WO2018211336A2 - Solid dosage form containing sorafenib tosylate - Google Patents

Solid dosage form containing sorafenib tosylate Download PDF

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Publication number
WO2018211336A2
WO2018211336A2 PCT/IB2018/001009 IB2018001009W WO2018211336A2 WO 2018211336 A2 WO2018211336 A2 WO 2018211336A2 IB 2018001009 W IB2018001009 W IB 2018001009W WO 2018211336 A2 WO2018211336 A2 WO 2018211336A2
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WIPO (PCT)
Prior art keywords
dosage form
solid dosage
sorafenib tosylate
form containing
containing sorafenib
Prior art date
Application number
PCT/IB2018/001009
Other languages
French (fr)
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WO2018211336A3 (en
Inventor
Mohit Jaya ABRAHAM
S. Gattani YOGESH
He Yen FANG
Chieh Shan LAI
Original Assignee
Alvogen Malta Operations (Row) Ltd
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.)
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Application filed by Alvogen Malta Operations (Row) Ltd filed Critical Alvogen Malta Operations (Row) Ltd
Priority to PCT/IB2018/001009 priority Critical patent/WO2018211336A2/en
Publication of WO2018211336A2 publication Critical patent/WO2018211336A2/en
Publication of WO2018211336A3 publication Critical patent/WO2018211336A3/en

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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
    • A61K9/2022—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
    • 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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone

Definitions

  • the invention relates to a solid dosage form containing Sorafenib tosylate which is used in pharmacy and medicine, in particular for the treatment of unresectablehepatocellular carcinoma, advanced renal cell carcinoma, and progressive, locally advanced or metastatic, differentiated thyroid carcinoma.
  • Sorafenib also known as BAY 43-9006, is omega carboxyaryl substituted diphenyl urea with the chemical name 4- ⁇ 4 - [( ⁇ [4-chloro-3- (trifluoromethyl) phenyl] amino ⁇ amino] phenoxy ⁇ -N-methylpyridine-2-carboxamide. Sorafenib has been synthesized by Bayer and has been described for the first time in patent application WO0042012. Various polymorphic modifications of the chemical substance sorafenib (WO2006034797) are also known, each of which exhibits different stability.
  • Sorafenib has been specified to be an inhibitor of the raf kinase enzyme and is indicated for the treatment of hyperproliferative diseases, such as cancer, especially for the treatment of unresectablehepatocellular carcinoma, advanced renal cell carcinoma and progressive, locally advanced or metastatic, differentiated (papillary / follicular (Hurthle-cell) thyroid carcinoma, radioactive iodine-refractory. Sorafenib is used as a single agent or in combination with other anticancer therapeutics.
  • Sorafenib is practically insoluble in water, poorly soluble in ethanol and soluble in PEG. Due to its water insolubility, there is a problem with the dissolution rate and the bioavailability of the conventional formulations containing it. It would be desirable to increase the dissolution rate and bioavailability for a faster infusion of the drug.
  • Application of sorafenib are usually associated also with high and serious side effects such as ischemic heart disease and/or infarction, bleeding, hypertension, skin reaction at the limbs, gastrointestinal perforations, thrombocytopenia, anemia, etc., which are directly dependent of the dose. Therefore, dose reduction would reduce the side effects associated with taking this drug.
  • Patent application WO2008008733 describes a tablet formulation of good pharmacokinetic properties and bioavailability that contains sorafenib nanoparticles of dimensions less than 2000 nm stabilized with at least one surface stabilizer.
  • the dosage form containing these nanoparticles may be prepared with or without the addition of further pharmaceutically acceptable excipients such as fillers and binders.
  • the European Patent EP 1868579 of Bayer discloses an immediate release tablet formulation containing more than 55% of the total weight of sorafenib tosylate salt with a particle size of 0.5 to 10 pm and as auxiliaries: microcrystalline cellulose as a filler in a portion of from 3 to 20%, croscarmellose sodium as a disintegrant in a proportion of 5 to 12%, hypromellose as a binder in a proportion of 0.5 to 8%, magnesium stearate as a lubricant in a proportion of from 0.2 to 8% and sodium lauryl sulfate as a surfactant in a proportion of from 0.1 to 2% by weight of the composition.
  • the tablet Prior to administration, the tablet dissolves in water and disintegrates for 6 minutes.
  • This patent protects the Nexavar® market product that Bayer has marketed since 2006.
  • the disadvantage of this dosage form is that in order to achieve the optimal therapeutic effect it has to be taken in a specific way and the optimal therapeutic daily intake is high.
  • Object of the present invention is to provide a pharmaceutical composition of sorafenyl tosylate with improved bioavailability and tolerability applicable at lower optimal therapeutic doses to balance the reduction of adverse drug reactions with the need for dose adjustment to overcome the acquired resistance in the therapy process.
  • the solid formulation according to the invention includes sorafenib tosylate and a precipitation inhibitor in an amount of 0.5 to 25% by weight, more preferably from 0.5% to 15%, and most preferably from 1% to 10% as well as optionally one or more other excipients.
  • the precipitation inhibitor is hydroxypropyl methylcellulose (hypromellose) with a viscosity higher than 10 cps.
  • the precipitation inhibitor is selected from the group of compounds: hydroxypropylcellulose, carboxymethylcellulose, methylcellulose, hydroxyethylcellulose, polyvinyl alcohol, polyacrylates, methylcellulose, polyvinyl pyrrolidone, copovidone and pregelatinised starch.
  • the precipitation inhibitor is included in the solid dosage formulation to eliminate the precipitation of sorafenib tosyl after passing into the gastrointestinal fluids of the patient by preventing growth of the active compound crystals in the solution.
  • a greater amount of sorafenib tosylate remains in the dissolved state, which improves the extent of absorption, increases efficacy, and increases its bioavailability.
  • the pharmaceutical composition also includes other excipients such as binders, fillers, plasticizers, surfactants and wetting agents.
  • the pharmaceutical composition of the solid dosage form according to the invention may be in the form of a tablet in a form of coated tablets, which is coated with film-forming agents, coating materials and colorants or in the form of a pharmaceutical capsule.
  • the oral solid formulation containing sorafenib tosylate is prepared by the wet granulation process, as the manufacturing process includes the following steps: a) sorafenib tosylate with at least one pharmaceutically acceptable excipient is wet granulated with an aqueous solution of the precipitantion inhibitor ; (b) the granulate is blended with the lubricant and optionally with one or more further pharmaceutically acceptable excipient;
  • Lubricated granules are compressed as tablets or filled into capsules or filling them into pharmaceutical capsules.
  • the resulting tablets may be coated with one or more pharmaceutically acceptable coatings.
  • the granulation process may be dry granulation and direct compression.
  • composition according to the invention is the creation of a pharmaceutical composition of sorafenyl tosylate with improved bioavailability and tolerability applicable at lower optimal therapeutic doses that balance between reduction of adverse drug reactions and dose adjustment in order to overcome acquired resistance in the course of therapy.
  • Figure 1 presents graphically the results of a dissolution profile study of the composition of the film-coated tablet of Example 1 according to the invention.
  • Figure 2 graphically represents the comparative evaluation of the results of the in vitro dissolution of the tablet formulation obtained according to Example 1 and the market medicinal product of sorafenib tosylate Nexavar®.
  • Figure 3 presents a graphical representation of the comparative evaluation of an in vivo study of the tablet formulation prepared according to Example 1 and the market medicinal product of sorafenib tosylate Nexavar®.
  • Example 1 Preparation of a film-coated tablet containing Sorafenib tosylate To prepare the film-coated tablet containing Sorafenib tosylate according to the invention, the following components are used:
  • Sorafenib tosylate was co-sifted along with microcrystalline cellulose and sodium starch glycolate.
  • the blend is loaded in to the Fluidized bed processor and granulated using solution of hypromellose and Sodium lauryl sulfate in water. Granules were lubricated with Sodium stearyl fumarate and compressed into tablet. The core tablets were then coated with Opadry film coating.
  • Example 2 Test to determine the dissolution profile of the film-coated tablets prepared in Example 1.
  • Example 1 The dissolution profile of the film-coated tablets prepared in Example 1 was carried out according to the method described in USP under the following conditions: 0.01 N HCI with 0.25% SLS, 900ml_, 50rpm, in dissolution apparatus 2 over a time period of 60 min. The results of the dissolution test conducted are shown in Table 1 and are presented graphically in Figure 1. Table 1
  • Example 3 Comparative evaluation of in vitro dissolution of the tablet formulation prepared according to Example 1 and the market medicinal product of sorafenib tosylate Nexavar®.
  • Example 4 Comparative Evaluation of an In Vivo Study of the Tablet Form prepared according to Example 1 and the market medicinal product of sorafenib tosylate Nexavar®.
  • Test show higher T/R ratio for Cmax and AUC.
  • the batch showed 194.32% T/R for Cmax and 199.58% T/R for AUC72.

