WO2023054310A1 - Intravenous drip infusion set provided with air-vented infusion filter - Google Patents

Intravenous drip infusion set provided with air-vented infusion filter Download PDF

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Publication number
WO2023054310A1
WO2023054310A1 PCT/JP2022/035833 JP2022035833W WO2023054310A1 WO 2023054310 A1 WO2023054310 A1 WO 2023054310A1 JP 2022035833 W JP2022035833 W JP 2022035833W WO 2023054310 A1 WO2023054310 A1 WO 2023054310A1
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infusion
filter
isavuconazole
air
vented
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PCT/JP2022/035833
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French (fr)
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Yutaka Osawa
Takahiro Yamaguchi
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Basilea Pharmaceutica International Ag, Allschwil
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Publication of WO2023054310A1 publication Critical patent/WO2023054310A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
    • A61M5/14—Infusion devices, e.g. infusing by gravity; Blood infusion; Accessories therefor
    • 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
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • 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
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2205/00—General characteristics of the apparatus
    • A61M2205/75—General characteristics of the apparatus with filters
    • A61M2205/7527—General characteristics of the apparatus with filters liquophilic, hydrophilic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2205/00—General characteristics of the apparatus
    • A61M2205/75—General characteristics of the apparatus with filters
    • A61M2205/7545—General characteristics of the apparatus with filters for solid matter, e.g. microaggregates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
    • A61M5/14—Infusion devices, e.g. infusing by gravity; Blood infusion; Accessories therefor
    • A61M5/165—Filtering accessories, e.g. blood filters, filters for infusion liquids

Definitions

  • the present invention relates to an intravenous drip infusion set provided with an air-vented infusion filter.
  • An infusion set has been disclosed wherein a venous needle or the like, for puncturing the patient, is connected to a lock connector, and the infusion route is secured by puncturing the infusion agent using a bottle needle, so that drip-injection can be performed (Non-patent Document 7).
  • Non-patent Document 10 An infusion filter comprising a hydrophilic membrane that filters the infusion and a hydrophobic membrane that removes only air that has been incorporated in the infusion has been reported. It has been reported that the main reason for using an infusion filter is to remove microorganisms, microparticles and air that have been incorporated in the infusion (Non-patent Document 10).
  • Non-patent Document 2 preparations containing isavuconazonium sulfate are used clinically outside Japan as therapeutic agents for mycosis.
  • NPL 1 Guidelines for diagnosis and treatment of deep mycoses (2014) Kyowa Kikaku [NPL 2] Med. Mycol. J. (2016), Vol. 57J, J77-J88 [NPL 3] CRESEMBA (registered trademark) (isavuconazonium sulfate) 186 mg capsules, PATIENT EDUCATION (2020) [NPL 4] CRESEMBA (registered trademark) revised package insert (2019) [NPL 5] PRODUCT MONOGRAPH INCLUDING PATIENT MEDICATION INFORMATION Pr CRESEMBA TM , AVIR Pharma Inc. (2016) [NPL 6] Medical Safety Measures Document No.
  • NPL 7 Terufusion Infusion Set package insert, revised October 2019 (6 th edition), marketing authorization holder: Terumo Corporation
  • NPL 8 Infusion Filter Set package insert, revised July 2016 (4 th edition (revised based on new guidelines)), marketing authorization holder: JMS Co., Ltd.
  • NPL 9 JMS Infusion Set package insert, revised April 2017 (5 th edition (revised based on new guidelines)), marketing authorization holder: JMS Co., Ltd.
  • NPL 10 Parenteral nutrition, vol.
  • NPL 11 “Infusion Filter Set” (JR-PF05, JR-PF06) manufacturer/distributor: JMS Co., Ltd.
  • NPL 12 Parenteral nutrition, vol. 29, no 2, 2014, pp 39-45
  • the problem addressed by the present invention is the provision of an air-vented infusion filter, etc., having excellent filtration performance, for use in an intravenous drip infusion set containing as an active ingredient 200 mg isavuconazole or prodrug thereof, calculated as isavuconazole, per administered dose.
  • One mode of the present invention is an intravenous drip infusion set containing as an active ingredient 200 mg isavuconazole or prodrug thereof, calculated as isavuconazole, per administered dose, where said intravenous drip infusion set is provided with at least: infusion agent comprising isavuconazole or prodrug thereof, bottle needle, drip tube, clamp, air-vented infusion filter and infusion tube; and said infusion tube is a tube that connects said bottle needle, said drip tube and said air-vented infusion filter, and the material of the hydrophilic filter membrane provided inside said air-vented infusion filter is polysulfone or Posidyne.
