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WO2024144413A1 - Composition pharmaceutique liquide pour administration nasale contenant du rizatriptan - Google Patents

Composition pharmaceutique liquide pour administration nasale contenant du rizatriptan Download PDF

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Publication number
WO2024144413A1
WO2024144413A1 PCT/RU2022/000396 RU2022000396W WO2024144413A1 WO 2024144413 A1 WO2024144413 A1 WO 2024144413A1 RU 2022000396 W RU2022000396 W RU 2022000396W WO 2024144413 A1 WO2024144413 A1 WO 2024144413A1
Authority
WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
liquid pharmaceutical
composition according
rizatriptan
composition
Prior art date
Application number
PCT/RU2022/000396
Other languages
English (en)
Russian (ru)
Inventor
Юлия Васильевна ВЛАСЕНКО
Мария Андреевна МЕРКУЛОВА
Original Assignee
Общество С Ограниченной Ответственностью "Ферринг Продакшн"
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 Общество С Ограниченной Ответственностью "Ферринг Продакшн" filed Critical Общество С Ограниченной Ответственностью "Ферринг Продакшн"
Priority to PCT/RU2022/000396 priority Critical patent/WO2024144413A1/fr
Publication of WO2024144413A1 publication Critical patent/WO2024144413A1/fr

Links

Classifications

    • 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
    • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4196—1,2,4-Triazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/40—Cyclodextrins; 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/12—Aerosols; Foams
    • 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

