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WO2024191389A1 - Composition pharmaceutique de régorafénib - Google Patents

Composition pharmaceutique de régorafénib Download PDF

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Publication number
WO2024191389A1
WO2024191389A1 PCT/TR2024/050229 TR2024050229W WO2024191389A1 WO 2024191389 A1 WO2024191389 A1 WO 2024191389A1 TR 2024050229 W TR2024050229 W TR 2024050229W WO 2024191389 A1 WO2024191389 A1 WO 2024191389A1
Authority
WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
regorafenib
pharmaceutically acceptable
poloxamer
acceptable excipient
Prior art date
Application number
PCT/TR2024/050229
Other languages
English (en)
Inventor
Kaan KIRAYLAR
Ali Osman Sarikaya
Udaya Kumar DUDE
Emre Erol ALDENİZ
Original Assignee
Abdi Ibrahim Ilac Sanayi Ve Ticaret Anonim Sirketi
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
Priority claimed from TR2023/002707 external-priority patent/TR2023002707A2/tr
Application filed by Abdi Ibrahim Ilac Sanayi Ve Ticaret Anonim Sirketi filed Critical Abdi Ibrahim Ilac Sanayi Ve Ticaret Anonim Sirketi
Publication of WO2024191389A1 publication Critical patent/WO2024191389A1/fr

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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
    • A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
    • 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