  • Another mode of the present invention is an air-vented infusion filter, for use in an intravenous drip infusion set containing as an active ingredient 200 mg isavuconazole or prodrug thereof, calculated as isavuconazole, per administered dose, where the material of the hydrophilic filter membrane provided in the infusion filter is polysulfone or Posidyne.
  • Another mode of the present invention is a method for intravenous drip administration of isavuconazole or prodrug thereof to a patient, characterized in that said infusion set is used; this is a method whereby microparticles and/or analogs of isavuconazole or prodrug thereof that are or may be contained in the therapeutic preparation for mycosis constituting said infusion set, and/or in the infusion agent provided in said infusion set, are filtered using said air-vented infusion filter provided in said infusion set.
  • the present invention relates to the following inventions or the like.
  • An intravenous drip infusion set containing as an active ingredient 200 mg isavuconazole or prodrug thereof, calculated as isavuconazole, per administered dose, wherein said intravenous drip infusion set is provided with at least: an infusion agent comprising isavuconazole or prodrug thereof, a bottle needle, a drip tube, a clamp, an air-vented infusion filter and an infusion tube; and said infusion tube is a tube that connects said bottle needle, said drip tube and said air-vented infusion filter, and a hydrophilic filter membrane provided inside said air-vented infusion filter is a polysulfone membrane or a Posidyne membrane.
  • An air-vented infusion filter for use in an intravenous drip infusion set containing as an active ingredient 200 mg isavuconazole or prodrug thereof, calculated as isavuconazole, per administered dose, wherein a hydrophilic filter membrane provided in said infusion filter is a polysulfone membrane or a Posidyne membrane.
  • a method for intravenous drip administration of isavuconazole or prodrug thereof to a patient characterized in that an intravenous drip infusion set according to any of [1], [3] or [4] above is used.
  • a therapeutic preparation for mycosis comprising an intravenous drip infusion set according to any of [1], [3] or [4] above.
  • the present invention provides an air-vented infusion filter having excellent filtration performance, an intravenous drip infusion set provided with the same filter, and the like.
  • Figure 1 is an example of part of the inventive intravenous drip infusion set, in the stage before the inventive infusion agent is provided.
  • isavuconazole denotes a compound represented by formula (I) below.
  • Isavuconazole is also called isabukonazoru [Japanese phonetic spelling] or aisabukonazoru [alternative Japanese phonetic spelling].
  • the CAS number of isavuconazole is 241479-67-4.
  • Preparations containing isavuconazonium sulfate, which is a prodrug of isavuconazole, are used clinically in the US (Non-patent Documents 3-5).
  • Isavuconazonium sulfate is a compound represented by formula (II) below. Isavuconazonium sulfate is hydrolysed in vivo to isavuconazole.
  • the CAS number of isavuconazonium sulfate is 946075-13-4.
  • Isavuconazole or prodrug thereof can be produced or prepared by a common method (Patent Document 1, Non-patent Documents 3-5, etc.). Isavuconazonium sulfate is preferred as a prodrug of isavuconazole.
  • the infusion filter refers to a filtration device, the main purpose of which is to remove or decrease the amount of microparticles such as foreign substances (glass fragments, rubber fragments, fibre fragments) that have become incorporated in the infusion and microorganisms (bacteria, fungi (mold), etc.) that have become incorporated in the infusion.
  • microparticles such as foreign substances (glass fragments, rubber fragments, fibre fragments) that have become incorporated in the infusion and microorganisms (bacteria, fungi (mold), etc.
  • the infusion filter is provided with at least a housing, a fluid inlet, a fluid outlet and a hydrophilic filter membrane.
  • the air vent is the part that discharges or decreases the amount of air (gaseous component) that has become incorporated in the infusion, and it usually comprises a hydrophobic filter membrane and an aperture in the housing for discharging air. Air that has been in contact with the hydrophobic filter membrane can be discharged to the outside through said aperture.
  • the hydrophilic filter membrane provided inside the infusion filter is a polysulfone membrane or a Posidyne membrane.
  • Posidyne filter membrane is a charge-modified nylon 6,6 filter membrane, and usually it exhibits a positively-charged Zeta potential in solution. Posidyne is a registered trademark of Pall Corporation.
