WO2022079591A1 - Composition pharmaceutique de lasmiditan et procédé de préparation associé - Google Patents

Composition pharmaceutique de lasmiditan et procédé de préparation associé Download PDF

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Publication number
WO2022079591A1
WO2022079591A1 PCT/IB2021/059337 IB2021059337W WO2022079591A1 WO 2022079591 A1 WO2022079591 A1 WO 2022079591A1 IB 2021059337 W IB2021059337 W IB 2021059337W WO 2022079591 A1 WO2022079591 A1 WO 2022079591A1
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WO
WIPO (PCT)
Prior art keywords
pharmaceutical
pharmaceutical composition
lasmiditan
hemisuccinate
subject matter
Prior art date
Application number
PCT/IB2021/059337
Other languages
English (en)
Inventor
Sagar SHETH
Mehul UMARAVKAR
Viral Vaidya
Original Assignee
Alembic Pharmaceuticals Limited
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 Alembic Pharmaceuticals Limited filed Critical Alembic Pharmaceuticals Limited
Publication of WO2022079591A1 publication Critical patent/WO2022079591A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • 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
    • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
    • 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
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose

Definitions

  • the present subject matter relates to a solid oral pharmaceutical composition
  • a solid oral pharmaceutical composition comprising lasmiditan or a pharmaceutically acceptable salt thereof and at least one pharmaceutical acceptable excipient, wherein the solid oral pharmaceutical composition is prepared by a dry manufacturing process.
  • Lasmiditan (COL-144, LY573144) is a serotonin (5-HT) IF receptor agonist. It was developed by CoLucid (now part of Eli Lilly) for the treatment of migraine. Lasmiditan is available as hemisuccinate salt and is also known by its chemical name: 2,4,6- trifluoro- N- [6-(l- methylpiperidine -4- carbonyl) pyridine-2-yl] benzamide hemisuccinate salt and is reported to have the following chemical structure:
  • Lasmiditan is approved in the USA as 50 mg and 100 mg film coated tablets under the brand name Reyvow®. It is administered orally, as needed, with or without food for the acute treatment of migraine with or without aura in adults.
  • Lasmiditan hemisuccinate is a white, crystalline powder that is sparingly soluble in water, slightly soluble in ethanol, and soluble in methanol. A 1 mg/mL aqueous solution of lasmiditan hemisuccinate is estimated to have a pH of 6.8 at ambient conditions.
  • United States Patent No. US8748459 discloses lasmiditan and its hemisuccinate salt. It further discloses method of treatment of migraine in a mammal comprising administering to a mammal effective amount of lasmiditan or salt thereof.
  • US20100256187 discloses oral delivery compositions comprising 50 to 200mg of lasmiditan or salt therefore for the treatment of migraine.
  • US’ 187 publication also discloses lasmiditan compositions in the form of dry powder inhaler, tablet, capsule, suspension, intravenous formulation, sublingual or buccal tablet.
  • the sublingual and buccal tablets are also disclosed with HC1 and succinate salts of lasmiditan. It further discloses specific tablets containing certain excipients and also discloses wet granulation as manufacturing process for one such tablet.
  • United States Patent No. US8697876 discloses solid crystalline Form A, Form B and Form C of lasmiditan hemisuccinate.
  • US2020087279 discloses new pseudo-polymorphic crystalline Form D, Form E and Form F of lasmiditan hemisuccinate. It also discloses that starting with either Form A or the amorphous form of lasmiditan hemisuccinate, addition of water alone or water/solvent mixtures results in the conversion from Form A or the amorphous form to one of the pseudo-polymorphic Forms D, E, or F.
  • Form A is the dominant form in the absence of water (up to 10% by volume of water; a water activity of approximately 0.6) or at low water activities, e.g. in pure ethanol, at any temperature. At higher water activities, temperature and water content are determinative.
  • the present subject matter relates to a solid oral pharmaceutical composition comprising lasmiditan or its pharmaceutically acceptable salt there of as an active ingredient and at least one excipients, wherein the solid oral pharmaceutical composition is prepared by dry manufacturing process.
  • the present subject matter also relates to a non-aqueous wet granulation process.
  • the present subject matter relates to a solid oral pharmaceutical composition
  • a solid oral pharmaceutical composition comprising lasmiditan or its pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient, wherein the solid oral pharmaceutical composition is prepared by a dry manufacturing process.
  • the present subject matter relates to solid oral pharmaceutical composition
  • solid oral pharmaceutical composition comprising lasmiditan hemisuccinate as an active ingredient and at least one excipient, wherein the solid oral pharmaceutical composition is prepared by a dry manufacturing process.
  • the dry manufacturing process according to the subject matter refers to processes such as direct compression process, dry granulation process, roller compaction etc.
  • Another objective of the present subject matter is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising,
  • Another objective of the present subject matter is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising,
  • Another objective of the present subject matter is to provide pharmaceutical composition comprising,
