxide red.
  • NEXAVAR ® film-coated tablet consisting sorafenib tosylate (274 mg) equivalent to 200 mg of sorafenib and the following excipients: croscarmellose sodium, microcrystalline cellulose, hypromellose, sodium lauryl sulphate, magnesium stearate, polyethylene glycol, titanium dioxide and ferric oxide red.
  • sorafenib are not optimal in regard to polymorphic and chemical stability, flow properties, compressibility, dissolution rate. These properties cause disadvantages in the preparation of pharmaceutical compositions, such as tablets.
  • sorafenib tosylate is practically insoluble in water. As such, the dissolution rate and bioavailability of conventional sorafenib tosylate formulations are likely poor.
  • WO 2006/034796 discloses a process for preparing sorafenib and its tosylate salt. The tosylate salt is said to be obtained in crystalline form.
  • WO 2006/026501 discloses pharmaceutical compositions comprising a solid dispersion of sorafenib which comprises microcrystalline cellulose. Also, the patent application is the patent of the originator.
  • the patent application WO2013/1 10644 A1 discloses a tablet form comprising a crystalline sorafenib tosylate characterized by an X-ray powder diffraction pattern showing peak maxima at 2 theta/ 0 values of 7.7 ⁇ 0.2, 12.0 ⁇ 0.2, 19.9 ⁇ 0.2, and 21.6 ⁇ 0.2, the X-ray powder diffraction pattern being determined at a temperature of about 22° C and at least one excipient. Used excipients are microcrystalline cellulose, croscarmellose, hypromellose, magnesium stearate, sodium lauryl sulfate.
  • sorafenib tosylate having microcrystalline cellulose as a filler.
  • microcrystalline cellulose has poor to moderate flow properties. Due to these poor flow properties of both sorafenib tosylate and microcrystalline cellulose, the combination of these two substances causes some disadvantages.
  • Microcrystalline cellulose and magnesium stearate are also highly hygroscopic. It may also make over lubrication and which make compressibility problems when used together. The combined use of these excipients is obviously risky to provide stability of a solid dosage form.
  • the main object of the present invention is to provide an oral dosage form comprising sorafenib tosylate which shows improved polymorphic and chemical stability, improved dissolution rate, excellent flow properties and the desired compressibility.
  • Another object of the present invention is to provide wet granulation process to obtain excellent uniformity.
  • Another object of the present invention is to formulate an oral dosage form which is used for the treatment of cancer, such as advanced renal carcinoma (“RCC”) and metastatic renal cell carcinoma (“mRCC”).
  • cancer such as advanced renal carcinoma (“RCC”) and metastatic renal cell carcinoma (“mRCC”).
  • the oral dosage form comprises sorafenib tosylate and at least one pharmaceutically acceptable excipient which is selected from the group comprising fillers, disintegrants or mixtures thereof.
  • the weight ratio of fillers to disintegrants is 1.0-10.0, preferably 2.0-5.0. These ratios are important in order to provide stability in the form.
  • the oral dosage form comprising sorafenib tosylate is present in the form of polymorph III.
  • particle size means the cumulative volume size distribution as tested by any conventionally accepted method such as the laser diffraction method (i.e. Malvern analysis).
  • d (0.1 ) means, the size at which 10% by volume of the particles are finer and d (0.5) means the size at which 50% by volume of the particles are finer and d (0.9) means the size at which %90 by volume of the particles are finer.
  • sorafenib tosylate is micronized and has a mean particle size less than 10 pm, preferably less than 8 pm.
  • sorafenib tosylate has a d (0.1 ) particle size is less than 4 pm, preferably less than 3 pm, preferably less than 2 pm, d (0.5) particle size is less than 6 pm, preferably less than 5 pm, preferably less than 4 pm, d (0.9) particle size is less than 10 pm, preferably less than 9 pm, preferably less than 8 pm.
  • the oral dosage form comprising micronized sorafenib tosylate provides improved dissolution profiles. Rapid dissolution of an administered active agent is preferable, as faster dissolution generally leads to faster onset of action and greater bioavailability. Additionally, a faster dissolution rate would allow for a larger dose of the drug to be absorbed, which would increase drug efficacy.
  • the dosage form is free of microcrystalline cellulose. It is known that microcrystalline cellulose has poor to moderate flow properties so the filler is not appropriate for the oral dosage forms comprising sorafenib tosylate.
  • magnesium stearate is used as a lubricant. It makes over lubrication and which make compressibility problems when used together with microcrystalline cellulose and magnesium stearate. And the combined use of these excipients is obviously risky to provide stability of a solid dosage form.
  • microcrystalline cellulose may create an allergic reaction in some patients. Because it is not absorbed, symptoms of allergic reaction are likely to be limited to gastrointestinal symptoms such as diarrhea or gas.
  • the present invention provides at least one filler which, on the one hand, fulfills the requirements which are demanded of such a material but, on the other hand, is more cost favourable than the expensive microcrystalline cellulose.