  • the polysulfone material used for the polysulfone membrane is a synthetic polymer compound having a sulfonyl group-containing repeat structure, and is a hydrophobic material.
  • a hydrophilic polysulfone membrane can be produced by treating it with a hydrophilizing agent (e.g. polyvinylpyrrolidone) to increase the hydrophilicity of the polysulfone material.
  • the pore size of the Posidyne filter membrane or polysulfone membrane is preferably 0.2-1.2 ⁇ m. In order to substantially completely remove the risk of contamination by fungi and Gram-negative bacteria, the pore size is preferably 0.2 ⁇ m. It should be noted that here, the pore size refers not to a numerical value measured physically, but to the numerical value obtainable by judging whether or not the target microbes can be removed. For example, a 0.2 ⁇ m filter membrane is decided upon by evaluating the ability to remove the target bacteria Brevundimonas diminuta. Such evaluation can be easily performed by a person skilled in the art.
  • the Posidyne filter membrane/polysulfone membrane has as uniform a pore size as possible and that it is integrated so that membrane separation is unlikely.
  • the infusion agent denotes an infusion loaded in the vessel for housing the infusion to be drip-injected; there are no particular limitations, and it can be an infusion loaded in a plastic bottle, plastic bag or the like.
  • the bottle needle is the connecting part for the infusion agent and infusion tube, and it can be used to pass the infusion into the infusion tube; it is usually needle-shaped, and using it to pierce a specified position of the infusion agent (e.g. the rubber bung) allows the infusion to pass through the infusion tube.
  • the bottle needle is also called the introduction needle.
  • the type of bottle needle it may be a side-hole needle, tsubomi needle, shibori needle or the like, and it may be a metal needle or a plastic needle.
  • the bottle needle is preferably a plastic needle.
  • the drip tube (also called the drip chamber) may be understood as a reservoir for fluid in an infusion line.
  • the main role of the drip tube is to make it easier to check that the infusion is flowing, to estimate the drip rate, and to bleed air.
  • the clamp is usually placed midway on the infusion line, and is used to adjust the amount of fluid, and so forth.
  • the clamp can also be referred to as the klemme.
  • the infusion tube is the conduit for the infusion; it is, for example, a flexible transparent tube made from a material such as polyvinyl chloride (PVC).
  • PVC polyvinyl chloride
  • the type of infusion tube however, because polyvinyl chloride (PVC) can harden slightly when used for infusion tubes, it is preferable to use a plasticiser to lessen the hardening.
  • the amount of active ingredient per administration is 200 mg, calculated as isavuconazole.
  • 200 mg calculated as isavuconazole is equivalent to 372.6 mg isavuconazonium sulfate. This can be stated simply as equivalent to 372 mg isavuconazonium sulfate.
  • the amount of isavuconazole or prodrug thereof contained in the infusion agent provided in the inventive intravenous drip infusion set can be 200 mg, calculated as isavuconazole.
  • An infusion agent containing 200 mg isavuconazonium sulfate calculated as isavuconazole (372.6 mg as isavuconazonium sulfate), and an intravenous drip infusion set provided with the same infusion agent, are examples.
  • the amount of isavuconazole or prodrug thereof in the inventive infusion agent is 200 mg per administration
  • said freeze-dried preparation can be dissolved in physiological saline, injection water, or the like when the inventive intravenous drip infusion set is to be used; the redissolved solution can also be incorporated into a commercially available infusion agent or the like.
  • freeze-dried isavuconazonium sulfate preparation (CRESEMBA (registered trademark); Non-patent Document 6), which is used in clinical practice outside Japan, can be dissolved in injection water or the like at the time of use; the redissolved solution can also be incorporated into a commercially available infusion agent or the like.
  • Non-patent Document 13 Japanese Pharmacopoeia Physiological Saline (Terumo Corporation)”
  • Non-patent Document 14 Japanese Pharmacopoeia Glucose Injection Solution (5 w/v%) (Terumo Corporation)
  • Non-patent Document 14 Terumo TP-A03G05V
  • Excipient stabilizer, pH regulator, antiseptic, solubility enhancer, antioxidant, buffer, preservative, antifreeze agent and the like can be added, as appropriate, when preparing a preparation (e.g. freeze-dried preparation, prefilled syringe solution) containing 200 mg isavuconazole or prodrug thereof per administration.
