EP4673118A2 - Composition de lenvatinib à biodisponibilité améliorée - Google Patents

Composition de lenvatinib à biodisponibilité améliorée

Info

Publication number
EP4673118A2
EP4673118A2 EP24712411.8A EP24712411A EP4673118A2 EP 4673118 A2 EP4673118 A2 EP 4673118A2 EP 24712411 A EP24712411 A EP 24712411A EP 4673118 A2 EP4673118 A2 EP 4673118A2
Authority
EP
European Patent Office
Prior art keywords
lenvatinib
salt
pharmaceutical composition
amount
minutes
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.)
Pending
Application number
EP24712411.8A
Other languages
German (de)
English (en)
Inventor
Jessica Schönborn
Niklas RENNER
Andreas WIEDERER
Hao Chen
Jun Liu
Shuhua Chen
Zhiguo Zheng
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.)
Zhejiang Hisun Pharmaceutical Co Ltd
Stada Arzneimittel AG
Original Assignee
Zhejiang Hisun Pharmaceutical Co Ltd
Stada Arzneimittel AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Zhejiang Hisun Pharmaceutical Co Ltd, Stada Arzneimittel AG filed Critical Zhejiang Hisun Pharmaceutical Co Ltd
Publication of EP4673118A2 publication Critical patent/EP4673118A2/fr
Pending 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1611—Inorganic compounds
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds

Definitions

  • alkaline excipients are included in the pharmaceutical composition.
  • Suitable alkaline excipients are for example sodium carbonates and alkaline earth metal carbonates such as magnesium carbonate and calcium carbonate.
  • the content of the components (A) and (B) is not limited, and as long as it contains a small amount, it can have an effect of improving dissolution and increasing stability.
  • the content of component (A) may range from 0.5% to 90%, preferably from 1% to 50%, more preferably from 1 to 35%, most preferably 5-20%, based on the total weight of the composition.
  • the component (B) is present in an amount of from 0.5% to 90% by weight based on the total weight of the composition; preferably from 1% to 50%; more preferably from 1% to 25%; most preferably from 10% to 15%.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective dose of Lenvatinib salt and potassium carbonates, wherein the weight ratio of Lenvatinib salt to potassium carbonates is selected within a range from 1 : 0.3 to 1 : 2.0.
  • the present inventors have found that by addition of a low amount of potassium carbonates gelification of the pharmaceutical composition can be supressed such that a quick disintegration of the composition at a pH as present in the gastrointestinal tract, in particular in the stomach, can be achieved. Further, the pharmaceutical is stable under long- term storage and quick dissolution is maintained.
  • the pharmaceutical composition of the present invention is excellent in dissolution of the Lenvatinib salt, which is the active ingredient.
  • the pharmaceutical composition is also excellent in long-term stability. Quick disintegration of the pharmaceutical composition is prevented even after long term storage .
  • Fig. 1 is a diagram displaying the saturation solubility of Lenvatinib mesylate at 37 ⁇ 1°C;
  • Potassium carbonates within this invention encompass potassium carbonate (K2CO3), potassium hydrogen carbonate (KHCO3), or mixtures of both.
  • a preferred carbonate within the invention is potassium hydrogen carbonate.
  • potassium carbonates In the acidic environment of the gastrointestinal tract, potassium carbonates produce carbon dioxide gas, which acts as a disintegrating agent and allows Lenvatinib salt to disperse in very small fine particles thereby avoiding gelation.
  • the alkaline nature of the potassium carbonates prevents degradation and.reduces impurity formation, including genotoxic impurities that may be formed upon hydrolysation of Lenvatinib salt.
  • the stability and the disintegration properties of these carbonates are such that Lenvatinib salt basically can be formulated without the addition of an extra dis integrant.
  • Lenvatinib salts to be used according to the invention are mesylate, esylate, tosylate, besylate, phosphate, camphorsulphonate, isethionate, napadisylate, sulphate, bromide or chloride salt.
  • the pharmaceutical composition comprises the Lenvatinib salt in an amount of from 10 mg to 15 mg, preferably in an amount of 12.25 mg.
  • the pharmaceutical composition of the invention may also contain a glidant.
  • Glidants enhance product flow by reducing interparticulate friction.
  • a suitable example is colloidal silicon dioxide.
  • Lubricants and glidants preferably are used in a total amount of from 0.05% to 5% by weight based on the total weight of the composition.
  • the composition further comprises: a) at least one diluent, preferably in an amount of from 35% to 90% by weight, preferably in an amount from 50% to 85% by weight based on the total weight of the composition; b) optionally, a disintegrant in an amount of from 1% to 30% by weight based on the total weight of the composition; c) optionally, a binder in an amount from 2% to 10% by weight based on the total weight of the composition d) optionally, a lubricant in an amount of from 1 to 5% by weight based on the total weight of the composition.
  • the diluent is a mixture of mannitol and MCC and wherein the weight ratio of Lenvatinib salt to mannitol is selected within a range from 1 : 0.1 to 1 : 1.0, preferably selected within a range from 1 : 0.5 to 1 : 1.0.
  • the pharmaceutical composition when added to a test medium comprising 900 mL of 0.1 N HC1 at 37°C in a standard USP 2 rotating paddle apparatus with the paddles spinning at 50 rpm dissolves: (a) 0 % to 5 % of the Lenvatinib salt in 5 minutes; (b) 24 % to 36 % of the Lenvatinib salt in 10 minutes; and (c) more than 50 % of the Lenvatinib salt in 20 minutes .
  • composition when added to a test medium comprising 900 mL of 0.1 N HC1 at 37°C in a standard USP 2 rotating paddle apparatus with the paddles spinning at 50 rpm dissolves: (a) 1 % to 5 % of the Lenvatinib salt in 5 minutes; (b) 27 % to 33 % of the Lenvatinib salt in 10 minutes; and (c) more than 57 % of the Lenvatinib salt in 20 minutes.
  • the pharmaceutical composition when added to a test medium comprising 900 mL of 10 mM pH 4.5 acetate buffer at 37°C in a standard USP 2 rotating paddle apparatus with the paddles spinning at 50 rpm dissolves: (a) 0 % to 5 % of the Lenvatinib salt in 5 minutes; (b) 11 % to 17 % of the Lenvatinib salt in 10 minutes; and (c) 25 % to 37 % of the Lenvatinib salt in 20 minutes.
  • the pharmaceutical composition of the present invention can be prepared by a method common in the art, for example, high shear wet granulation, dry granulation, one-step granulation, etc., to prepare granules of a pharmaceutical composition, and then filled into capsules to prepare a hard capsule.
  • the pharmaceutical composition of the present invention is prepared by a granulation process or by a simple mixing process whereby a non-granulated powder is obtained.
