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WO2022107182A1 - Composition de fentanyl et d'acides gras, et son procédé de préparation - Google Patents

Composition de fentanyl et d'acides gras, et son procédé de préparation Download PDF

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Publication number
WO2022107182A1
WO2022107182A1 PCT/JO2020/050011 JO2020050011W WO2022107182A1 WO 2022107182 A1 WO2022107182 A1 WO 2022107182A1 JO 2020050011 W JO2020050011 W JO 2020050011W WO 2022107182 A1 WO2022107182 A1 WO 2022107182A1
Authority
WO
WIPO (PCT)
Prior art keywords
fentanyl
fatty acids
pharmaceutical composition
weight
capric acid
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/JO2020/050011
Other languages
English (en)
Inventor
Faisal Tawfiq ALAKAYLEH
Mayyas Al-Remawi
Rana OBEIDAT
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
Petra, University of
Original Assignee
JORDAN UNIVERSITY OF SCIENCE AND TECHNOLOGY
Petra, University of
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, Petra, University of filed Critical JORDAN UNIVERSITY OF SCIENCE AND TECHNOLOGY
Priority to PCT/JO2020/050011 priority Critical patent/WO2022107182A1/fr
Publication of WO2022107182A1 publication Critical patent/WO2022107182A1/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
    • 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
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • 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
    • A61K31/4468—Non condensed piperidines, e.g. piperocaine having a nitrogen directly attached in position 4, e.g. clebopride, fentanyl
    • 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
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • 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
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions

Definitions

  • the present disclosure relates to compositions and methods of preparation, and more particularly to compositions containing fentanyl and one or more fatty acids and preparation methods thereof.
  • Fentanyl is a lipophilic compound with an n-octanol to water partition coefficient of 860 to 1 and a pKa value of 8.4. Fentanyl suffers from extensive first past metabolism after oral administration. Therefore, providing a safer and less toxic solubilizing vehicle is of crucial importance. This could be achieved by deep eutectic solvents technology.
  • DESs Deep eutectic solvents
  • DESs Deep eutectic solvents
  • the most important properties of many of the DESs are their low melting point, easy preparation, cheap, nontoxic, nonflammable, and can be formed from biodegradable and biocompatible natural species.
  • One of the most valuable properties of DESs is their low melting point.
  • Such depression of melting point has many pharmaceutical advantages such as enhanced skin flux, and improved drug solubility and dissolution rate especially for those that exhibit melting points lower than body temperature.
  • DESs have diverse fields of applications such as electrochemistry, drug delivery, solubility, organic synthesis and bioconversion.
  • the U.S. patent application publication 20140005617 discloses a fentanyl transdermal patch comprising an acrylic-rubber hybrid as a drug-adhesive layer.
  • the fentanyl transdermal patch can maintain constant fentanyl skin permeability for three days by maintaining close contact with the skin such that desorption, release by moisture and sweat, and skin stimulation are all improved.
  • the U.S. patent number 7556823 discloses silicone adhesive formulations, in which fentanyl particles are suspended in one or more solvated silicone adhesives.
  • the formulations can be used for manufacturing improved, matrix -type transdermal devices for administering Fentanyl.
  • the European patent application publication 0375689 discloses a pharmaceutical composition adapted for transdermal delivery of an opioid drug to the systemic circulation of a mammal, containing an opioid drug or a pharmaceutically acceptable salt.
  • the opioid is a natural or synthetic opioid analgesic such as morphine, oxymorphone, fentanyl, meperidine, propoxyphene, or oxycodone.
  • the commercially available product “Duragesic®” is a gel composition containing a suspended crystals of Fentanyl, and ethanol as a solvent. Also, the product is a patch product that sustains the drug release for about 72 hours.
  • one or more fatty acids could be capric acid, lauric acid, or a combination thereof.
  • the ratio of Fentanyl to the one or more fatty acids in the pharmaceutical composition of the present disclosure may range from about 10 to 90 to about 90 to 10 (weight/weight).
  • the eutectic mixtures could be obtained by gently mixing the components without the aid of solvents, temperature, or mechano-chemical grinding.
  • a method for preparing a pharmaceutical composition comprising Fentanyl and one or more fatty acids, the method may comprise the steps of:
  • one or more fatty acids may include Capric acid, Lauric acid, or a combination thereof.
  • heating of the glass vials is above the melting point of the one or more fatty acids.
  • the ratio of Fentanyl to the one or more fatty acids may range from about 10 to 90 to about 90 to 10 (weight/ weight).
  • FIG. 1 illustrates a flowchart of a method of preparing a pharmaceutical composition of Fentanyl and one or more fatty acids, the method being configured in accordance with embodiments of the present disclosure.
  • FIG. 2A illustrates a polarized optical microscopic image of a mixture of fentanyl and capric acid, wherein (X) is Fentanyl crystals and (Y) is Capric acid, the image is taken at the time of mixing Fentanyl and Capric acid.
  • FIG. 2B illustrates a polarized optical microscopic image of a eutectic mixture of Fentanyl and Capric acid, the image is taken after about 5 seconds of mixing Fentanyl and Capric acid.
  • FIG. 2C illustrates a polarized optical microscopic image of a eutectic mixture of Fentanyl and Capric acid, the image is taken after about 10 seconds of mixing Fentanyl and Capric acid.
  • FIG. 2D illustrates a polarized optical microscopic image of a eutectic mixture of Fentanyl and Capric acid, the image is taken after about 15 seconds of mixing Fentanyl and Capric acid.
  • FIG. 2E illustrates a polarized optical microscopic image of a eutectic mixture of Fentanyl and Capric acid, the image is taken after about 20 seconds of mixing Fentanyl and Capric acid.
  • FIG. 3 illustrates a Differential Scanning Calorimeter thermogram of Lauric acid, Fentanyl, and a pharmaceutical composition of the present disclosure.
  • FIG. 4 illustrates Fourier Transmission Infrared of Lauric acid, Fentanyl and a pharmaceutical composition of the present disclosure.
  • FIG. 1 illustrates a method of preparing a composition of Fentanyl and one or more fatty acids configured in accordance with embodiments of the present disclosure, the method may include the steps of weighing Fentanyl and the one or more fatty acids (process block 1-1) and combining the Fentanyl and the one or more fatty acids in glass vials (process block 1-2).
  • process block 1-4 Followinged by heating the vials at a temperature of about 10 °C above the melting point of the one or more fatty acids for about ten minutes (process block 1-3) and finally allowing the combined Fentanyl and one or more fatty acids to equilibrate at room temperature from about 21 to about 25 °C for about 24 hours before use (process block 1-4).
  • Embodiments of the present disclosure also provide a pharmaceutical composition including Fentanyl and one or more fatty acids that is liquid at room temperature, for use as a therapeutic agent with analgesic capabilities.
  • Fentanyl may act as the base of the pharmaceutical composition, and the one or more fatty acids may act as transdermal penetration enhancers.
  • the ratios of fentanyl to the one or more fatty acids may range from about 10 to 90 to about 90 to 10 (weight/weight).
  • the one or more fatty acids may include Capric acid, Lauric acid, or a combination thereof.
  • composition in embodiments of the present disclosure may be delivered through several routes of administration, including, but not limited to transdermal route of administration such as patches or ointments through a clear green liquid vehicle.
  • composition in embodiments of the present disclosure may also be filled into a soft gelatin capsule, filled into a hard gelatin capsule, formulated as a sublingual liquid formulation, intranasal liquid formulation, transdermal liquid formulation, transdermal gel formulation, transdermal patch formulation, or oral liquisolid formulation.
  • Embodiments of the present disclosure are now further illustrated based on Examples and a detailed description from which further features and advantages may be taken. It is to be noted that the following explanations are presented to illustration and description only; they are not intended to be exhaustive or to limit the disclosure to the precise forms disclosed.
  • the pharmaceutical composition in embodiments of the present disclosure is a liquid form that can withstand Fentanyl crystallization even at low temperatures due to the high interaction between Fentanyl and the fatty acids.
  • Various physical and chemical properties may be tested, including, but not limited to, rheological properties, syringability, surface tension, contact angle, miscibility with solvents, surfactants, oils, or co-surfactants.
  • Fentanyl to the one or more Fatty acids ratios ranged from about 10 to 90 to about 90 to 10 (weight/weight) were prepared and their eutectic mixtures were tested. Samples were stored in closed vials at room temperature for further characterizations. The physicochemical stability of the samples was re-evaluated after six months.
  • Example 2 This example aims at providing further evidence for the results obtained in Example 1, whereby reference is being made to FIGS. 2A-2E, which illustrates polarized optical microscopic images of Fentanyl and Capric Acid.
  • FIG. 2 A shows the samples of Fentanyl and Capric acid in solid state, where Fentanyl appears as fine crystals (X), while Capric acid is irregular shaped particles (Y).
  • Fentanyl appears as fine crystals (X)
  • Capric acid is irregular shaped particles (Y).
  • FIGS. 2B-2E objects in the images became brighter with time and gradual disappearance of Fentanyl crystals (appeared as black) due to liquid formation. This comelting was due to eutectic formation and in some ratios, it takes less than one minute at room temperature.
  • FIGS 4 and 5 The temperature/ composition phase diagrams of Fentanyl to Lauric acid were obtained using hot stage microscopy. Samples of Fentanyl and Lauric acid were heated at about 1°C /minute using a polarizing microscope (Zeiss) equipped with a hot stage (FP82HT stage and FP90 processor, Mettler Instruments, New Jersey, U.S.A.). The hot stage was calibrated using benzophenone and benzoic acid.
  • DSC Differential Scanning Calorimetry
  • Fentanyl was mixed, using a small spatula, with Lauric acid at weight ratios from about 10 to 90 to about 90 to 10 in a small glass vial with a final total weight of about 100 mg. Approximately, 5 mg of the resulting mixtures was carefully sealed in aluminum DSC sample pans for thermal analysis. Samples of Fentanyl and Lauric acid were also tested using DSC. Calibration of DSC was done using indium and zinc as the reference with the standard values for the melting temperature and heat of fusion. Thermograms were obtained at a heating rate of about 1 °C/min against an empty reference pan with a temperature range from about 0 to about 100 °C. All DSC runs were performed in triplicates.
  • FIG. 3 depicts that Fentanyl had a melting point of about 85.9°C, while Lauric acid exhibited melting points at about 46.4 °C, and the pharmaceutical composition of Fentanyl and Lauric acid is having a ratio of about 30 to about 70 (weight/weight) exhibited a melting point of about 20°C.
  • FTIR Fourier Transform Infrared
  • FIG. 4 presents a sample of FTIR spectra.
  • the intensity of this peak decreases and it is completely absent at compositions of greater than equimolar amounts of Fentanyl about 60% (weight/weight) for fentanyl to Capric acid.
  • Fentanyl produced a sharp peak at 1590 cm-1 due to NH stretching of the amino group.
  • the intensity of the peak due to the amino group decreased and was absent at less than the equimolar compositions of Fentanyl.