  • a preparation e.g. freeze-dried preparation, prefilled syringe solution
  • a freeze-dried preparation containing 200 mg isavuconazole or prodrug thereof per administration can be produced by preparing a solution containing isavuconazonium sulfate (372.6 mg), sugar alcohol such as mannitol (10-200 mg) and pH regulator (sulfuric acid or the like), loading the resulting solution into a vial, and freeze-drying it by a common method.
  • the inventive infusion agent can also contain sodium chloride and glucose, as appropriate.
  • osmotic pressure of the inventive infusion agent and the ratio (osmotic pressure ratio) to the osmotic pressure of blood or physiological saline is preferably around 1-3.
  • pH of the inventive infusion agent and on considering stimulation of blood vessels and blood cells or the like, it is generally preferably around 6-8.
  • the inventive air-vented infusion filter can easily be obtained or produced by a method known per se (Patent Document 3, Non-patent Documents 7-11).
  • the “Infusion filter (ELD)” provided in “JMS Infusion Set (JMS JR-PF06)” (Non-patent Document 8) manufactured and distributed by JMS Co., Ltd. is preferred as the air-vented infusion filter provided with a hydrophilic filter membrane where the hydrophilic filter membrane is a Posidyne membrane.
  • the “Air-vented filter” provided in “Terufusion Infusion Set” (Non-patent Document 7, “TI-J352P”) manufactured and distributed by Terumo Corporation is preferred as the air-vented infusion filter provided with a hydrophilic filter membrane where the hydrophilic filter membrane is a polysulfone membrane.
  • the inventive intravenous drip infusion set can easily be obtained or produced by a method known per se (Patent Document 3, Non-patent Documents 7-11).
  • the inventive intravenous drip infusion set is provided with at least: an infusion agent comprising isavuconazole or prodrug thereof, a bottle needle, a drip tube, a clamp, an air-vented infusion filter and an infusion tube; as described above, the infusion agent and infusion filter can easily be produced or obtained by a person skilled in the art, and for the other parts, a commercially available infusion set provided with at least a bottle needle, a drip tube, a clamp and an infusion tube can be purchased and used.
  • “Terufusion Infusion Set” (Non-patent Document 7, “TI-J352P”) manufactured and distributed by Terumo Corporation and “JMS Infusion Set” (Non-patent Document 9, “JMS JY-PB343L”) manufactured and distributed by JMS Co., Ltd. are examples of these commercially available infusion sets.
  • JMS Infusion Set (Non-patent Document 9, “JMS JY-PB343L”)
  • JMS JY-PB343L” it is necessary to replace the infusion filter with an inventive infusion filter
  • the “Infusion filter (ELD)” provided in “JMS Infusion Set” (Non-patent Document 8, “JMS JR-PF06”) is a preferred example of a replacement filter.
  • an inventive intravenous drip infusion set product can be produced by obtaining or producing an inventive infusion agent and then puncturing said infusion agent using the bottle needle provided in a “Terufusion Infusion Set”.
  • an inventive intravenous drip infusion set product can be produced by obtaining or producing an inventive infusion agent and then puncturing said infusion agent using the bottle needle provided in a “JMS Infusion Set”.
  • An infusion set obtained by puncturing and thereby connecting an inventive infusion agent using 1) or 2) is a preferred inventive intravenous drip infusion set product.
  • Priming and drip infusion can be performed using an inventive intravenous drip infusion set by obtaining or producing a venous needle, as described later, and appropriately fitting the venous needle into the connector provided at the end opposite the bottle needle, provided in the inventive intravenous drip infusion set.
  • inventive intravenous drip infusion set there are two types of infusion supply for intravenous drip infusion; one is infusion supply by gravity (natural fall), and the other is infusion supply using an infusion pump or device.
  • the type of infusion supply can easily be selected by a person skilled in the art.
  • the venous needle is a needle for insertion into a vein in the arm or the like, and there are no particular limitations; it can be an infusion needle, butterfly needle or peripheral intravenous indwelling needle. Usually, if the intravenous drip infusion is to proceed for about several hours, it is preferable to use an infusion needle or butterfly needle as the venous needle, and in longer cases it is preferable to use a peripheral intravenous indwelling needle.
  • a peripheral intravenous indwelling needle is a plastic catheter that is inserted into a vein in the arm or the like, and usually, after puncturing the patient using the peripheral intravenous indwelling needle, the metal needle housed in the peripheral intravenous indwelling needle is pulled out and the catheter is left in place.
