WO2021133299A1 - Comprimés à désintégration orale comprenant du flurbiprofène et de l'élétriptan - Google Patents

Comprimés à désintégration orale comprenant du flurbiprofène et de l'élétriptan Download PDF

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Publication number
WO2021133299A1
WO2021133299A1 PCT/TR2020/051000 TR2020051000W WO2021133299A1 WO 2021133299 A1 WO2021133299 A1 WO 2021133299A1 TR 2020051000 W TR2020051000 W TR 2020051000W WO 2021133299 A1 WO2021133299 A1 WO 2021133299A1
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WO
WIPO (PCT)
Prior art keywords
orally disintegrating
disintegrating tablet
tablet according
flurbiprofen
eletriptan
Prior art date
Application number
PCT/TR2020/051000
Other languages
English (en)
Inventor
Fatih Sunel
Ediz Yildirim
Yesim YILMAZ MURATOGLU
Original Assignee
Sanovel 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
Application filed by Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi filed Critical Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi
Publication of WO2021133299A1 publication Critical patent/WO2021133299A1/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
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents

Definitions

  • the present invention relates to orally disintegrating tablets comprising flurbiprofen or a pharmaceutically acceptable salt thereof in combination with eletriptan or a pharmaceutically acceptable salt thereof.
  • Flurbiprofen is a propionic acid derivative, also known as NSAID (non-steroidal anti inflammatory drug), having analgesic and anti-inflammatory activities. Its chemical structure is illustrated with Formula 1 given below.
  • Flurbiprofen is used for alleviating pain in muscle-skeleton system and joint disorders such as ankylosing spondylitis, osteoarthritis, and rheumatoid arthritis, in soft tissue injuries such as sprains and strains, in postoperative cases, and in painful and severe menstruation. Flurbiprofen is further used as a lozenge in the symptomatic amelioration of sore throats.
  • 5-FIT is a key mediator in the pathogenesis of migraine.
  • 5-HT 1 -receptor agonists commonly known as the 'triptans', are the mainstay for acute treatment of migraine headaches.
  • Eletriptan is a selective 5-hydroxytryptamine 1 B/1 D receptor agonist (5-HT 1 -receptor agonist). Eletriptan (trade name Relpax ® , used in the form of eletriptan hydrobromide) is a second generation triptan drug intended for treatment of migraine headaches. Its chemical name is 3-[[(2R)-1 -methylpyrrolidin-2-yl]methyl]-5-(2-phenylsulfonylethyl)-1 H-indole and its chemical structure is shown in Formula 2.
  • Formula 2 Eletriptan Eletriptan molecule and the use for the treatment of migraine is first disclosed in the patent application WO9206973.
  • Migraines are likely due to local cranial vasodilatation and/or to the release of sensory neuropeptides (vasoactive intestinal peptide, substance P and calcitonin gene-related peptide) through nerve endings in the trigeminal system.
  • the therapeutic activity of eletriptan for the treatment of migraine headache is thought to be due to the agonist effects at the 5- HT1 B/1 D receptors on intracranial blood vessels (including the arterio-venous anastomoses) and sensory nerves of the trigeminal system which result in cranial vessel constriction and inhibition of pro-inflammatory neuropeptide release.
  • patent application EP2306998 (A1) discloses a combination comprising a 5- HT1 -agonist and a NSAID, but either in this application or in other patent application a pharmaceutical composition comprising flurbiprofen or a pharmaceutically acceptable salt thereof and eletriptan or a pharmaceutically acceptable salt thereof in orally disintegrating tablets dosage form is not specifically disclosed. Moreover, there is no combination of flurbiprofen or a pharmaceutically acceptable salt thereof and eletriptan or a pharmaceutically acceptable salt thereof in the market for the treatment of migraine headache.
  • Flurbiprofen is defined as being a practically insoluble drug. It is also a drug with an acidic group. These factors need to be considered to provide a fast-acting tablet. In addition, relatively fast disintegration of the tablet, facilitating desirable dissolution properties, are particularly valuable characteristics for a therapeutic composition adapted for the treatment of pain where fast onset of action is desirable.
  • composition of the present invention it is desired to provide a dosage form comprising in combination a therapeutically effective amount of flurbiprofen free base or a pharmaceutically acceptable salt thereof and eletriptan free base or a pharmaceutically acceptable salt thereof which overcomes the above described problems.
  • the main challenges when combining those molecules in the same pharmaceutical form are: a) to guarantee desired stability for example; the physico-chemical compatibility between those different active ingredients and/or between the active ingredients and the excipients used; and b) to ensure the pharmaceutical compatibility between those active ingredients regarding their stability characteristics. c) to provide the desired dissolution profile.