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  • Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Chemical & Material Sciences (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)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention relates to a solid dosage form containing Sorafenib tosylate which is used in pharmacy and medicine. An advantage of the composition according to the invention is improved bioavailability and tolerability, possibility of its applicable at lower optimal therapeutic doses that created balance between reduction of adverse drug reactions and abilility to overcome acquired resistance in the course of therapy. A solid dosage form, according to the invention, comprising Sorafenib tosylate, a precipitation inhibitor in an amount of 0.5 to 25% by weight, preferably from 0.5% to 15%, and most preferably from 1% to 10% and optionally other excipients.

Description

Solid dosage form containing Sorafenib tosylate Field of the invention
The invention relates to a solid dosage form containing Sorafenib tosylate which is used in pharmacy and medicine, in particular for the treatment of unresectablehepatocellular carcinoma, advanced renal cell carcinoma, and progressive, locally advanced or metastatic, differentiated thyroid carcinoma.
Background of the invention
Sorafenib, also known as BAY 43-9006, is omega carboxyaryl substituted diphenyl urea with the chemical name 4- {4 - [({[4-chloro-3- (trifluoromethyl) phenyl] amino} amino] phenoxy} -N-methylpyridine-2-carboxamide. Sorafenib has been synthesized by Bayer and has been described for the first time in patent application WO0042012. Various polymorphic modifications of the chemical substance sorafenib (WO2006034797) are also known, each of which exhibits different stability. Sorafenib has been specified to be an inhibitor of the raf kinase enzyme and is indicated for the treatment of hyperproliferative diseases, such as cancer, especially for the treatment of unresectablehepatocellular carcinoma, advanced renal cell carcinoma and progressive, locally advanced or metastatic, differentiated (papillary / follicular (Hurthle-cell) thyroid carcinoma, radioactive iodine-refractory. Sorafenib is used as a single agent or in combination with other anticancer therapeutics.
Sorafenib is practically insoluble in water, poorly soluble in ethanol and soluble in PEG. Due to its water insolubility, there is a problem with the dissolution rate and the bioavailability of the conventional formulations containing it. It would be desirable to increase the dissolution rate and bioavailability for a faster infusion of the drug. Application of sorafenib are usually associated also with high and serious side effects such as ischemic heart disease and/or infarction, bleeding, hypertension, skin reaction at the limbs, gastrointestinal perforations, thrombocytopenia, anemia, etc., which are directly dependent of the dose. Therefore, dose reduction would reduce the side effects associated with taking this drug.
Patent application WO2008008733 describes a tablet formulation of good pharmacokinetic properties and bioavailability that contains sorafenib nanoparticles of dimensions less than 2000 nm stabilized with at least one surface stabilizer. The dosage form containing these nanoparticles may be prepared with or without the addition of further pharmaceutically acceptable excipients such as fillers and binders. The European Patent EP 1868579 of Bayer discloses an immediate release tablet formulation containing more than 55% of the total weight of sorafenib tosylate salt with a particle size of 0.5 to 10 pm and as auxiliaries: microcrystalline cellulose as a filler in a portion of from 3 to 20%, croscarmellose sodium as a disintegrant in a proportion of 5 to 12%, hypromellose as a binder in a proportion of 0.5 to 8%, magnesium stearate as a lubricant in a proportion of from 0.2 to 8% and sodium lauryl sulfate as a surfactant in a proportion of from 0.1 to 2% by weight of the composition. Prior to administration, the tablet dissolves in water and disintegrates for 6 minutes. This patent protects the Nexavar® market product that Bayer has marketed since 2006. The disadvantage of this dosage form is that in order to achieve the optimal therapeutic effect it has to be taken in a specific way and the optimal therapeutic daily intake is high.
Object of the present invention is to provide a pharmaceutical composition of sorafenyl tosylate with improved bioavailability and tolerability applicable at lower optimal therapeutic doses to balance the reduction of adverse drug reactions with the need for dose adjustment to overcome the acquired resistance in the therapy process.
Summary of the invention The solid formulation according to the invention includes sorafenib tosylate and a precipitation inhibitor in an amount of 0.5 to 25% by weight, more preferably from 0.5% to 15%, and most preferably from 1% to 10% as well as optionally one or more other excipients.
Preferably, the precipitation inhibitor is hydroxypropyl methylcellulose (hypromellose) with a viscosity higher than 10 cps.
In one embodiment, the precipitation inhibitor is selected from the group of compounds: hydroxypropylcellulose, carboxymethylcellulose, methylcellulose, hydroxyethylcellulose, polyvinyl alcohol, polyacrylates, methylcellulose, polyvinyl pyrrolidone, copovidone and pregelatinised starch.