  • the infusion filter refers to a filtration device, the main purpose of which is to remove or decrease the amount of microparticles contained in the infusion such as foreign substances that have become incorporated in the infusion or microorganisms that have become incorporated in the infusion.
  • Infusion filter performance can easily be evaluated by a person skilled in the art.
  • the inventive intravenous drip infusion set can be evaluated by comparing 1) analysis results for the inventive infusion agent with 2) analysis results for the inventive infusion agent after it has been filtered using the inventive intravenous drip infusion set.
  • Gross examination, removal or decrease in the amount of microparticles, and removal or decrease in the amount of analogs of isavuconazole or prodrug thereof are preferred evaluation items. Clarity and coloration are examples of evaluation items in the gross examination.
  • the removal rate of ⁇ 10 ⁇ m microparticles and the removal rate of ⁇ 25 ⁇ m microparticles can be used as items for evaluating the removal or decrease in the amount of microparticles.
  • Isavuconazole can be used as the item for evaluating the removal or decrease in the amount of analogs of isavuconazole or prodrug thereof. A person skilled in the art can easily perform these evaluations by methods known per se.
  • an inventive freeze-dried preparation containing isavuconazole or prodrug thereof (e.g. CRESEMBA (registered trademark); Non-patent Document 6) is dissolved in physiological saline or injection water at the time of use, and the resulting redissolved solution is mixed with a commercially available infusion agent to produce the inventive infusion agent; the commercially available infusion agent is preferably physiological saline or glucose injection solution.
  • One mode of the present invention is an intravenous drip administration method of isavuconazole or prodrug thereof into a patient, characterized by the use of the inventive intravenous drip infusion set.
  • the administration route, administration site, administration frequency, etc. can be decided by the medical staff, as appropriate.
  • the dose per administration is 200 mg calculated as isavuconazole (if using isavuconazonium sulfate, this is equivalent to 372.6 mg isavuconazonium sulfate).
  • Another mode of the present invention is a preparation for the treatment of mycosis comprising the inventive intravenous drip infusion set.
  • Deep-seated mycosis such as invasive aspergillosis (IA) is a preferred example of mycosis.
  • IA invasive aspergillosis
  • Another mode of the present invention is a method for the treatment of mycosis, characterized by the use of the inventive intravenous drip infusion set.
  • the administration route, administration site, administration frequency, etc. can be decided by the medical staff, as appropriate.
  • the dose per administration is 200 mg calculated as isavuconazole.
  • An intravenous drip infusion set provided with an air-vented infusion filter where an inventive infusion agent obtained by adding a redissolved freeze-dried isavuconazonium sulfate preparation to physiological saline is connected by puncture, and the hydrophilic filter membrane provided inside the air-vented infusion filter is a polysulfone membrane (hereinafter also referred to as a physiological saline-polysulfone type infusion set)
  • An intravenous drip infusion set provided with an air-vented infusion filter where an inventive infusion agent obtained by adding a redissolved freeze-dried isavuconazonium sulfate preparation to physiological saline is connected by puncture, and the hydrophilic filter membrane provided inside the air-vented infusion filter is a Posidyne membrane (hereinafter also referred to as a physiological saline-Posidyne type infusion set)
  • An intravenous drip infusion set provided with an air-vented infusion filter, where an inventive infusion agent obtained by adding a redissolved freeze-dried isavuconazonium sulfate preparation to a glucose injection solution is connected by puncture, and the hydrophilic filter membrane provided inside the air-vented infusion filter is a polysulfone membrane (hereinafter also referred to as a glucose injection solution-polysulfone type infusion set)
  • An intravenous drip infusion set provided with an air-vented infusion filter, where an inventive infusion agent obtained by adding a redissolved freeze-dried isavuconazonium sulfate preparation to a glucose injection solution is connected by puncture, and the hydrophilic filter membrane provided inside the air-vented infusion filter is a Posidyne membrane (hereinafter also referred to as a glucose injection solution-Posidyne type infusion set)
  • Non-patent Document 13 Japanese Pharmacopoeia Physiological Saline (Terumo Corporation)” (Non-patent Document 13, Terumo TP-A03NS) was used as the physiological saline.
  • the amount of physiological saline used was 250 mL, and the salt concentration was 0.9%. It was physiological saline for intravenous injection or intravenous drip infusion.