  • Another objective of the present subject matter is to provide a pharmaceutical composition comprising,
  • Another objective of the present subject matter is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising,
  • Another objective of the present subject matter is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising,
  • Another objective of the present subject matter is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising,
  • Another objective of the present subject matter is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising,
  • the present subject matter relates to a solid oral pharmaceutical composition
  • a solid oral pharmaceutical composition comprising lasmiditan or a pharmaceutically acceptable salt thereof as an active ingredient, at least one pharmaceutically acceptable excipient, where in the solid oral pharmaceutical composition is prepared by a dry manufacturing process.
  • the dry manufacturing process according to the subject matter refers to a process generally known in the art.
  • Non-limiting examples of such processes are direct compression process, dry granulation process, roller compaction etc.
  • the non-aqueous wet granulation process according to the subject matter refers to a process generally known in the art such as rapid mixer granulation, fluidized bed granulation, spray granulation etc.
  • solvent used in non-aqueous wet granulation process is selected from isopropyl alcohol, ethanol, methanol, acetone, dichloromethane, acetonitrile or mixture thereof.
  • composition may comprise lasmiditan in the ‘free base form’ or as a pharmaceutically acceptable salt, or as any mixture thereof.
  • lasmiditan present in pharmaceutical composition is in the form of hemisuccinate salt form.
  • lasmiditan hemisuccinate is in crystalline form.
  • lasmiditan hemisuccinate crystalline form is polymorphic Form A (wherein polymorphic Form A of the lasmiditan hemisuccinate may be defined in any of the ways described in United States Patent No. US8697876).
  • crystalline lasmiditan hemisuccinate salt exhibits an x-ray diffraction pattern using Cu-Ka radiation includes peaks at about 15.3, 16.4, 19.3, 22.1, 23.6 and 25.9 degrees 29.
  • composition comprising,
  • composition comprising,
  • Suitable diluents can be selected from the group of, but not limited to microcrystalline cellulose (MCC), pregelatinized starch, sugar and sugar alcohol such as mannitol, lactose, fructose, isomalt, lactitol, maltitol, sorbitol, erythritol, maltose, polydextrose, sucrose, trehalose, xylitol, calcium carbonate, dicalcium phosphate, calcium sulfate, cellulose acetate, ethylcellulose, inulin, magnesium carbonate, magnesium oxide, maltodextrin, sodium bicarbonate, sodium carbonate and sodium chloride.
  • MCC microcrystalline cellulose
  • sugar alcohol such as mannitol, lactose, fructose, isomalt, lactitol, maltitol, sorbitol, erythritol, maltose, polydextrose, sucrose, trehalose,
  • the diluent is microcrystalline cellulose.
  • binder is intended to be interpreted in the context of pharmaceutical formulation science.
  • Suitable binder according to the present subject matter can be selected from the group of, but not limited to povidone, pregelatinized starch, cellulose, methyl cellulose, ethyl cellulose, cellulose derivatives (e.g., hydroxypropyl methyl cellulose (HPMC), hydroxypropyl cellulose (HPC)), and polyethylene glycol.
  • the binder is povidone.
  • disintegrant and “disintegrants” are intended to be interpreted in the context of pharmaceutical formulation science.
  • Suitable disintegrants according to the present subject matter can be selected from but not limited to croscarmellose sodium (CCS), sodium starch glycolate (SSG), pregelatinized starch, alginic acid, sodium alginate, carboxymethylcellulose calcium, chitosan, crospovidone, glycine, guar gum, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, magnesium aluminum silicate, methylcellulose, povidone, sodium alginate, sodium carboxymethylcellulose and starch.
  • CCS croscarmellose sodium
  • SSG sodium starch glycolate
  • pregelatinized starch alginic acid, sodium alginate, carboxymethylcellulose calcium, chitosan, crospovidone, glycine, guar gum, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, magnesium aluminum si
  • one or more disintegrants are selected from the group of croscarmellose sodium, pregelatinized starch or a mixture thereof.
  • Suitable pharmaceutical surfactant can be selected from but not limited to sodium lauryl sulfate (SLS), poloxamers, polysorbate, sodium dodecyl benzene sulfonate, alkali metal or ammonium salts of lauroyl sarcosinate, myristoyl sarcosinate, palmitoyl sarcosinate, stearoyl sarcosinate and oleoyl sarcosinate, polyoxyethylene sorbitan monostearate, isostearate and laurate, sodium lauryl sulfoacetate, N-lauroyl sarcosine, the sodium, potassium, and ethanolamine salts of N-lauroyl, N-myristoyl or N-palmitoyl sarcosine, polyethylene oxide condensates of alkyl phenol
  • the surfactant is sodium lauryl sulphate.
  • lubricant and “lubricants” are intended to be interpreted in the context of pharmaceutical formulation science.
  • Suitable pharmaceutical lubricant according to the present subject matter can be selected from but not limited to magnesium, aluminium, zinc or calcium stearate, glyceryl behenate, glyceryl dibehenate, glyceryl monostearate, glyceryl palmitostearate, a mixture of behenate esters of glycerine (e.g.
  • glyceryl dibehenate tribehenin and glyceryl behenate