The precipitation inhibitor is included in the solid dosage formulation to eliminate the precipitation of sorafenib tosyl after passing into the gastrointestinal fluids of the patient by preventing growth of the active compound crystals in the solution. Thus, a greater amount of sorafenib tosylate remains in the dissolved state, which improves the extent of absorption, increases efficacy, and increases its bioavailability.
In another embodiment, the pharmaceutical composition also includes other excipients such as binders, fillers, plasticizers, surfactants and wetting agents.
The pharmaceutical composition of the solid dosage form according to the invention may be in the form of a tablet in a form of coated tablets, which is coated with film-forming agents, coating materials and colorants or in the form of a pharmaceutical capsule.
The oral solid formulation containing sorafenib tosylate is prepared by the wet granulation process, as the manufacturing process includes the following steps: a) sorafenib tosylate with at least one pharmaceutically acceptable excipient is wet granulated with an aqueous solution of the precipitantion inhibitor ; (b) the granulate is blended with the lubricant and optionally with one or more further pharmaceutically acceptable excipient;
c) Lubricated granules are compressed as tablets or filled into capsules or filling them into pharmaceutical capsules.
In another embodiment, the resulting tablets may be coated with one or more pharmaceutically acceptable coatings.
In another embodiment, the granulation process may be dry granulation and direct compression.
An advantage of the composition according to the invention is the creation of a pharmaceutical composition of sorafenyl tosylate with improved bioavailability and tolerability applicable at lower optimal therapeutic doses that balance between reduction of adverse drug reactions and dose adjustment in order to overcome acquired resistance in the course of therapy.
Description of the enclosed figures
The pharmaceutical composition and its properties have been investigated and the results of the investigations are presented graphically in the following figures:
Figure 1 presents graphically the results of a dissolution profile study of the composition of the film-coated tablet of Example 1 according to the invention.
Figure 2 graphically represents the comparative evaluation of the results of the in vitro dissolution of the tablet formulation obtained according to Example 1 and the market medicinal product of sorafenib tosylate Nexavar®.
Figure 3 presents a graphical representation of the comparative evaluation of an in vivo study of the tablet formulation prepared according to Example 1 and the market medicinal product of sorafenib tosylate Nexavar®.
Examples of implementation The pharmaceutical composition of the solid formulation containing sorafenib tosylate according to the invention is illustrated by the following exemplary embodiments:
Example 1 : Preparation of a film-coated tablet containing Sorafenib tosylate To prepare the film-coated tablet containing Sorafenib tosylate according to the invention, the following components are used:
Figure imgf000006_0001
Sorafenib tosylate was co-sifted along with microcrystalline cellulose and sodium starch glycolate. The blend is loaded in to the Fluidized bed processor and granulated using solution of hypromellose and Sodium lauryl sulfate in water. Granules were lubricated with Sodium stearyl fumarate and compressed into tablet. The core tablets were then coated with Opadry film coating.
Example 2: Test to determine the dissolution profile of the film-coated tablets prepared in Example 1.
The dissolution profile of the film-coated tablets prepared in Example 1 was carried out according to the method described in USP under the following conditions: 0.01 N HCI with 0.25% SLS, 900ml_, 50rpm, in dissolution apparatus 2 over a time period of 60 min. The results of the dissolution test conducted are shown in Table 1 and are presented graphically in Figure 1. Table 1
Figure imgf000007_0001
Example 3. Comparative evaluation of in vitro dissolution of the tablet formulation prepared according to Example 1 and the market medicinal product of sorafenib tosylate Nexavar®.
The in vitro study was conducted in 900 ml of pH 6.8 buffer with 1.0% SLS using USP Apparatus II. In vitro dissolution demonstrates faster and greater dissolution compared to the formulation available on the market. The results obtained are shown in Table 2 and are shown graphically in Figure 2.
Table 2
Figure imgf000007_0002
In vitro dissolution exhibited faster, and higher dissolution compared to marketed formulation. Example 4 Comparative Evaluation of an In Vivo Study of the Tablet Form prepared according to Example 1 and the market medicinal product of sorafenib tosylate Nexavar®.
In-vivo pharmacokinetic study in healthy human volunteers in complete crossover manner.
Results of the in-vivo study are shown in Table 3 and graphically in Figure 3.
Table 3
Figure imgf000008_0001
Test show higher T/R ratio for Cmax and AUC. The batch showed 194.32% T/R for Cmax and 199.58% T/R for AUC72.
Based on these observations, a bio-enhanced formulation with increased bioavailability was developed.