  • the pharmaceutically acceptable excipients to be used in accordance with the present invention can be used only intragranularly, only extragranularly, or both.
  • the pharmaceutical composition according to the invention is prepared by wetgranulation, which process comprises: a. mixing Lenvatinib salt, potassium carbonates wherein the weight ratio of Lenvatinib salt to potassium carbonates ranges from 1 : 0.3 to 1 : 3.0; b. add one or more pharmaceutically acceptable excipients to form a mixture; c. wet -granulating the resulting mixture; d. further mixing the obtained granulate with one or more further pharmaceutically acceptable excipients to form a further mixture; e. Optionally encapsulating the granules
  • the granules of the present invention typically have a particle size distribution Dso of from 200 pm - 350 pm, more preferably from 250 pm - 300 pm.
  • the present invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising granulates as described hereinabove in the form of a capsule or a tablet, preferably a capsule.
  • the equilibrium solubility of Lenvatinib mesylate in different dissolution media at 37 °C ⁇ 1 °C was measured by shake-flask technique.
  • the dissolution media were prepared according to USP.
  • the pH for each test solution was measured after the addition of the drug substance and at the end of the equilibrium solubility study.
  • L-HPC low-substituted hydroxypropyl cellulose
  • a USP apparatus II(paddle) is used,to test the dissolution profile with is a rotation speed of 50 rpm and 900 ml 0.1 N HC1 as a dissolution medium.
  • the temperature is set to 37 °C+ 0.5 °C and the sampling times are 5 min, 10 min, 15 min, 20 min, 30 min, 45 min, 60 min and infinity (15 min with a rotation speed of 150 rpm)
  • Capsules obtained,in examples 1 and 2 are packed in Polyamide- Alu-PVC pack and loaded in a climate chamber adjusted to 60°C/75% RH. After time periods indicated in table 4 a Polyamide -Alu-PVC pack was removed from the climate chamber and a capsule was taken from the pack. The capsule was opened and the ingredients were analysed by HPLC method (shown below) . The total amount of impurities was determined by summing up the peak areas of the HPLC-chromatogram. Peak areas were calculated as percentage of the total area of peaks in the HPLC chromatogram.
  • HPLC methods of related substances are as follows:
  • the capsules of example 2 (formulation with KHCO3) showed good stability.
  • the amount of known/Unknown degradation products is within the ICH guideline Q3b(R2) limits.
  • example 1 (without KHCO3) showed more degradation. After storage in the climate chamber for 10 days a slight colour change to a light brown colour was observed.
  • Capsules were prepared as described for examples 1 and 2 above. The amounts of excipients are summarized in table 5.
  • Table 5 composition of capsules comprising Lenvatinib and varying amounts of KHCO 3
  • composition of capsules of example 7 is the same as in example 2. Dissolution of Lenvatinib capsules-10 mg on Stress stability (60°C/75% RH):
  • Dissolution tests were performed in 900 ml 0.1 N HC1 as described above, however on capsules obtained according to examples 2 and 3 described above and stored in a climate chamber for 5 or 10 days as described above.
  • Dissolution profile of stress stability samples are similar to initial dissolution (in 0.1 N HC1).
  • Lenvatinib capsules with the constitution according to Table 10 have been prepared by means of the process as described for Examples 1 to 8 wherein in the case of Examples 9 and 10 only mixing and no wet granulation occurs.
  • Lenvatinib Mesylate correspond to 10 mg Lenvatinib.
  • MCC micro-crystalline cellulose
  • HPC Hydroxypropyl cellulose
  • L-HPC low-substituted hydroxypropyl cellulose
  • a USP apparatus II(paddle) is used to test the dissolution profile with a rotation speed of 50 rpm in the dissolution medium.
  • the temperature is set to 37 °C ⁇ 0.5 °C and the sampling times are 5 min, 10 min, 15 min, 20 min, 30 min, 45 min
  • Table 11 Dissolution profile of capsules of examples 9, 10 and 11, 0.1 N HC1; 900 ml; Paddle at 50 rpm speed; with sinker, 6 units have been tested
  • Fig. 2 shows the dissolution profile of Example 9 of the composition according to the present invention in 0.1 N HC1 at 37 + 0.5 °C and at a paddle speed of 50 rpm in comparison with the Levatinib originator capsules marketed under the trademark name Lenvima®.
  • Fig. 3 shows the dissolution profile of Example 9 of the composition according to the present invention in acetate buffer at pH 4.5, at 37 + 0.5 °C and at a paddle speed,of 50 rpm in comparison with Lenvima®.
  • Lenvatinib capsules with,the constitution according to Table 13 have been prepared by means of the process as described for Examples 1 to 8 wherein in the case of Examples 12 and 13 only mixing and no wet granulation occurs.
  • Lenvatinib Mesylate correspond to 10 mg Lenvatinib.
  • MCC micro-crystalline cellulose
  • HPC Hydroxypropyl cellulose
  • L-HPC low-substituted hydroxypropyl cellulose
  • a USP apparatus II(paddle) is used to test the dissolution profile with a rotation speed of 50 rpm in the dissolution medium.
  • the temperature is set to 37 °C ⁇ 0.5 °C and the sampling times are 5 min, 10 min, 15 min, 20 min, 30 min, 45 min , 60 min and infinity (15 min with a rotation speed of 150 rpm )
  • Table 14 Dissolution profile of capsules of examples 12, 13 and 14, 0.1 N HC1; 900 ml; Paddle at 50 rpm speed; with sinker, 6 units have been tested
  • Table 15 Dissolution profile of capsules of examples 12, 13 and 14, acetate buffer, pH 4.5; 900 ml; Paddle at 50 rpm speed; with sinker, 6 units have been tested relative standard deviation