  • “Japanese Pharmacopoeia Glucose Injection Solution (5 w/v%) (Terumo Corporation)” (Non-patent Document 14, Terumo TP-A03G05V) was used as the glucose injection solution.
  • the amount of glucose injection solution used was 250 mL, and the glucose concentration was 5%. It was a glucose injection solution for intravenous injection or intravenous drip infusion.
  • CRESEMBA registered trademark
  • Non-patent Document 6 which is used in clinical practice outside Japan, was the freeze-dried isavuconazonium sulfate preparation used in the redissolved freeze-dried isavuconazonium sulfate preparation that was added to the physiological saline or glucose injection solution.
  • the redissolved solution was prepared by adding 5.0 mL injection water to the freeze-dried preparation “CRESEMBA (registered trademark)” (Non-patent Document 6), and shaking the vial containing the freeze-dried preparation.
  • physiological saline or glucose injection solution was removed to obtain 245 mL physiological saline or glucose injection solution, to which 5 mL redissolved freeze-dried isavuconazonium sulfate preparation was added, and the resulting system was shaken 20 times in 40 seconds; thus two types of inventive infusion agent (hereinafter also referred to as a physiological saline-based infusion agent and a glucose injection solution-based infusion agent) were produced.
  • inventive infusion agent hereinafter also referred to as a physiological saline-based infusion agent and a glucose injection solution-based infusion agent
  • a physiological saline-polysulfone type infusion set (A) and a glucose injection solution-polysulfone type infusion set (C) were produced by connecting an inventive infusion agent to “Terufusion Infusion Set” (Non-patent Document 7, “TI-J352P”) by puncture.
  • a physiological saline-Posidyne type infusion set (B) and a glucose injection solution-Posidyne type infusion set (D) were produced by connecting an inventive infusion agent to “JMS Infusion Set” (Non-patent Document 9, “JMS JY-PB343L”) by puncture.
  • JMS Infusion Set Non-patent Document 9, “JMS JY-PB343L”
  • the infusion filter provided in the infusion set was replaced by “JMS Infusion Filter Set (Non-patent Document 8, “JMS JR-PF06”)”.
  • a physiological saline-based infusion agent or glucose injection solution-based infusion agent was passed through the inventive intravenous drip infusion set and filtered; the first 20 mL filtrate were discarded, and a post-filtration infusion agent sample was taken from the filtrate obtained thereafter.
  • a pre-filtration infusion agent was shaken 20 times in 40 seconds, and a pre-filtration infusion agent sample was taken from the resulting pre-filtration infusion agent.
  • the gross examination comprised 3 items: clarity, coloration and visible microparticles.
  • the rate of removal of microparticles comprised 2 items: ⁇ 10 ⁇ m microparticles removal rate (%) and ⁇ 25 ⁇ m microparticles removal rate (%).
  • the rate of removal of analogs of isavuconazole or prodrug thereof was the isavuconazole removal rate (%).
  • physiological saline-polysulfone type infusion set can not only markedly decrease the amount of microparticles, but also, contrary to expectation, markedly decrease the amount of isavuconazole.
  • physiological saline-Posidyne type infusion set can markedly decrease the amount of ⁇ 10 ⁇ m microparticles.
  • glucose injection solution-polysulfone type infusion set not only markedly decreased the amount of microparticles, but also, contrary to expectation, markedly decreased the amount of analogs of isavuconazole.
  • the physiological saline-polysulfone type infusion set also exhibited the same excellent characteristics, which suggests that an infusion set provided with an air-vented infusion filter wherein the hydrophilic filter membrane provided inside the air-vented infusion filter is a polysulfone membrane can markedly decrease the amount of isavuconazole regardless of the type of infusion.
  • glucose injection solution-Posidyne type infusion set affords an excellent ⁇ 10 ⁇ m microparticles removal rate.
  • the present invention provides an air-vented infusion filter having excellent filtration performance, and an intravenous drip infusion set provided with the same filter.
  • the present invention is extremely useful in the pharmaceutical industry.

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Abstract

The provision of an intravenous drip infusion set containing as an active ingredient 200 mg isavuconazole or prodrug thereof, calculated as isavuconazole, per administered dose, and having excellent filtration performance. The provision of at least: an infusion agent comprising isavuconazole or prodrug thereof, a bottle needle, a drip tube, a clamp, an air-vented infusion filter and an infusion tube, wherein said infusion tube is a tube that connects said bottle needle, said drip tube, said air-vented infusion filter and said venous needle, and the hydrophilic filter membrane provided inside said air-vented infusion filter is a polysulfone membrane or a Posidyne membrane.