  • a combination comprising flurbiprofen free base or a pharmaceutically acceptable salt thereof and eletriptan free base or a pharmaceutically acceptable salt thereof is in the form of orally disintegrating tablets has been developed by using standard techniques which are simple and cost-effective which overcomes the above-described problems in the prior art and has additive advantages over them.
  • the main object of the present invention is to provide orally disintegrating tablets comprising flurbiprofen free base or a pharmaceutically acceptable salt thereof and eletriptan free base or a pharmaceutically acceptable salt thereof with high stability, having desired level of dissolution rate which overcomes the above described problems in the prior art and have additive advantages over them.
  • ODTs Orally disintegrating tablets
  • an orally disintegrating tablet comprises flurbiprofen free base or a pharmaceutically acceptable salt thereof in combination with eletriptan free base or a pharmaceutically acceptable salt thereof.
  • an orally disintegrating tablet comprising flurbiprofen free base or a pharmaceutically acceptable salt thereof in combination with eletriptan free base or a pharmaceutically acceptable salt thereof has been developed with safe and effective dissolution profiles for each drug molecule.
  • the orally disintegrating tablet for use in the treatment of migraine headaches.
  • the amount of flurbiprofen free base or a pharmaceutically acceptable salt thereof is between 10.0% and 40.0% by weight in the tablet.
  • the amount of flurbiprofen free base or a pharmaceutically acceptable salt thereof is between 15.0% and 35.0% or between 20.0% and 30.0% by weight in the tablet.
  • flurbiprofen free base is used.
  • flurbiprofen is present in an amount of between 10mg and 300mg, preferably between 10mg and 200mg and more preferably it is in an amount of between 50mg and 150mg.
  • flurbiprofen is present in an amount of 100mg.
  • the amount of eletriptan free base or a pharmaceutically acceptable salt thereof is between 4.0% and 30.0% by weight in the tablet.
  • the amount of eletriptan free base or a pharmaceutically acceptable salt thereof is between 5.0% and 25.0% or between 5.0% and 20.0% or between 5.0% and 15.0% by weight in the tablet.
  • eletriptan free base is used.
  • eletriptan is present in an amount of between 10mg and 200mg, preferably between 10mg and 150mg and more preferably it is in an amount of between 10mg and 100mg.
  • eletriptan is present in an amount of 40 mg.
  • the ratio of flurbiprofen to eletriptan is in the range of 0.3-10.0 by weight, preferably the ratio is 1.0-6.0 or 2.0 -4.0 by weight.
  • the orally disintegrating tablet further comprises at least one pharmaceutically acceptable excipient which is selected from binders/fillers, disintegrants, lubricants, aroma, flavouring agents, taste masking or mixtures thereof.
  • Suitable fillers/binders are selected from group comprising microcrystalline cellulose, mannitol (i.e. mannitol 60, mannitol DC), Eudragit EPO (dimethylaminoethyl methacrylate, butyl methacrylate, methyl methacrylate), Kollidon VA 64 (vinylpyrrolidone-vinyl acetate copolymers), Soluplus (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft co polymer), lactose monohydrate, starch, dibasic calcium phosphate, tribasic calcium phosphate, trehalose, isomalt, sodium carbonate, sodium bicarbonate, calcium carbonate, carboxymethyl cellulose, polydextrose, polyethylene oxide, hydroxypropyl methyl cellulose, methyl cellulose, polyethylene glycol or mixtures thereof.
  • mannitol i.e. mannitol 60, mannitol DC
  • the amount of fillers/binders is between 20.0% to 65.0% by weight. Preferably, the amount of fillers/binders is between 30.0% to 55.0% by weight. This ratio helps to achieve dissolution profile.
  • the filler/binder is microcrystalline cellulose, mannitol, Eudragit EPO (dimethylaminoethyl methacrylate, butyl methacrylate, methyl methacrylate), Kollidon VA 64 (vinylpyrrolidone-vinyl acetate copolymers), Soluplus (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft co-polymer) or mixtures thereof.
  • the selection of excipients has importance to obtain the ideal disintegrating time during the shelf life.
  • the choice of the disintegrant has a major role in the manufacture of the orally disintegrating tablets. Therefore, the choice of a suitable disintegrant and an optimal use level are critical to ensure a high disintegration rate.
  • Suitable disintegrants are selected from the group comprising mannitol DC 400, crospovidone (Kollidon CL-SF), croscarmellose sodium (cross-linked carboxymethyl cellulose), polyvinylpyrrolidone, low-substituted hydroxypropyl cellulose, pregelatinized starch, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, docusate sodium, guar gum, polyacrylate potassium, sodium alginate, corn starch, sodium starch glycolate, alginic acid, alginates, ion-exchange resins, magnesium aluminum silica, poloxamer, sodium glycine carbonate or mixtures thereof.
  • the amount of disintegrant is between 5.0% to 30.0% by weight.