  • migraine without aura MB A
  • MA migraine with aura
  • rizatriptan is used orally as an antimigraine drug.
  • Commercially available forms of rizatriptan are tablets containing 5 mg or 10 mg of rizatriptan.
  • the minimum therapeutic dose of rizatriptan administered orally is 5 mg.
  • rizatriptan undergoes first-pass metabolism in the liver, resulting in an average absolute oral bioavailability of approximately 45% 3 (Label, 1998).
  • gastrointestinal disorders such as nausea and vomiting are common complications during migraine attacks, and food intake delays the time to reach maximum blood concentrations by approximately 1 hour. Given these circumstances, it is necessary to develop alternative routes of administration of rizatriptan.
  • nasal gels are not a common dosage form, and therefore dosing devices for them are practically not produced.
  • nasal gels may have disadvantages, such as delayed release of the active substance from the gel matrix.
  • emulsion particles it is possible to achieve both faster and slower release, however, the disadvantage of emulsion forms is their lower rheological stability compared to solutions, as well as the risk of uneven distribution of the active substance in the volume.
  • the concentration of the organic cosolvent in the liquid pharmaceutical composition for nasal administration is in the range of from about 0.5 mg/ml to about 800.0 mg/ml, preferably from 0.5 mg/ml to 400.0 mg/ml , most preferably from 0.5 mg/ml to 50.0 mg/ml.
  • the concentration of the antimicrobial preservative included in the liquid pharmaceutical composition for nasal administration is in the range of about 0.01 mg/ml to about 2.0 mg/ml, preferably in the range of about 0.05 mg/ml to approximately 1.2 mg/ml.
  • the buffering agents included in the liquid pharmaceutical composition for nasal administration to stabilize the pH in the range of 4.0 to 7.0 are selected from acetic acid, citric acid, succinic acid, sodium acetate, sodium citrate, phosphoric acid, sodium phosphate, sodium hydroxide or their solvates, hydrates or other salts, and where these buffering agents are used in combination.
  • the concentration of buffering agents included in the liquid pharmaceutical composition for nasal administration is in the range of from about 0.01 mg/ml to about 10.0 mg/ml.
  • liquid pharmaceutical composition for nasal administration further comprises a thickening agent with or without mucoadhesive properties.
  • the thickener included in the liquid pharmaceutical composition for nasal administration is selected from cellulose or derivatives thereof, or pharmaceutically acceptable salts thereof, polyvinylpyrrolidone or derivatives thereof, acrylic acid derivatives, polyoxyethylene-polyoxypropylene block copolymers.
  • the thickener included in the liquid pharmaceutical composition for nasal administration is selected from one or more than from the group consisting of hydroxyethylcellulose, hydroxypropylcellulose, carboxymethylcellulose, methylcellulose, cellulose and pharmaceutically acceptable salts thereof.
  • the thickener included in the liquid pharmaceutical composition for nasal administration is hydroxyethylcellulose.
  • the concentration of the thickener included in the liquid pharmaceutical composition for nasal administration is in the range of from about 0.01 mg/ml to about 10.0 mg/ml.
  • the pharmaceutically acceptable salt of rizatriptan is rizatriptan benzoate.
  • liquid pharmaceutical composition for nasal administration is used for the treatment of migraine.
  • liquid pharmaceutical composition for nasal administration is used for the treatment of migraine with aura.
  • liquid pharmaceutical composition for nasal administration is used for the treatment of migraine without aura.
  • the treatment is relief or management of headaches associated with migraine attacks.
  • the liquid pharmaceutical composition for nasal administration further comprises an osmolarity-regulating agent.
  • the osmolarity adjusting agent included in the liquid pharmaceutical composition for nasal administration is selected from inorganic salts or polyols.
  • the osmolarity-regulating agent included in the liquid pharmaceutical composition for nasal administration is selected from inorganic salts such as sodium chloride or sodium sulfate.
  • the osmolarity adjusting agent included in the liquid pharmaceutical composition for nasal administration is selected from polyols such as glycerol, mannitol, sorbitol, maltitol, dextrose or sucrose.
  • the concentration of the osmolarity-regulating agent included in the liquid pharmaceutical composition for nasal administration is in the range of from about 0.01 mg/ml to about 100.0 mg/ml.
  • the invention also relates to a dosage form containing the above-described liquid pharmaceutical composition for nasal administration.
  • the dosage form containing the above-described liquid pharmaceutical composition for nasal administration is a metered-dose nasal spray.
  • the present invention also relates to the use of the above-described liquid pharmaceutical composition for nasal administration for the relief or management of headaches associated with migraine attacks with or without aura.
  • the present invention also relates to the use of the above-described dosage form for relieving or stopping headaches during migraine attacks with or without aura.
  • the present invention also relates to a method of treating migraine with or without aura, comprising nasally administering an effective amount of the above-described liquid pharmaceutical composition for nasal administration.
  • Figure 1 is a graph of rizatriptan plasma concentration versus time showing the change in plasma rizatriptan concentration versus time for the nasal compositions of Formulations No. 15 and No. 16 of the present invention and for the oral composition prepared from oral tablets. Maxalt®.
  • the present inventors have identified a need to provide a liquid pharmaceutical composition containing a triptan for nasal administration, which can be used for the manufacture of dosage forms for nasal administration, and which can be used in patients to relieve or control headaches associated with migraine attacks with or without aura.
  • compositions must be physically and chemically stable, contain a therapeutic concentration of the active ingredient in a small volume (from 1 mg to 5 mg in 100 ⁇ l), ensure an even faster achievement of rizatriptan Cmax in the blood plasma and, as a result, an even faster onset of analgesic effect, as well as a more uniform flow of rizatriptan into the blood plasma from the nasal cavity.