Description

INTRAVENOUS DRIP INFUSION SET PROVIDED WITH AIR-VENTED INFUSION FILTER
The present invention relates to an intravenous drip infusion set provided with an air-vented infusion filter.
Background technology
An infusion set has been disclosed wherein a venous needle or the like, for puncturing the patient, is connected to a lock connector, and the infusion route is secured by puncturing the infusion agent using a bottle needle, so that drip-injection can be performed (Non-patent Document 7).
An infusion filter comprising a hydrophilic membrane that filters the infusion and a hydrophobic membrane that removes only air that has been incorporated in the infusion has been reported (Non-patent Document 10). It has been reported that the main reason for using an infusion filter is to remove microorganisms, microparticles and air that have been incorporated in the infusion (Non-patent Document 10).
An infusion filter set having a hydrophilic membrane of Posidyne Nylon 66 material has been disclosed as an infusion filter for use in actual clinical practice (Non-patent Documents 8 and 11).
Outside Japan, it has been reported that the novel azole isavuconazole is effective against deep-seated mycosis such as invasive aspergillosis (IA) (Non-patent Document 2); and preparations containing isavuconazonium sulfate are used clinically outside Japan as therapeutic agents for mycosis (Non-patent Documents 3-5).
A freeze-dried preparation for intravenous administration containing 200 mg isavuconazonium sulfate, calculated as isavuconazole, is a known preparation containing isavuconazonium sulfate (Non-patent Document 4).
However, there is no known air-vented infusion filter set that uses an infusion that is a preparation for intravenous drip infusion containing 200 mg isavuconazonium sulfate, calculated as isavuconazole, wherein the material of the hydrophilic filter membrane provided inside the infusion filter is polysulfone or Posidyne; the characteristics of such an air-vented infusion filter set are unknown.
[PTL 1] Japanese patent No 3787307
[PTL 2] Republished publication WO2014/157137
[PTL 3] Japanese patent No 5856718
[NPL 1] Guidelines for diagnosis and treatment of deep mycoses (2014) Kyowa Kikaku
[NPL 2] Med. Mycol. J. (2016), Vol. 57J, J77-J88
[NPL 3] CRESEMBA (registered trademark) (isavuconazonium sulfate) 186 mg capsules, PATIENT EDUCATION (2020)
[NPL 4] CRESEMBA (registered trademark) revised package insert (2019)
[NPL 5] PRODUCT MONOGRAPH INCLUDING PATIENT MEDICATION INFORMATION PrCRESEMBATM, AVIR Pharma Inc. (2018)
[NPL 6] Medical Safety Measures Document No. 462, Funabashi Municipal Medical Center, Chiba Prefecture
[NPL 7] Terufusion Infusion Set package insert, revised October 2019 (6th edition), marketing authorization holder: Terumo Corporation
[NPL 8] Infusion Filter Set package insert, revised July 2016 (4th edition (revised based on new guidelines)), marketing authorization holder: JMS Co., Ltd.
[NPL 9] JMS Infusion Set package insert, revised April 2017 (5th edition (revised based on new guidelines)), marketing authorization holder: JMS Co., Ltd.
[NPL 10] Parenteral nutrition, vol. 24, no 6, 2009, pp 5-8
[NPL 11] “Infusion Filter Set” (JR-PF05, JR-PF06) manufacturer/distributor: JMS Co., Ltd.
[NPL 12] Parenteral nutrition, vol. 29, no 2, 2014, pp 39-45
The problem addressed by the present invention is the provision of an air-vented infusion filter, etc., having excellent filtration performance, for use in an intravenous drip infusion set containing as an active ingredient 200 mg isavuconazole or prodrug thereof, calculated as isavuconazole, per administered dose.
Means of solving the problem
One mode of the present invention is an intravenous drip infusion set containing as an active ingredient 200 mg isavuconazole or prodrug thereof, calculated as isavuconazole, per administered dose, where said intravenous drip infusion set is provided with at least: infusion agent comprising isavuconazole or prodrug thereof, bottle needle, drip tube, clamp, air-vented infusion filter and infusion tube; and said infusion tube is a tube that connects said bottle needle, said drip tube and said air-vented infusion filter, and the material of the hydrophilic filter membrane provided inside said air-vented infusion filter is polysulfone or Posidyne.
