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WO2022009248A1 - Composition pharmaceutique pour le traitement des migraines et son procédé de préparation par cosolvant - Google Patents

Composition pharmaceutique pour le traitement des migraines et son procédé de préparation par cosolvant Download PDF

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Publication number
WO2022009248A1
WO2022009248A1 PCT/JO2020/050005 JO2020050005W WO2022009248A1 WO 2022009248 A1 WO2022009248 A1 WO 2022009248A1 JO 2020050005 W JO2020050005 W JO 2020050005W WO 2022009248 A1 WO2022009248 A1 WO 2022009248A1
Authority
WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
solution
pharmaceutically acceptable
chamber
chamber temperature
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.)
Ceased
Application number
PCT/JO2020/050005
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English (en)
Inventor
Abeer Al-Ghananeem
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.)
JORDAN UNIVERSITY OF SCIENCE AND TECHNOLOGY
Original Assignee
JORDAN UNIVERSITY OF SCIENCE AND TECHNOLOGY
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 JORDAN UNIVERSITY OF SCIENCE AND TECHNOLOGY filed Critical JORDAN UNIVERSITY OF SCIENCE AND TECHNOLOGY
Priority to PCT/JO2020/050005 priority Critical patent/WO2022009248A1/fr
Publication of WO2022009248A1 publication Critical patent/WO2022009248A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • 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
    • A61K31/48—Ergoline derivatives, e.g. lysergic acid, ergotamine
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • A61K9/0043—Nose