  • the selection of using filler has also importance to obtain the desired dissolution rate.
  • Suitable fillers are selected from the group comprising lactose, dicalcium phosphate, lactose monohydrate, starch, pregelatinized starch, dextrose, sucrose, fructose, maltose, sorbitol, polysaccharides, dextrates, lactitol, maltodextrin, trehalose or mixtures thereof.
  • the filler is lactose or dicalcium phosphate or mixtures thereof.
  • the selected filler, lactose or dicalcium phosphate or mixtures thereof, according to the present invention is very well suited. Using the excipients in the form provides excellent flow properties so overcome compressibility problems. It also provides long-term stability.
  • the amount of fillers in the dosage form is 20.0% to 45.0%, preferably 30.0% to 40.0%, more preferably 30.0% to 35.0% and most preferably 32.0% to 35.0% by weight.
  • Suitable disintegrants are selected from the group comprising crospovidone, low-substituted hydroxypropyl cellulose, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, carboxymethyl cellulose, docusate sodium, guar gum, polyacryline potassium, sodium alginate, sodium starch glycolate, alginic acid, alginates, ion-exchange resins, magnesium aluminum silica or mixtures thereof.
  • the disintegrant is crospovidone or low-substituted hydroxypropyl cellulose or mixtures thereof.
  • the amount of disintegrants in the dosage form is 3.0% to 20.0%, preferably 5.0% to 15.0%, more preferably 7.0% to 13.0% and most preferably 9.0% to 12.0%by weight.
  • the dosage form further comprising binders, surfactants, lubricants or mixtures thereof.
  • Suitable binders are selected from group comprising hydroxypropyl methyl cellulose, methyl cellulose, carboxymethyl cellulose, polyethylene glycol, polyvinyl alcohol, polyvinyl acetate, polyvinylpyrrolidone, sugars, glucose syrups, natural gums, pregelatinized starch, gelatins, pullulan, agar, alginate, sodium alginate, glycyrrhizin, polymethacrylates, collagen, hyaluronic acid, poloxamer, polyacrylamide, aluminum hydroxide, bentonite, cetostearyl alcohol, polyoxyethylene-alkyl ethers, polydextrose, polyethylene oxide, xylitol, sucrose stearate or mixtures thereof.
  • the binder is hydroxypropyl methyl cellulose and the amount of hydroxypropyl methyl cellulose in the dosage form is 1 .0% to 10.0%, preferably 1 .0% to 5.0%, preferably 2.0% to 5.0% by weight.
  • Suitable surfactants are selected from the group comprising sodium lauryl sulfate, benzalkonium chloride, docusate sodium, glyceryl esters, poloxamer, polyethylene alkyl ethers, polyglyceryl esters, polysorbates, sorbitan esters, polyoxyethylene esters, polyoxyethylene stearates, sodium stearate, calcium oleate, hexadecyl pyridinium chloride or mixtures thereof.
  • the surfactant is sodium lauryl sulfate and the amount of sodium lauryl sulfate in the dosage form is 0.01% to 3.0%, preferably 0.01% to 2.0%, preferably 0.1 % to 1.0% by weight.
  • Suitable lubricants are selected from the group comprising magnesium stearate, silica, silicon dioxide, talc, calcium stearate, stearic acid, polyethylene glycol, sodium stearyl fumarate, magnesium lauryl sulfate, fumaric acid, glyceryl palmito sulphate, hydrogenated vegetable oil, zinc stearate or mixtures thereof.
  • the lubricant is magnesium stearate and the amount of magnesium stearate in the dosage form is 0.01% to 3.0%, preferably 0.01% to 2.0%, preferably 0.1% to 1.0% by weight.
  • the dosage form is a tablet or a capsule or a granule.
  • the dosage form is a tablet, more preferably coated tablet.
  • the oral dosage form further comprises at least one coating to protect the composition against the moisture and maintain the stability.
  • the coating is film coating.
  • Suitable film coating ingredients are selected from the group comprising hydroxypropylmethyl cellulose (hypromellose), hydroxypropyl cellulose, polyvinyl alcohol (PVA), polyethylene glycol (PEG), talc, polyvinyl alcohol-polyethylene glycol copolymers (Kollicoat IR), ethylcellulose dispersions (Surelease), polyvinylpyrrolidone, polyvinylpyrrolidone-vinyl acetate copolymer (PVP-VA) and all kinds of Opadry®, pigments, dyes, titanium dioxide, iron oxides or polymethylmetacrylate copolymers (Eudragit) or mixtures thereof.
  • the oral dosage form of the present invention is prepared using standard techniques and manufacturing processes well known in the art, such as direct compression, wet or dry granulation, hot melt granulation, hot melt extrusion, fluidized bed granulation, extrusion, spheronization, slugging, spray drying or solvent evaporation.
  • the oral dosage form of excellent uniformity and showing improved dissolution can be obtained when it is prepared by wet granulation process.
  • Wet granulation process provides efficiently compressibility, so it can achieve good dissolution and disintegration properties.
  • the oral dosage form is prepared by using wet granulation.
  • a liquid solvent is used.
  • suitable liquid solvents are selected from the group comprising pure water, safflower oil, ethanol, t-butanol, glycerin, polyethylene glycol (PEG), hexane, glycol or mixtures thereof.
  • the solvent is pure water.
  • the process for the preparation of the tablet comprises the following steps:

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

Abstract

L'invention concerne une forme posologique orale comprenant du tosylate de sorafénib en tant que principe actif qui présente des propriétés améliorées. La présente invention concerne également un procédé de préparation de ladite composition.
PCT/TR2019/050578 2018-08-10 2019-07-16 Forme posologique orale de tosylate de sorafénib Ceased WO2020055359A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
TR201811686 2018-08-10
TR2018/11686 2018-08-10

Publications (2)

Publication Number Publication Date
WO2020055359A2 true WO2020055359A2 (fr) 2020-03-19
WO2020055359A3 WO2020055359A3 (fr) 2020-06-04

Family

ID=69776588

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/TR2019/050578 Ceased WO2020055359A2 (fr) 2018-08-10 2019-07-16 Forme posologique orale de tosylate de sorafénib

Country Status (1)

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WO (1) WO2020055359A2 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023155307A1 (fr) * 2022-02-21 2023-08-24 北京睿创康泰医药研究院有限公司 Préparation orale de sorafénib ou donafénib à faible dose et exposition élevée à un médicament, et application associée

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2466762A1 (fr) * 2001-12-04 2003-06-12 Onyx Pharmaceuticals, Inc. Inhibiteurs de la voie raf-mek-erk pour traiter le cancer
CA2629863A1 (fr) * 2005-11-14 2007-05-24 Scott Wilhelm Utilisation de sorafenib pour le traitement des cancers ayant une resistance acquise aux inhibiteurs kit

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023155307A1 (fr) * 2022-02-21 2023-08-24 北京睿创康泰医药研究院有限公司 Préparation orale de sorafénib ou donafénib à faible dose et exposition élevée à un médicament, et application associée

Also Published As

Publication number Publication date
WO2020055359A3 (fr) 2020-06-04

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