  • magnesium stearate myristic acid, palmitic acid, stearic acid, talc, tribehenin, sodium stearyl fumarate (SSF) and sucrose stearate.
  • SSF sodium stearyl fumarate
  • the one or more pharmaceutical lubricants comprise magnesium stearate, stearic acid or a mixture thereof.
  • the lubricant is magnesium stearate.
  • Glidants are frequently used in tablet formulations to improve flow.
  • glidant and “glidants” are intended to be interpreted in the context of pharmaceutical formulation science.
  • Suitable glidants according to the present subject matter can be selected from but not limited to magnesium oxide, colloidal silicon dioxide, pyrogenic silica and hydrated sodium silicoaluminate.
  • glidant is colloidal silicon dioxide.
  • a pharmaceutical tablet comprising the pharmaceutical composition as defined herein.
  • a pharmaceutical tablet comprising a pharmaceutical composition in the form of tablet core, wherein the tablet core is coated with a layer of coating.
  • the coating is a film coating.
  • the film coating may be applied using conventional methods.
  • a coating can be used to provide protection against, for example, moisture ingress or degradation by light, to colour the formulation or to modify or control the release of lasmiditan hemisuccinate from the formulation.
  • the pharmaceutical composition is a pharmaceutical tablet composition (for oral administration).
  • the pharmaceutical composition is a pharmaceutical tablet composition suitable for oral administration to a human.
  • the pharmaceutical composition is a pharmaceutical tablet composition suitable for oral administration for the treatment of migraine.
  • the pharmaceutical tablet comprises 100 mg lasmiditan free base, equivalent to 115.65 mg of lasmiditan hemisuccinate respectively.
  • the pharmaceutical tablet comprises 50 mg lasmiditan free base, equivalent to 57.824 mg of lasmiditan hemisuccinate respectively.
  • a pharmaceutical composition as defined herein, for the manufacture of a medicament for the treatment of migraine.
  • a pharmaceutical composition for use as a medicament.
  • a pharmaceutical composition is a pharmaceutical tablet.
  • a method of acute treatment of migraine with or without aura in adults in need thereof comprises the oral administration of the pharmaceutical tablet(s), as needed, to the patient.
  • lasmiditan hemisuccinate tablet is prepared by dry manufacturing process or a non-aqueous wet manufacturing process.
  • Table 2 Pharmaceutical composition of Lasmiditan hemisuccinate.
  • Lasmiditan hemisuccinate, microcrystalline cellulose (Avicel PH 112), povidone, croscarmellose sodium (Ac-di-sol) and sodium lauryl sulfate were sifted and mixed properly to get uniform blend.
  • Magnesium stearate was sifted and a blend obtained in step 1 was lubricated using magnesium stearate in step 2.
  • step 3 The lubricated blend of step 2 was compressed into tablets. Core tablets were coated using Opadry dispersion with inlet temperature of 60-65°C and product temperature 38-44°C.
  • Above example 2 can be prepared using a dry manufacturing process, e.g. direct compression process, dry granulation process, roller compaction etc.
  • Dissolution tests The dissolution described herein was performed according to the general procedure of the United States Pharmacopoeia using Apparatus II (Paddle), at 75 rpm with 500 ml of 0.01N HC1 media at a temperature of 37° C. The samples were withdrawn at 5, 10, 15, 20 and 30 minutes.
  • the intragranular material was sifted and mixed properly to get uniform blend.
  • Magnesium stearate was sifted and a blend obtained in step 1 was lubricated using magnesium stearate in step 2.
  • step 3 The lubricated blend of step 2 was compressed into tablets. Core tablets were coated using Opadry dispersion with inlet temperature of 60-65°C and product temperature of 38-44°C.
  • Step 1 excipients were mixed with lasmiditan and pass through Quadro comil with 0.610mm screen.
  • step 4 Lubricated blend of step 4 was compressed into tablets. Core tablets were coated using Opadry dispersion with inlet temperature of 60-65°C and product temperature of 38-44°C.
  • Lasmiditan hemisuccinate, microcrystalline cellulose (Avicel PH 112), L- HPC LH-11 and sodium lauryl sulphate were passed through suitable sieve and mixed properly to get uniform blend.
  • step 2 The material obtained in step 1 was subjected to roller compaction and granules were prepared.
  • Step 3 material was lubricated using magnesium stearate and compressed into tablets. Core tablets were coated using Opadry dispersion with inlet temperature of 60-65°C and product temperature of 38-44°C.
  • Lasmiditan hemisuccinate, microcrystalline cellulose (Avicel PH 112), PVPK-30, croscarmellose sodium and sodium lauryl sulphate were passed through suitable sieve and mixed properly to get uniform blend.
  • step 3 The material obtained in step 3 was milled and granules were obtained.
  • Extragranular microcrystalline cellulose (Avicel PH 112) and croscarmellose sodium were sieved and mixed with step 4 granules.
  • Step 5 material was lubricated using magnesium stearate and compressed into tablets. Core tablets were coated using Opadry dispersion with inlet temperature of 60-65°C and product temperature of 38-44°C.
  • Lasmiditan hemisuccinate, sodium lauryl sulfate, microcrystalline cellulose (Avicel PH 112) and L HPC LH 11/ croscarmellose sodium were passed through suitable sieve and mixed properly to get uniform blend.
  • Step 1 material was granulated with solvent (IPA/Ethanol).
  • step 6 Lubricated blend of step 6 was compressed into tablet at target weight i.e. 230 mg.