  • the amount of disintegrant is between 7.0% to 25.0% by weight.
  • the disintegrant is mannitol DC 400, crospovidone (Kollidon CL-SF), croscarmellose sodium (cross-linked carboxymethyl cellulose) or mixtures thereof.
  • Suitable lubricants are selected from the group comprising colloidal silicon dioxide, sodium stearyl fumarate, magnesium stearate, calcium stearate, zinc stearate, talc, hydrogenated vegetable oil, sodium chlorate, magnesium lauryl sulfate, sodium oleate, sodium acetate, sodium benzoate, glyceryl palmate sulphate, sodium lauryl sulphate or mixtures thereof.
  • the amount of lubricants is between 0.5% to 5.0% by weight.
  • the lubricant is colloidal silicon dioxide, sodium stearyl fumarate or mixtures thereof.
  • Suitable aromas are selected from the group comprising peppermint, tutti frutti, menthol, cinnamon, chocolate, vanillin, fruit essences, cherry, orange, strawberry, grape, black currant, raspberry, banana, red fruits, wild berries, cardamom, anise, ethyl vanillin or mixtures thereof.
  • the amount of aroma is between 0.5% to 5.0% by weight.
  • the aroma is peppermint, tutti frutti or mixtures thereof.
  • Suitable flavoring agents are selected from the group comprising sucralose, sugar alcohols, sugars, liquid glucose, sucrose, saccharine sodium, xylitol, sorbitol, erythritol or mixtures thereof.
  • the amount of flavoring agent is between 0.05% to 3.0% by weight.
  • the flavoring agent is sucralose.
  • Suitable taste masking agents are selected from the group comprising Eudragit EPO (dimethylaminoethyl methacrylate, butyl methacrylate, methyl methacrylate), stearic acid, Carbomer-934, Carbomer 974 or mixtures thereof.
  • the amount of taste masking agents is between 1.0% to 10.0% by weight.
  • the taste masking agent is Eudragit EPO (dimethylaminoethyl methacrylate, butyl methacrylate, methyl methacrylate), stearic acid or mixtures thereof.
  • the orally disintegrating tablet of the present invention can be prepared, using standard techniques and manufacturing processes well known in the art, such as direct compression, wet or dry granulation, hot melt granulation, hot melt extrusion, fluidized bed granulation, extrusion/spheronization, slugging, spray drying and solvent evaporation.
  • the orally disintegrating tablet is obtained by using a wet granulation method or hot melt extrusion.
  • the orally disintegrating tablet is obtained by using a wet granulation method.
  • Granulation solution is used in the method.
  • Suitable granulation solutions are selected from a group comprising pure water, ethyl alcohol, glycerin, sorbitol, polyethylene glycol, propylene glycol, isopropyl alcohol, or mixtures thereof, preferably granulation solution is pure water.
  • the orally disintegrating tablet is obtained by using hot melt extrusion.
  • polymers are used as dispersion carrier.
  • the polymers are selected from the above described binders/fillers group.
  • Example 1 Example 2:
  • Example 3 Example 4: Combination comprising flurbiprofen and eletriptan processed by wet granulation q.s.: quantity sufficient
  • Example 5 Combination comprising flurbiprofen and eletriptan processed by wet granulation q.s.: quantity sufficient
  • the process for the preparation of the combination comprises the following steps: a) Adding flurbiprofen, eletriptan, mannitol 60, microcrystalline cellulose, Kollidon CL-SF, mannitol DC 400, peppermint, tutti frutti, sucralose and then, mixing, b) Preparing granulation solution using stearic acid, Eudragit (EPO) in water, c) Mixing the mixture at step (a) with the granulation solution at step (b) and obtained a granulation, d) After drying the granulation, dry grinding is performed, e) Adding colloidal silicon dioxide and sodium stearyl fumarate and mixing, f) The resulting final granules are compressed to tablet.
  • Example 6 Combination comprising flurbiprofen and eletriptan processed by hot melt extrusion q.s.: quantity sufficient
  • Fillers/binders is microcrystalline cellulose PH 101 or Eudragit EPO or Kollidon VA 64 or Soluplus or mixtures thereof.
  • Example 7 Combination comprising flurbiprofen and eletriptan processed by hot melt extrusion q.s.: quantity sufficient
  • Fillers/binders is microcrystalline cellulose PH 101 or Eudragit EPO or Kollidon VA 64 or Soluplus or mixtures thereof.
  • the process for the preparation of the combination comprises the following steps: a) Adding flurbiprofen, eletriptan and fillers/binders * and then, mixing, b) Passing through the extruder in the temperature range of 100°C-180°C, c) Sieving the mixture, d) Mixing the mixture at step (c), mannitol DC, croscarmellose sodium, peppermint, tutti frutti, sucralose, microcrystalline cellulose, e) Adding colloidal silicon dioxide and mixing, f) Adding sodium stearyl fumarate and mixing, g) Then, pressing to form orally disintegrating tablets.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
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  • Pain & Pain Management (AREA)
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  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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Abstract