  • the combination of excipients includes a pharmaceutically acceptable carrier, buffering agents, a solubilizer and an organic co-solvent, where the composition contains hydroxypropyl beta-cyclodextrin (2-hydroxypropyl) as a solubilizer -P-cyclodextrin) or monoethyl ether Both diethylene glycol and the composition contains propylene glycol as an organic co-solvent.
  • the composition contains buffering agents.
  • the specified pH of the composition minimizes irritation of the nasal cavity.
  • buffering agents acetic acid, citric acid, succinic acid, sodium acetate, sodium citrate, phosphoric acid, sodium phosphate, sodium hydroxide or their solvates, hydrates or other salts used in combination can be used.
  • the concentration of the organic co-solvent is in the range from about 0.5 mg/ml to about 800.0 mg/ml, preferably from about 0.5 mg/ml to about 700.0 mg/ml, preferably from about 0.5 mg/ml to about 600.0 mg/ml, preferably from about 0.5 mg/ml to about 500.0 mg/ml, preferably from about 0.5 mg/ml to about 400.0 mg/ml, preferably from about 0.5 mg/ml to about 300.0 mg/ml, preferably from about 0.5 mg/ml to about 200.0 mg/ml, preferably from about 0.5 mg/ml to about 150.0 mg/ ml, preferably from about 0.5 mg/ml to about 100.0 mg/ml, preferably from about 0.5 mg/ml to about 50.0 mg/ml, preferably from about 0.5 mg/ml to about 45 .0 mg/ml, preferably from about 0.5 mg/ml to about 40.0 mg/ml, preferably from about 0.5 mg/m/l to
  • an antimicrobial preservative from nasal formulations can be achieved by observing the following (or a combination): aseptic production, terminal sterilization of the product, the use of so-called preservative-free systems (PFS), i.e. dosing devices, where the formulations can be packaged without preservatives, and dosing devices, which must also be manufactured and packaged either aseptically or using sterilization, and must also ensure that microorganisms do not enter the product after it is first opened, e.g. use of a membrane filter or silver components in the design of the dosing device.
  • PFS preservative-free systems
  • PFS dosing devices may include dosing devices from AptarGroup, which produces a range of innovative dosing devices that provide excellent microbiological protection and stability for sensitive formulations using purely mechanical means 12 (AptarGroup).
  • AptarGroup a filter is used in the design
  • URSATEC's 3K®-system dosing devices use an airless dispensing system for liquid pharmaceutical formulations and provide triple protection against microbiological contamination, which includes bacteriostatic packaging surfaces, a microbiological sealed shut-off valve and an air purification filter 13 (URSATEC).
  • a thickener to the composition provides a narrower spray angle when exiting the nozzle of the dispensing device, which allows for more precise targeting of the spray to the upper (including olfactory) region of the nasal cavity, which facilitates delivery of the drug from the nose directly to the brain.
  • the thickener is selected from the group consisting of hydroxyethylcellulose, hydroxypropylcellulose, carboxymethylcellulose, methylcellulose, cellulose, including microcrystalline cellulose, or pharmaceutically acceptable salts thereof. These thickeners can be used in combination.
  • compositions of the present invention without a thickener are prepared as follows.
  • rizatriptan benzoate is added to the technological container with the resulting solution.
  • the resulting mixture is stirred (in the laboratory process at a speed of 600 rpm) when heated to 35 °C until the component is completely dissolved.
  • Propylene glycol and an antimicrobial preservative are sequentially added to the resulting solution.
  • the solution is kept with constant stirring with a stirrer for at least 25 minutes.
  • rizatriptan benzoate is added to the technological container with the resulting solution.
  • the resulting mixture is stirred (in the laboratory process at a speed of 600 rpm) when heated to 35 °C until the component is completely dissolved.
  • Propylene glycol and an antimicrobial preservative are sequentially added to the resulting solution.
  • the solution is kept with constant stirring with a stirrer for 25 minutes.
  • liquid compositions of the present invention for nasal administration provide sufficient bioavailability, as well as an even faster achievement of Cmax of rizatriptan in blood plasma than oral tablets, which means a faster onset of therapeutic effect.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Dispersion Chemistry (AREA)
  • Neurosurgery (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Pain & Pain Management (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Inorganic Chemistry (AREA)
  • Otolaryngology (AREA)
  • Pulmonology (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention se rapporte au domaine de la médecine, et concerne une composition pharmaceutique liquide pour administration nasale, qui consiste en une solution et qui comprend en qualité d'ingrédient actif du rizatriptan ou son sel pharmaceutiquement acceptable ou son solvat ou un dérivé pharmaceutiquement acceptable, ainsi qu'un excipient pharmaceutiquement acceptable, des agents tampons, un solubilisant et un cosolvant organique, caractérisé en ce que la composition contient en qualité de solubilisant de l'hydroxypropyle de beta-cyclodextrine ou un ester monoéthylique de diéthylèneglycol et, en qualité de cosolvant organique, la composition contient du propylèneglycol. L'invention concerne également l'utilisation de la présente composition afin de traiter ou de mettre un terme au mal de tête en cas d'attaque de migraine. L'invention concerne également une forme médicamenteuse contenant ladite composition, et un procédé de traitement de la migraine comprenant l'administration nasale de ladite composition. La composition assure une biodisponibilité suffisante et une pénétration uniforme du rizatriptan dans la plasma sanguin depuis la cavité nasale et, donc, un soulagement efficace et plus rapide ou la fin du mal de tête lors d'une attaque de migraine.
PCT/RU2022/000396 2022-12-28 2022-12-28 Composition pharmaceutique liquide pour administration nasale contenant du rizatriptan WO2024144413A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/RU2022/000396 WO2024144413A1 (fr) 2022-12-28 2022-12-28 Composition pharmaceutique liquide pour administration nasale contenant du rizatriptan