Definitions

  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising: (i) intragranular component comprising regorafenib and at least one pharmaceutically acceptable excipient, and (ii) extragranular component comprising poloxamer (polyoxyethylene-polyoxypropylene copolymer) and at least one pharmaceutically acceptable excipient.
  • the invention further relates to a process for the preparation of the said pharmaceutical composition and its use for treating disorders.
  • Regorafenib is chemically known as 4-[4-( ⁇ [4-chloro-3-(trifluoromethyl) phenyl] carbamoyl ⁇ amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide (I).
  • Regorafenib is low molecular weight, orally available, inhibitor of multiple membranebound and intracellular kinases involved in normal cellular functions and in pathologic processes such as oncogenesis, tumor angiogenesis, and maintenance of the tumor microenvironment.
  • Regorafenib is marketed as Stivarga® by Bayer Pharma in Europe since 2013. The marketed product is approved in the form of 40 mg film coated tablet. Stivarga® is indicated as monotherapy for the treatment of adult patients with metastatic colorectal cancer (CRC) who have been previously treated with, or are not considered candidates for, available therapies. These include fluoropyrimidine-based chemotherapy, an anti-VEGF therapy and an anti-EGFR therapy, unresectable or metastatic gastrointestinal stromal tumours (GIST) who progressed on or are intolerant to prior treatment with imatinib and sunitinib and hepatocellular carcinoma (HCC) who have been previously treated with sorafenib.
  • CRC metastatic colorectal cancer
  • GIST unresectable or metastatic gastrointestinal stromal tumours
  • HCC hepatocellular carcinoma
  • regorafenib is a white to slightly pink or slightly brownish solid substance, practically insoluble in water.
  • Regorafenib is BCS Class II compound based on Biopharmaceutical Classification System.
  • BCS Class II compounds are drug substances with low solubility and high permeability. The bioavailability of these compounds is limited by their solubility (solvation rate). Hence, the absorption of a poorly water-soluble compound from orally administered solid dosage form is controlled by its dissolution rate in the gastrointestinal fluid present at the absorption site. It is known in the pharmaceutical arts that low-solubility drugs often show poor bioavailability or irregular absorption, the degree of irregularity being affected by factors such as dose level, fed state of the patient, and form of the drug.
  • WO 2006026500 discloses a composition comprising a solid dispersion comprising regorafenib and a pharmaceutically acceptable matrix, wherein the matrix comprises at least one polymer from the group consisting of polyvinylpyrrolidone, copovidone, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyethylene glycol or polyethylene oxide.
  • CN 111166724 A discloses a regorafenib nano dispersion, a tablet and a preparation method thereof; the dispersion can be prepared by dissolving regorafenib in solvent, separately dissolving a carrier material in water, and performing liquid component precipitation crystallization reaction to obtain regorafenib nano-suspension; it is spray dried to obtain a regorafenib nano-dispersion.
  • WO 2014039677 discloses a pharmaceutical composition comprising regorafenib, a hydrate, solvate, metabolite or pharmaceutically acceptable salt of regorafenib, or a polymorph thereof and at least one pharmaceutically acceptable excipient wherein the pharmaceutical composition is coated by a coating comprising a polyvinyl alcohol based polymer and optionally one or more further pharmaceutically acceptable excipients.
  • polyvinyl alcohol based polymer coating effectively controls particular impurity AFP-PMA as compared to conventional HPMC coating.
  • WO 2021156172 A1 discloses a pharmaceutical composition comprising a solid dispersion comprising regorafenib and at least one pharmaceutically acceptable excipient inside of the solid dispersion, and at least one stabilizing agent, wherein the stabilizing agent is outside of the solid dispersion and the pharmaceutical composition is enteric coated.
  • the stabilizing agent is hydroxypropylmethylcellulose acetate succinate (HPMCAS).
  • HPMCAS hydroxypropylmethylcellulose acetate succinate
  • a pharmaceutical composition of Regorafenib comprising poloxamer (polyoxyethylene-polyoxypropylene copolymer) in extragranular phase provides storage stable composition having similar impurity profile and bioequivalence profile when compared to the reference product Stivarga® tablet.
  • Yet another object of the present invention is to provide a pharmaceutical composition of regorafenib, which has similar impurity profile when compared to the reference product Stivarga® tablet.
  • Yet another object of the present invention is to provide a pharmaceutical composition of regorafenib, which has similar dissolution profile and bioequivalence profile when compared to the reference product Stivarga® tablet.
  • Yet another object of the present invention is to provide a pharmaceutical composition of regorafenib, which is devoid of above mentioned problems associated with solid dispersion of regorafenib.
  • Yet another object of the invention is to provide a commercially scalable, cost effective, environment friendly and robust process for the preparation of a pharmaceutical composition comprising regorafenib.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising: i) intragranular component comprising regorafenib and at least one pharmaceutically acceptable excipient, and ii) extragranular component comprising poloxamer and at least one pharmaceutically acceptable excipient.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising: i) intragranular component comprising 1 to 20 wt.% of regorafenib and at least one pharmaceutically acceptable excipient, ii) extragranular component comprising 0.1 to 5 wt.% of poloxamer and at least one pharmaceutically acceptable excipient, and wherein the weight percent is based on the total weight of the composition.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising: i) intragranular component comprising 5 to 10 wt.% of regorafenib and at least one pharmaceutically acceptable excipient, ii) extragranular component comprising 0.1 to 1 wt.% of poloxamer and at least one pharmaceutically acceptable excipient, and wherein the weight percent is based on the total weight of the composition.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising: i) intragranular component comprising solid dispersion of regorafenib and at least one pharmaceutically acceptable excipient, and ii) extragranular component comprising poloxamer and at least one pharmaceutically acceptable excipient.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising: i) intragranular component comprising solid dispersion of regorafenib and povidone, and ii) extragranular component comprising poloxamer and at least one pharmaceutically acceptable excipient.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising: i) intragranular component comprising solid dispersion of regorafenib and povidone, ii) extragranular component comprising 0.1 to 1 wt.% of poloxamer and at least one pharmaceutically acceptable excipient, and wherein the solid dispersion containing 1 to 20 wt.% of regorafenib based on the total weight of the composition.