Definitions

  • the present disclosure relates to pharmaceutical compositions in general, and more particularly to those pharmaceutical compositions that are used for treating migraine headaches based on dihydroergotamine with minimal levels of additives, and a cosolvent method of preparation thereof.
  • DHE Dihydroergotamine
  • ergot alkaloids drugs that are used to a treat migraine headache attack by narrowing the blood vessels around the brain.
  • the efficacy of DHE in migraine is clear; however, the use of the molecule in recent years has been limited due to the drug poor physiochemical properties.
  • DHE DHE
  • its salts One of the major problems of DHE and its salts is stability; the compound is highly susceptible to oxidation. While improving the stability of DHE formulations, agents such as caffeine are used as excipient to improve the solubility and stability of DHE.
  • the Dutch patent number DE 3,302,949 discloses a formulation of DHE mesylate as liquid or powder, the formulation contains a compound stimulating ciliary movement, such as xanthine (e.g., Caffeine), an agent to provide isotonicity, such as glucose (e.g. Dextrose); H2O; and CO2.
  • xanthine e.g., Caffeine
  • an agent to provide isotonicity such as glucose (e.g. Dextrose); H2O; and CO2.
  • a solution formed by the mentioned materials was filtered in the presence of CO2. Ampoules were filled with 1 mL solution under CO2, and sterilized. In use, the solution was used to fill a nasal spray, and is administered 2-4 times daily in the treatment of migraine
  • Caffeine can cause undesirable effects when administered to humans. Some of these undesirable effects include severe allergic reactions in some people, especially in people with asthma, as caffeine may cause inflammation in the sinus cavity. The common side effect of using caffeine includes increased heart rate and sleeplessness.
  • the commercially available DHE-based drug is marketed as injection and as nasal spray.
  • the currently marketed nasal spray formulation contains DHE Mesylate at 4 mg/mL also contains glucose 5% and caffeine 1% is an effective DHE delivery system but is cumbersome to use because the spray device must be assembled at the time of use, since DHE is not stable in solution. For a nasal dose of 2 mg, a volume of 0.5 mL must be administered, which sometimes leads to spillage of the formulation.
  • DHE had poor aqueous solubility that is not enough for delivery of the therapeutic dose in solution.
  • a complicated dosage regimen had to be employed; involving the administration of one spray (0.5mg) to each nostril at the onset of the attack followed by a further two sprays 15 minutes later.
  • Such dosage regimen presented significant difficulties to a patient in a debilitating migraine attack seeking rapid relief of symptoms.
  • the Ei.S. patent number 8158152 discloses a lyophilization process which comprises dissolving a material in one or more solvents for said material to form a solution; forcing said material at least partially out of solution by combining the solution and a non-solvent for the material, which non-solvent is miscible with the solvent or solvents used and wherein said non-solvent is volatilizable under freeze- drying conditions.
  • the anti solvent can be omitted, and the solution of the material in the solvent can be subjected directly to freeze drying.
  • the lyophilizates can then be reconstituted with typical aqueous diluent in the case of hydrophilic materials.
  • Hydrophobic and or lipophilic materials can be initially reconstituted with propylene glycol and/or polyethylene glycol to form a high concentration solution therein and this is further diluted for use with a diluent of Intralipid, plasma, serum, or even whole blood.
  • the concentration of DHE or its pharmaceutically acceptable salt is 10 mg/mL.
  • the and a pharmaceutically acceptable carrier may include dextrose.
  • a lyophilized powder of DHE was prepared using ethanol as co-solvent in order to increase solubility and stability of DHE.
  • the pharmaceutically acceptable salt is preferably mesylate salt.
  • composition in aspects of the present disclosure may include from about 1% to less than about 99% (w/w) ethanol.
  • the pharmaceutical composition preferably includes from about 5% to less than about 45% (w/w) ethanol.
  • the pharmaceutical composition preferably includes from about 45% to less than about 55% (w/w) ethanol.
  • the pharmaceutical composition is stable for at least 6 months at 40° C/75% RH.
  • the pharmaceutical composition is in powder form.
  • the powder may have an average particle diameter of about 50 microns to about 100 microns.
  • the pharmaceutical composition may be dissolved in water for nasal injection.
  • the DHE salt may be DHE Mesylate.
  • the pharmaceutically acceptable carrier may include dextrose.
  • the solution comprises from about 45% to about 55% ethanol.
  • performing lyophilization to the solution may include the steps of: introducing the solution into a chamber at -5 °C; reducing the chamber temperature to about -20 °C; holding the chamber temperature at about -20 °C for about 10 hours during a first freezing step; reducing the chamber temperature to about -50 °C; holding the chamber temperature at about -50 °C for about 5 hours during a second freezing step.
  • performing lyophilization to the solution may include the steps of: - introducing the solution into a chamber;
  • performing lyophilization to the solution may include the steps of:
  • the method of lyophilizing the solution may further include the steps of:
  • FIG. 1 illustrates a flow chart of a method for preparing a pharmaceutical composition including DHE or a pharmaceutically salt thereof, configured according to embodiments of the present disclosure.
  • FIG. 2 illustrates a flowchart of the steps of the method of lyophilizing a solution of DHE or its pharmaceutically acceptable salt, dextrose, ethanol, and water configured in accordance with embodiments of the present disclosure.
  • FIG. 3 illustrates a flow chart of steps of an alternative method of lyophilizing a solution of DHE or its pharmaceutically acceptable salt, dextrose, ethanol, and water configured in accordance with other embodiments of the present disclosure.
  • FIG. 4 illustrates a flow chart of steps of an alternative method of lyophilizing a solution of DHE or its pharmaceutically acceptable salt, dextrose, ethanol, and water configured in accordance with other embodiments of the present disclosure.
  • stable refers to a minimal change in physical and chemical properties of DHE composition over time relative to when it is manufactured. Stability over time is evaluated based on pre-defmed criteria including assay of active and related compounds, appearance, and particulate size.