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/RU2022/000396 WO2024144413A1 (fr) 2022-12-28 2022-12-28 Composition pharmaceutique liquide pour administration nasale contenant du rizatriptan

Publications (1)

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WO2024144413A1 true WO2024144413A1 (fr) 2024-07-04

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2259418A1 (fr) * 1996-07-11 1998-01-22 Farmarc Nederland B.V. Composition pharmaceutique contenant un sel d'addition acide d'un medicament de base
RU2130022C1 (ru) * 1992-06-05 1999-05-10 Мерк Шарп энд Дом Лимитед N,n-диметил-2-[5-(1,2,4-триазол-1-илметил)-1н-индол-3-ил] этиламина сульфатная соль (2:1) и ее фармацевтически приемлемые гидраты, способы ее получения, фармацевтическая композиция на ее основе, способ ее получения и лекарственное средство

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2130022C1 (ru) * 1992-06-05 1999-05-10 Мерк Шарп энд Дом Лимитед N,n-диметил-2-[5-(1,2,4-триазол-1-илметил)-1н-индол-3-ил] этиламина сульфатная соль (2:1) и ее фармацевтически приемлемые гидраты, способы ее получения, фармацевтическая композиция на ее основе, способ ее получения и лекарственное средство
CA2259418A1 (fr) * 1996-07-11 1998-01-22 Farmarc Nederland B.V. Composition pharmaceutique contenant un sel d'addition acide d'un medicament de base

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
BARAKAT SARA S., NASR MAHA, AHMED RANIA F., BADAWY SABRY S., MANSOUR SAMAR: "Intranasally administered in situ gelling nanocomposite system of dimenhydrinate: preparation, characterization and pharmacodynamic applicability in chemotherapy induced emesis model", SCIENTIFIC REPORTS, NATURE PUBLISHING GROUP, US, vol. 7, no. 1, 30 August 2017 (2017-08-30), US , pages 9910, XP093194896, ISSN: 2045-2322, DOI: 10.1038/s41598-017-10032-7 *
KEDIK, S. A. ET AL.: "Tsiklodekstriny i ikh primenenie v farmatsevticheskoy promyshlennosti (obzor) = Cyclodextrins and their application ini the pharmaceutical industry (review) ", DRUG DEVELOPMENT & REGISTRATION = RAZRABOTKA I REGISTRACIÂ LEKARSTVENNYH SREDSTV, vol. 16, no. 3, 1 January 2016 (2016-01-01), pages 68 - 75, XP009557756, ISSN: 2305-2066 *

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