  • the present invention provides a tablet comprising: i) 5 to 10 wt.% of regorafenib, ii) about 0.1 wt.% to about 5 wt.% of poloxamer, iii) 10 wt.% to 50 wt.% of one or more of diluents, iv) 5 wt.% to 50 wt.% of one or more of disintegrants, v) 0.1 wt.% to 5 wt.% of one or more lubricant, vi) 0.1 wt.% to 5 wt.% of one or more glidant, and vii) 10 wt.% to 50 wt.% of one or more of recrystallization inhibitor based on the total weight of the composition, wherein the poloxamer is present in extragranular component.
  • the present invention provides a pharmaceutical composition of any of the above aspects, wherein the said composition remains stable after storage for 3 months at 40°C and 75% relative humidity (RH).
  • the present invention discloses a use of such pharmaceutical composition as medicament in the treatment of metastatic colorectal cancer (CRC) and hepatocellular carcinoma (HCC).
  • CRC metastatic colorectal cancer
  • HCC hepatocellular carcinoma
  • % means the percentage by the total weight of the composition unless otherwise stipulated.
  • composition or “formulation” as used in the present invention means solid pharmaceutical composition includes, without limitation, tablets, caplets, pellets, granules, capsules and beads.
  • Intragranular component means granules comprising regorafenib and one or more pharmaceutically acceptable excipient.
  • the said granule can be obtained by granulation methods such as dry granulation, hot-melt granulation or wet granulation, preferably wet granulation.
  • Extragranular component means one or more pharmaceutically acceptable excipient(s) including poloxamer to be mixed with “Intragranular component”.
  • Regorafenib as used in the present invention includes, but is not limited to, Regorafenib per se or its pharmaceutically acceptable hydrates, pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable prodrugs thereof or anhydrous regorafenib, and also its various crystalline and amorphous forms.
  • the composition of present invention comprises anhydrous form of regorafenib or regorafenib monohydrate, which may be in the crystalline form, amorphous form or mixture thereof. More preferably, the composition of present invention comprises anhydrous regorafenib.
  • solid dispersion refers to a system in a solid state comprising at least two components, wherein one component is dispersed throughout the other component or components.
  • solid dispersion refers to stable solid dispersions comprising amorphous drug substance and carrier.
  • solid dispersion as used herein also refers to stable solid dispersions comprising amorphous drug substance and carrier with or without adsorbent/absorbent.
  • amorphous drug substance it is meant that the amorphous solid contains drug substance in a substantially amorphous solid state form i.e. at least about 80% of the drug substance in the dispersion is in an amorphous form. More preferably at least about 90% and most preferably at least about 95% of the drug substance in the dispersion is in amorphous form.
  • stable or “stability” means that the pharmaceutical dosage form is physically and chemically stable, whereas “chemically stable” means that the solid pharmaceutical dosage form when stored at 40 °C and 75 % relative humidity for 3 or 6 months, each of the degradation impurity and total impurities remain within ICH limit.
  • similarity factor or f2 factor as used herein refers to one way of comparing dissolution profiles of two different products.
  • Test and reference or two strengths, or pre- and post-approved products from the same manufacturer. Tests are recommended to be performed under the same test conditions.
  • the dissolution time points for both the profiles should be the same, for example for immediate release products e.g. 10, 15, 30, 45, 60 minutes and for extended release products, e.g., 1 , 2, 3, 5 and 8 hours.
  • a present invention provides a pharmaceutical composition comprising: i) intragranular component comprising regorafenib and at least one pharmaceutically acceptable excipient, and ii) extragranular component comprising poloxamer and at least one pharmaceutically acceptable excipient.
  • a composition of the present invention comprises 1 to 20 wt.% of regorafenib, preferably 5 to 10 wt.% of regorafenib based on the total weight of the composition.
  • a composition of the present invention comprises extragranular component comprising poloxamer in amount from about 0.1 to 5 wt.%, preferably, about 0.1 to 1 wt.% based on the total weight of the composition.
  • a pharmaceutical composition of the present invention further comprises one or more pharmaceutically acceptable excipients.
  • the excipients to be used in accordance with the present invention are well known and are those excipients which are conventionally used by the person skilled in the art. Depending on the dosage form chosen for the pharmaceutical composition, the person skilled in the art will be able to select suitable pharmaceutically acceptable excipients.
  • the pharmaceutical excipient can be selected from excipient can be selected from diluent, disintegrant, lubricant, glidant and recrystallization inhibitor.
  • Diluent includes, but are not limited to, lactose, mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch, dextrates, dextran, dextrin, dextrose, maltodextrin, calcium carbonate, dibasic calcium phosphate, calcium sulfate, magnesium carbonate, magnesium oxide and mixtures thereof.
  • the amount of diluent is from about 10 wt.% to about 50 wt.%, preferably from about 10 wt.% to about 30 wt.% based on the total weight of the composition.
  • Disintegrant includes, but are not limited to, sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methylcellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropyl cellulose, starch, pregelatinized starch, and sodium alginate and mixtures thereof.
  • the amount of the disintegrant is preferably from 5 wt.% to about 50 wt.%, more preferably from 20 wt.% to 40 wt.% based on the total weight of the composition.
  • Suitable lubricants and/or glidants are selected from magnesium stearate, hydrogenated vegetable oil, glyceryl behenate, glyceryl monostearate, stearic acid, sodium stearyl fumarate, sodium starch fumarate, calcium stearate, zinc stearate, aluminum silicate, talc, colloidal silicon dioxide, sucrose esters of fatty acid, waxes, silica gel, or mixtures thereof.