  • Embodiments of the present disclosure provide a stable pharmaceutical composition that is free of caffeine, the composition may include DHE or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier (dextrose).
  • DHE pharmaceutically acceptable salt thereof
  • Dextrose pharmaceutically acceptable carrier
  • the pharmaceutical composition may include a lyophilized powder of DHE or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition may include from about 5mg/mL to about 15 mg/mL DHE or a pharmaceutically acceptable salt thereof.
  • the concentration of DHE or the pharmaceutically acceptable salt thereof is about lOmg/mL.
  • the composition may contain ethanol as a co-solvent, wherein ethanol may be added to the pharmaceutical composition prior to the lyophilization process and subsequently removed during the freeze-drying process.
  • the ratio of ethanol to the pharmaceutical composition may be 50% volume/volume.
  • the residual concentration of the residual ethanol co-solvent after the freeze-drying process is less than 5000 ppm.
  • the resulting pharmaceutical composition in accordance with embodiments of the present disclosure is in power form.
  • the particle size of the powder may be in range of about 50pm to about 100 pm in diameter.
  • the pharmaceutically acceptable carrier may include, may include, but are not limited to, chitosan, cyclodextrins, poloxamer, or dextrose.
  • pharmaceutically acceptable DHE salts may include, but are not limited to DHE Mesylate, or DHE tartrate.
  • the pharmaceutically acceptable salt of DHE is DHE Mesylate.
  • the pharmaceutical composition is for use in the treatment of migraine headache.
  • FIGS. 1-4 illustrate flow charts of a method of producing a pharmaceutical composition containing DHE or a pharmaceutically acceptable salt thereof, configured in accordance with embodiments of the present disclosure.
  • the method may include preparing a solution comprising DHE or a pharmaceutically acceptable salt thereof, dextrose, ethanol, and water (process block 1-1); and then lyophilizing the solution to produce a lyophilized powder form of the pharmaceutical composition (process block 1-2).
  • the said solution may be prepared by adding DHE or its pharmaceutically acceptable salt to nitrogen purged water for injection, followed by an addition of ethanol. These additions cause the DHE or its pharmaceutically acceptable salt to be totally dissolved in water.
  • the said solution may be prepared by adding DHE or its pharmaceutically acceptable salt thereof to an aqueous solution containing ethanol.
  • the resulting product is a clear, colorless solution that can be readily passed through a sterilizing filter, such as a 0.22-micron filter.
  • the product may then be filled into vials prior to lyophilization.
  • the solution may include from about 45% to about 55% ethanol.
  • FIG. 2 illustrates a flowchart of the steps of the method of lyophilizing a solution of DHE or its pharmaceutically acceptable salt, dextrose, ethanol, and water configured in accordance with embodiments of the present disclosure, wherein the method may include two freezing cycles with the steps of introducing the solution into a chamber having a temperature of about -5 °C (process block 2-1); reducing the chamber’s temperature to about -20 °C (process block 2-2); holding the chamber temperature at about -20 °C for about 10 hours during a first freezing cycle (process block 2-3); then initiating a second freezing cycle by reducing the chamber temperature for another time to about -50 °C (process block 2-4); and holding the chamber temperature at about -50 °C for about 5 hours (process block 2-5).
  • process block 2-1 illustrates a flowchart of the steps of the method of lyophilizing a solution of DHE or its pharmaceutically acceptable salt, dextrose, ethanol, and water configured in accordance with embodiments of the present disclosure, wherein the
  • FIG. 3 illustrates a flow chart of steps of an alternative method of lyophilizing a solution of DHE or its pharmaceutically acceptable salt, dextrose, ethanol, and water configured in accordance with other embodiments of the present disclosure, wherein the method may include a single freezing cycle with the steps of introducing the solution into a chamber (process block 3-1); then initiating a freezing cycle by reducing the chamber’s temperature (process block 3-2); and evacuating the chamber to create a partial vacuum of about 100 mTorr (process block 3-3).
  • FIG. 4 illustrates a flow chart of steps of an alternative method of lyophilizing a solution of DHE or its pharmaceutically acceptable salt, dextrose, ethanol, and water configured in accordance with other embodiments of the present disclosure, wherein the method may include two freezing cycles with the steps of introducing the solution into a chamber (process block 4-1); initiating a first freezing cycle by reducing the chamber’s temperature (process block 4-2); evacuating the chamber to create a partial vacuum (process block 4-3); these steps are followed by increasing the chamber’s temperature to about 10 °C (process block 4-4); holding the chamber’s temperature at about 10 °C for about 30 hours (process block 4-5); then initiating a second freezing cycle by further increasing the chamber temperature to about 40 °C and increasing the pressure to about 150 mTorr (process block 4-6); and holding the chamber’s temperature at about 30 °C and about 150 mTorr pressure for about 12 hours (process block 4-7).
  • process block 4-1 illustrates a flow chart of steps of an alternative
  • the steps required to lyophilize a product includes three major controlled steps; freezing (thermal treatment) at atmospheric pressure, primary drying (sublimation) under vacuum and finally secondary drying (desorption) under vacuum.
  • Successful lyophilization requires very careful control of key parameters like temperature, pressure in time involved in the freeze-drying system.
  • Table 1 summarizes the set of preferred lyophilization conditions (temperature, pressure, ramping rate and time duration of each step) of the method of preparing the pharmaceutical composition in accordance with different embodiments of the present disclosure.
  • HPLC High performance liquid chromatography
  • the term “about”, when referring to a value or to an amount of mass, weight, time, volume, concentration or percentage is meant to encompass variations of in some embodiments ⁇ 20%, in some embodiments ⁇ 10%, in some embodiments ⁇ 5%, in some embodiments ⁇ 1%, in some embodiments ⁇ 0.5%, and in some embodiments ⁇ 0.1% from the specified amount, as such variations are appropriate to perform the disclosed method.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Molecular Biology (AREA)
  • Biochemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Otolaryngology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