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

Abstract

La présente divulgation concerne une composition pharmaceutique comprenant du fentanyl et un ou plusieurs acides gras présentant des capacités de mélanges eutectiques, destinée à être utilisée en tant qu'analgésique, et son procédé de préparation.
PCT/JO2020/050011 2020-11-18 2020-11-18 Composition de fentanyl et d'acides gras, et son procédé de préparation Ceased WO2022107182A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/JO2020/050011 WO2022107182A1 (fr) 2020-11-18 2020-11-18 Composition de fentanyl et d'acides gras, et son procédé de préparation

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/JO2020/050011 WO2022107182A1 (fr) 2020-11-18 2020-11-18 Composition de fentanyl et d'acides gras, et son procédé de préparation

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003097008A2 (fr) * 2002-05-15 2003-11-27 Thalas Group Incorporated Dispositif transdermique pour l'administration de fentanyle
US8232293B2 (en) * 2008-09-16 2012-07-31 Boehringer Ingelheim International Gmbh Crystalline forms of a potent HCV inhibitor
US20170340557A1 (en) * 2016-05-27 2017-11-30 Insys Development Company, Inc. Sublingual fentanyl formulations containing a permeation enhancer
US20190262335A1 (en) * 2009-12-10 2019-08-29 Collegium Pharmaceutical, Inc. Tamper-resistant pharmaceutical compositions of opioids and other drugs

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003097008A2 (fr) * 2002-05-15 2003-11-27 Thalas Group Incorporated Dispositif transdermique pour l'administration de fentanyle
US8232293B2 (en) * 2008-09-16 2012-07-31 Boehringer Ingelheim International Gmbh Crystalline forms of a potent HCV inhibitor
US20190262335A1 (en) * 2009-12-10 2019-08-29 Collegium Pharmaceutical, Inc. Tamper-resistant pharmaceutical compositions of opioids and other drugs
US20170340557A1 (en) * 2016-05-27 2017-11-30 Insys Development Company, Inc. Sublingual fentanyl formulations containing a permeation enhancer

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