  • the present invention comprises a lubricant and/or glidant in an amount of from about 0.1 wt.% to about 10 wt.%, preferably, 0.1 wt.% to about 2 wt.% based on the total weight of the composition.
  • the recrystallization inhibitor includes, but are not limited to, polyvinylpyrrolidone (povidone), tyloxapol, fatty acid glycerol polyethylene glycol esters, fatty acid polyethylene glycol esters, polyethylene glycols, glycerol ethers, a cyclodextrin (for example alpha-, beta- or gamma-cyclodextrin, e.g.
  • a cyclodextrin for example alpha-, beta- or gamma-cyclodextrin, e.g.
  • the recrystallization inhibitor is polyvinylpyrrolidone.
  • the present invention comprises a recrystallization inhibitor in an amount of from about 10 wt.% to about 50 wt.%, preferably, 10 wt.% to about 40 wt.% based on the total weight of the composition.
  • the present invention provides a tablet comprising: i) 5 to 10 wt.% of regorafenib, ii) about 0.1 %w/w to about 5 wt.% of poloxamer, iii) 10 wt.% to 50 wt.% of one or more of diluents, iv) 5 wt.% to 50 wt.% of one or more of disintegrants, v) 0.1 wt.% to 5 wt.% of one or more lubricant, vi) 0.1 wt.% to 5 wt.% of one or more glidant, and vii) 10 wt.% to 50 wt.% of one or more of recrystallization inhibitor based on the total weight of the composition, wherein the poloxamer is present in extragranular component.
  • the pharmaceutical composition of the present invention may further be coated with a film- forming polymer and one or more pharmaceutically acceptable excipients, using techniques well known in the art e.g., spray coating in a conventional coating pan, or a fluidized bed processor, or dip coating. Alternatively, coating can also be performed using a hot melt technique.
  • the film coating may contain one or more film-forming polymers, and optionally one or more pharmaceutically acceptable excipients.
  • a suitable film-forming polymer is selected from the group comprising hydroxypropyl methyl cellulose, ethyl cellulose, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, cellulose acetate, hydroxypropyl methyl cellulose phthalate, cellulose acetate trimellitate, methacrylic acid copolymers e.g., Eudragit®, polyvinylpyrrolidone, polyvinyl alcohol, polyethylene glycol, or mixtures thereof.
  • a preferred film- forming polymer is hydroxypropyl methyl cellulose.
  • Other suitable film- forming polymers which are known in the art may also be used.
  • the film coating may also contain opacifiers like titanium dioxide, plasticizer like polyethylene glycol, flow aids like talc and pigment like iron oxide yellow or red iron oxide.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising: i) intragranular component comprising solid dispersion of regorafenib and at least one pharmaceutically acceptable excipient, and ii) extragranular component comprising poloxamer and at least one pharmaceutically acceptable excipient.
  • the process to obtain solid dispersion of the present invention includes, but is not limited to, solvent evaporation method, fusion method, kneading method, melting method, spray drying method, co-grinding method, lyophilization technique, hot melt extrusion, melt agglomeration, supercritical fluid (SCF) technology and the like.
  • the solid dispersion of the present invention is prepared by dissolving regorafenib in a suitable solvent with or without additional excipient and spray it onto pharmaceutically acceptable excipients using suitable technology like fluid bed technology.
  • Suitable solvents in the present invention is, but are not limited to, ethanol, methanol, isopropanol, acetone, N,N-dimethylformamide, water or mixture thereof.
  • the pharmaceutical composition of the present invention can be obtained by using known conventional methods.
  • the process to obtain granulate includes, but is not limited to, wet granulation, fluid bed granulation, spray drying, dry granulation, slugging and roller compaction.
  • composition of the present invention is very suitable for production on commercial scale making use of equipment and techniques commonly used in industry.
  • Example 1 A tablet composition comprising regorafenib & extragranular component comprising poloxamer Table-1
  • Aquarius Prime Pink contains hypromellose, titanium dioxide, polyethylene glycol, talc, red iron oxide and yellow iron oxide
  • Example 2 A tablet composition comprising Regorafenib & extragranular component comprising Eudragit® E PO*
  • Eudragit® E PO Basic butylated methacrylate copolymer, sodium lauryl sulphate, stearic acid, talc, titanium dioxide #Aquarius Cool Vanilla: Hypromellose, titanium dioxide, polyethylene glycol, talc.
  • Process for the preparation The tablets were prepared using same process of example 1 by replacing poloxamer with Eudragit® E PO.
  • Example 3 A tablet composition comprising regorafenib & extragranular component comprising poloxamer
  • ’Aquarius Prime Pink contains hypromellose, titanium dioxide, polyethylene glycol, talc, red iron oxide and yellow iron oxide
  • step c) the granules of step c) were mixed with poloxamer 188 (13 mg), colloidal silicon dioxide (2.4 mg), croscarmellose sodium (4,20mg) and magnesium stearate (3.6 mg) to obtain granule mixture; e. the granules of step d) were compressed to obtain tablets; and f. the tablets were coated with Aquarius Prime Pink (15 mg).
  • Example 4 Dissolution data of Example 1 and Example 2 at pH: 4,5 Acetate + 0.1% SLS, 900 ml, 50 rpm with USP apparatus II at 37° C
  • example-1 , example-2 and reference product Stivarga® tablets were performed using standard USP apparatus II, paddles, at 50 rpm in 900 ml at pH: 4.5 Acetate + 0.1 % SLS. The drug release was determined by using an HPLC method. From the above dissolution data, It is evident that dissolution of example-1 (extragranular poloxamer) is better than example-2 (extragranular Eudragit® E PO). When f2 value of example-1 (extragranular poloxamer) is more than 50 indicates the sameness or equivalence of both example-1 (extragranular poloxamer) and reference product in terms of its dissolution.
  • Example 5 Stability Result of Example 1
  • Example 1 The tablets prepared in Example 1 were packed in HDPE bottles together with silica gel and stored for 30 days under conditions of 25°C/60% RH and 30 °C, 75% RH. The results of performed stability testing is shown herein below table- 5. Table-5
  • the pharmaceutical composition comprising intragranular component comprising regorafenib and extragranular component comprising poloxamer, not only provides storage stable composition but also, shows similar impurity profile and bioequivalence profile when compared to the reference product Stivarga® tablet.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Preparation (AREA)