La présente invention concerne une composition pharmaceutique pour le traitement des migraines, la composition pharmaceutique comprenant de la dihydroergotamine ou ses sels pharmaceutiquement acceptables, et un support pharmaceutiquement acceptable sans avoir recours à la caféine comme agent de conservation. La présente invention concerne également un procédé de production de la composition pharmaceutique.
PCT/JO2020/050005 2020-07-07 2020-07-07 Composition pharmaceutique pour le traitement des migraines et son procédé de préparation par cosolvant Ceased WO2022009248A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/JO2020/050005 WO2022009248A1 (fr) 2020-07-07 2020-07-07 Composition pharmaceutique pour le traitement des migraines et son procédé de préparation par cosolvant

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/JO2020/050005 WO2022009248A1 (fr) 2020-07-07 2020-07-07 Composition pharmaceutique pour le traitement des migraines et son procédé de préparation par cosolvant

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WO2022009248A1 true WO2022009248A1 (fr) 2022-01-13

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5942251A (en) * 1993-03-26 1999-08-24 Merkus; Franciscus W. H. M. Pharmaceutical compositions for intranasal administration of dihydroergotamine
US20030114476A1 (en) * 1999-03-26 2003-06-19 Pozen Inc. High potency dihydroergotamine compositions
US20060147388A1 (en) * 2003-02-28 2006-07-06 Merkus Franciscus W H Pharmaceutical compositions for nasal delivery
US20140179704A1 (en) * 2012-12-21 2014-06-26 Map Pharmaceuticals, Inc. 8'-hydroxy-dihydroergotamine compounds and compositions
US20190000753A1 (en) * 2017-07-02 2019-01-03 Dr. Reddy's Laboratories Ltd. Nasal dosage forms of dihydroergotamine
US10532049B1 (en) * 2018-08-27 2020-01-14 Pharmaceutical Industries Limited Parenteral unit dosage form of dihydroergotamine

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5942251A (en) * 1993-03-26 1999-08-24 Merkus; Franciscus W. H. M. Pharmaceutical compositions for intranasal administration of dihydroergotamine
US20030114476A1 (en) * 1999-03-26 2003-06-19 Pozen Inc. High potency dihydroergotamine compositions
US20060147388A1 (en) * 2003-02-28 2006-07-06 Merkus Franciscus W H Pharmaceutical compositions for nasal delivery
US20140179704A1 (en) * 2012-12-21 2014-06-26 Map Pharmaceuticals, Inc. 8'-hydroxy-dihydroergotamine compounds and compositions
US20190000753A1 (en) * 2017-07-02 2019-01-03 Dr. Reddy's Laboratories Ltd. Nasal dosage forms of dihydroergotamine
US10532049B1 (en) * 2018-08-27 2020-01-14 Pharmaceutical Industries Limited Parenteral unit dosage form of dihydroergotamine

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