La présente invention concerne des comprimés à désintégration orale comprenant du flurbiprofène ou un sel pharmaceutiquement acceptable de celui-ci en combinaison avec de l'élétriptan ou un sel pharmaceutiquement acceptable de celui-ci.
PCT/TR2020/051000 2019-12-27 2020-10-27 Comprimés à désintégration orale comprenant du flurbiprofène et de l'élétriptan WO2021133299A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
TR2019/21902 2019-12-27
TR2019/21902A TR201921902A1 (tr) 2019-12-27 2019-12-27 Flurbiprofen ve eletriptan içeren ağızda dağılan tabletler

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WO2021133299A1 true WO2021133299A1 (fr) 2021-07-01

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PCT/TR2020/051000 WO2021133299A1 (fr) 2019-12-27 2020-10-27 Comprimés à désintégration orale comprenant du flurbiprofène et de l'élétriptan

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WO (1) WO2021133299A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6586458B1 (en) * 1996-08-16 2003-07-01 Pozen Inc. Methods of treating headaches using 5-HT agonists in combination with long-acting NSAIDs
WO2008124081A2 (fr) * 2007-04-04 2008-10-16 Teva Pharmaceutical Industries Ltd. Dissolution rapide de produits de combinaison
WO2019190433A2 (fr) * 2017-12-15 2019-10-03 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi Compositions pharmaceutiques de flurbiprofène et d'agonistes du récepteur 5-ht1

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6586458B1 (en) * 1996-08-16 2003-07-01 Pozen Inc. Methods of treating headaches using 5-HT agonists in combination with long-acting NSAIDs
WO2008124081A2 (fr) * 2007-04-04 2008-10-16 Teva Pharmaceutical Industries Ltd. Dissolution rapide de produits de combinaison
WO2019190433A2 (fr) * 2017-12-15 2019-10-03 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi Compositions pharmaceutiques de flurbiprofène et d'agonistes du récepteur 5-ht1

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TR201921902A1 (tr) 2021-07-26

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