Claims

PATENT CLAIMS
1. A solid dosage form containing Sorafenib tosylate and excipients, characterized in that it also comprises a precipitation inhibitor in an amount of 0.5 to 25% by weight, preferably from 0.5% to 15%, and most preferably from 1% to 10%.
2. A solid dosage form containing Sorafenib tosylate according to claim 1 , characterized in that the precipitation inhibitor is hydroxypropyl methylcellulose (hypromellose) with a viscosity higher than 10 cps.
3. A solid dosage form containing Sorafenib tosylate according to claim 1 , characterized in that the precipitation inhibitor is selected from the group of of compounds: hydroxypropylcellulose, carboxymethylcellulose, methylcellulose, hydroxyethylcellulose, polyvinyl alcohol, polyacrylates, methylcellulose, polyvinyl pyrrolidone, copovidone and pregelatinized starch.
4. A solid dosage form containing Sorafenib tosylate according to any one of claims from 1 to 3, characterized in that it comprises and other excipients such as binders, fillers, plasticizers, surfactants and wetting agents.
5. A solid dosage form containing Sorafenib tosylate according to any one of claims from 1 to 4, characterized in that the solid dosage form may be a tablet, a film-coated tablet or a pharmaceutical capsule.
PCT/IB2018/001009 2018-09-07 2018-09-07 Solid dosage form containing sorafenib tosylate WO2018211336A2 (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022120512A1 (en) * 2020-12-07 2022-06-16 天津睿创康泰生物技术有限公司 Sorafenib pharmaceutical composition having high bioavailability and application
WO2023155307A1 (en) 2022-02-21 2023-08-24 北京睿创康泰医药研究院有限公司 Sorafenib or donafenib oral preparation with low dose and high drug exposure, and application thereof

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000042012A1 (en) 1999-01-13 2000-07-20 Bayer Corporation φ-CARBOXYARYL SUBSTITUTED DIPHENYL UREAS AS RAF KINASE INHIBITORS
WO2006034797A1 (en) 2004-09-29 2006-04-06 Bayer Healthcare Ag Thermodynamically stable form of bay 43-9006 tosylate
EP1868579A1 (en) 2005-03-07 2007-12-26 Bayer HealthCare AG Pharmaceutical composition comprising an omega-carboxyaryl substituted diphenyl urea for the treatment of cancer
WO2008008733A2 (en) 2006-07-10 2008-01-17 Elan Pharma International Ltd. Nanoparticulate sorafenib formulations

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000042012A1 (en) 1999-01-13 2000-07-20 Bayer Corporation φ-CARBOXYARYL SUBSTITUTED DIPHENYL UREAS AS RAF KINASE INHIBITORS
WO2006034797A1 (en) 2004-09-29 2006-04-06 Bayer Healthcare Ag Thermodynamically stable form of bay 43-9006 tosylate
EP1868579A1 (en) 2005-03-07 2007-12-26 Bayer HealthCare AG Pharmaceutical composition comprising an omega-carboxyaryl substituted diphenyl urea for the treatment of cancer
WO2008008733A2 (en) 2006-07-10 2008-01-17 Elan Pharma International Ltd. Nanoparticulate sorafenib formulations

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022120512A1 (en) * 2020-12-07 2022-06-16 天津睿创康泰生物技术有限公司 Sorafenib pharmaceutical composition having high bioavailability and application
CN114916221A (en) * 2020-12-07 2022-08-16 天津睿创康泰生物技术有限公司 Sorafenib pharmaceutical composition with high bioavailability and application thereof
CN114916221B (en) * 2020-12-07 2024-01-30 天津睿创康泰生物技术有限公司 Sorafenib pharmaceutical composition with high bioavailability and application
WO2023155307A1 (en) 2022-02-21 2023-08-24 北京睿创康泰医药研究院有限公司 Sorafenib or donafenib oral preparation with low dose and high drug exposure, and application thereof

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