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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)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicinal Preparation (AREA)

Abstract

La présente invention concerne une composition pharmaceutique orale solide comprenant du lasmiditan ou un sel pharmaceutiquement acceptable associé et au moins un excipient pharmaceutiquement acceptable, la composition pharmaceutique orale solide étant préparée au moyen d'un procédé de fabrication à sec.
PCT/IB2021/059337 2020-10-14 2021-10-12 Composition pharmaceutique de lasmiditan et procédé de préparation associé WO2022079591A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN202021044785 2020-10-14
IN202021044785 2020-10-14

Publications (1)

Publication Number Publication Date
WO2022079591A1 true WO2022079591A1 (fr) 2022-04-21

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ID=81207756

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2021/059337 WO2022079591A1 (fr) 2020-10-14 2021-10-12 Composition pharmaceutique de lasmiditan et procédé de préparation associé

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN100352817C (zh) * 2002-03-29 2007-12-05 伊莱利利公司 用作5－HT1f激动剂的吡啶酰基哌啶
US20130072524A1 (en) * 2010-04-02 2013-03-21 Jean-Francois Carniaux Compositions And Methods Of Synthesis Of Pyridinolypiperidine 5-HT1F Agonists

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN100352817C (zh) * 2002-03-29 2007-12-05 伊莱利利公司 用作5－HT1f激动剂的吡啶酰基哌啶
US20130072524A1 (en) * 2010-04-02 2013-03-21 Jean-Francois Carniaux Compositions And Methods Of Synthesis Of Pyridinolypiperidine 5-HT1F Agonists

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