Landscapes

  • Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Inorganic Chemistry (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne une composition pharmaceutique comprenant une dose thérapeutiquement efficace de sel de Lenvatinib et de carbonates de potassium, en particulier du carbonate d'hydrogène de potassium, le rapport en poids du sel de Lenvatinib aux carbonates de potassium étant sélectionné dans une plage de 1:0,3 à 1:3,0.
EP24712411.8A 2023-02-28 2024-02-28 Composition de lenvatinib à biodisponibilité améliorée Pending EP4673118A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP23159148.8A EP4424303A1 (fr) 2023-02-28 2023-02-28 Composition de lenvatinib présentant une biodisponibilité améliorée
PCT/EP2024/055150 WO2024180153A2 (fr) 2023-02-28 2024-02-28 Composition de lenvatinib à biodisponibilité améliorée

Publications (1)

Publication Number Publication Date
EP4673118A2 true EP4673118A2 (fr) 2026-01-07

Family

ID=85410207

Family Applications (2)

Application Number Title Priority Date Filing Date
EP23159148.8A Pending EP4424303A1 (fr) 2023-02-28 2023-02-28 Composition de lenvatinib présentant une biodisponibilité améliorée
EP24712411.8A Pending EP4673118A2 (fr) 2023-02-28 2024-02-28 Composition de lenvatinib à biodisponibilité améliorée

Family Applications Before (1)

Application Number Title Priority Date Filing Date
EP23159148.8A Pending EP4424303A1 (fr) 2023-02-28 2023-02-28 Composition de lenvatinib présentant une biodisponibilité améliorée

Country Status (3)

Country Link
EP (2) EP4424303A1 (fr)
CN (1) CN121038782A (fr)
WO (1) WO2024180153A2 (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN120837446B (zh) * 2025-09-23 2025-12-26 浙江奥翔药业股份有限公司 一种甲磺酸仑伐替尼胶囊及其制备方法

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
MY162940A (en) 2009-08-19 2017-07-31 Eisai R&D Man Co Ltd Quinoline derivative-containing pharmaceutical composition
CN106139156B (zh) 2014-11-14 2019-01-29 江苏恒瑞医药股份有限公司 一种含有喹啉衍生物或其盐的药物组合物
WO2017028660A1 (fr) * 2015-08-17 2017-02-23 江苏恒瑞医药股份有限公司 Composition pharmaceutique contenant un dérivé de la quinoléine ou un sel correspondant
PL3384901T3 (pl) 2017-04-04 2025-01-13 Synthon B.V. Kompozycja farmaceutyczna zawierająca mesylan lenwatynibu
PT3632436T (pt) 2018-10-04 2022-07-22 Synthon Bv Composição farmacêutica compreendendo sais de lenvatinib
EP4147689A1 (fr) * 2021-09-13 2023-03-15 Lotus Pharmaceutical Co., Ltd. Formulation de lenvatinib

Also Published As

Publication number Publication date
CN121038782A (zh) 2025-11-28
WO2024180153A3 (fr) 2024-11-14
WO2024180153A2 (fr) 2024-09-06
EP4424303A1 (fr) 2024-09-04

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