Abstract

La présente invention concerne une composition pharmaceutique comprenant : (i) un composant intragranulaire comprenant du régorafénib et au moins un excipient pharmaceutiquement acceptable, et (ii) un composant extragranulaire comprenant un poloxamère (copolymère polyoxyéthylène-polyoxypropylène) et au moins un excipient pharmaceutiquement acceptable. L'invention concerne en outre un procédé de préparation de ladite composition pharmaceutique et son utilisation pour le traitement de troubles.
PCT/TR2024/050229 2023-03-10 2024-03-08 Composition pharmaceutique de régorafénib WO2024191389A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
TR2023002707 2023-03-10
TR2023/002707 TR2023002707A2 (tr) 2023-03-10 Regorafenib içeren bir farmasötik bileşim.

Publications (1)

Publication Number Publication Date
WO2024191389A1 true WO2024191389A1 (fr) 2024-09-19

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/TR2024/050229 WO2024191389A1 (fr) 2023-03-10 2024-03-08 Composition pharmaceutique de régorafénib

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WO (1) WO2024191389A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20140065212A1 (en) * 2012-09-06 2014-03-06 Bayer Healthcare Llc Coated pharmaceutical composition containing regorafenib
CN113018274A (zh) * 2021-03-10 2021-06-25 药源生物科技（启东）有限公司 一种含羟丙甲纤维素的药物组合物及其制备方法
WO2021156172A1 (fr) * 2020-02-07 2021-08-12 Bayer Aktiengesellschaft Composition pharmaceutique contenant du régorafénib et un agent stabilisant

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20140065212A1 (en) * 2012-09-06 2014-03-06 Bayer Healthcare Llc Coated pharmaceutical composition containing regorafenib
WO2021156172A1 (fr) * 2020-02-07 2021-08-12 Bayer Aktiengesellschaft Composition pharmaceutique contenant du régorafénib et un agent stabilisant
CN113018274A (zh) * 2021-03-10 2021-06-25 药源生物科技（启东）有限公司 一种含羟丙甲纤维素的药物组合物及其制备方法

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