Another mode of the present invention is an air-vented infusion filter, for use in an intravenous drip infusion set containing as an active ingredient 200 mg isavuconazole or prodrug thereof, calculated as isavuconazole, per administered dose, where the material of the hydrophilic filter membrane provided in the infusion filter is polysulfone or Posidyne.
And another mode of the present invention is a method for intravenous drip administration of isavuconazole or prodrug thereof to a patient, characterized in that said infusion set is used; this is a method whereby microparticles and/or analogs of isavuconazole or prodrug thereof that are or may be contained in the therapeutic preparation for mycosis constituting said infusion set, and/or in the infusion agent provided in said infusion set, are filtered using said air-vented infusion filter provided in said infusion set.
Specifically, the present invention relates to the following inventions or the like.
[1] An intravenous drip infusion set containing as an active ingredient 200 mg isavuconazole or prodrug thereof, calculated as isavuconazole, per administered dose, wherein said intravenous drip infusion set is provided with at least: an infusion agent comprising isavuconazole or prodrug thereof, a bottle needle, a drip tube, a clamp, an air-vented infusion filter and an infusion tube; and said infusion tube is a tube that connects said bottle needle, said drip tube and said air-vented infusion filter, and a hydrophilic filter membrane provided inside said air-vented infusion filter is a polysulfone membrane or a Posidyne membrane.
[2] An air-vented infusion filter, for use in an intravenous drip infusion set containing as an active ingredient 200 mg isavuconazole or prodrug thereof, calculated as isavuconazole, per administered dose, wherein a hydrophilic filter membrane provided in said infusion filter is a polysulfone membrane or a Posidyne membrane.
[3] An intravenous drip infusion set according to [1] above, wherein the material of said hydrophilic filter membrane is polysulfone, and it is possible to decrease the amount of analogs of isavuconazole or prodrug thereof that may be contained in said infusion agent.
[4] An intravenous drip infusion set according to [1] above, wherein said infusion agent comprising isavuconazole or prodrug thereof contains a glucose injection solution.
[5] A method for intravenous drip administration of isavuconazole or prodrug thereof to a patient, characterized in that an intravenous drip infusion set according to any of [1], [3] or [4] above is used.
[6] A therapeutic preparation for mycosis comprising an intravenous drip infusion set according to any of [1], [3] or [4] above.
Effect of the invention
The present invention provides an air-vented infusion filter having excellent filtration performance, an intravenous drip infusion set provided with the same filter, and the like.
Figure 1 is an example of part of the inventive intravenous drip infusion set, in the stage before the inventive infusion agent is provided.
Modes of carrying out the invention
The present invention is described in detail below with reference to specific modes. It should be noted that the present invention is not limited to the following modes, and any mode can be employed provided that the scope of the present invention is not exceeded.
1. Active ingredient
In the present invention, isavuconazole denotes a compound represented by formula (I) below.
Figure JPOXMLDOC01-appb-C000001
Isavuconazole is also called isabukonazoru [Japanese phonetic spelling] or aisabukonazoru [alternative Japanese phonetic spelling]. The CAS number of isavuconazole is 241479-67-4. Preparations containing isavuconazonium sulfate, which is a prodrug of isavuconazole, are used clinically in the US (Non-patent Documents 3-5). Isavuconazonium sulfate is a compound represented by formula (II) below. Isavuconazonium sulfate is hydrolysed in vivo to isavuconazole. The CAS number of isavuconazonium sulfate is 946075-13-4.
Figure JPOXMLDOC01-appb-C000002
Isavuconazole or prodrug thereof can be produced or prepared by a common method (Patent Document 1, Non-patent Documents 3-5, etc.). Isavuconazonium sulfate is preferred as a prodrug of isavuconazole.
2. Air-vented infusion filter
Here, the infusion filter refers to a filtration device, the main purpose of which is to remove or decrease the amount of microparticles such as foreign substances (glass fragments, rubber fragments, fibre fragments) that have become incorporated in the infusion and microorganisms (bacteria, fungi (mold), etc.) that have become incorporated in the infusion.
The infusion filter is provided with at least a housing, a fluid inlet, a fluid outlet and a hydrophilic filter membrane. The air vent is the part that discharges or decreases the amount of air (gaseous component) that has become incorporated in the infusion, and it usually comprises a hydrophobic filter membrane and an aperture in the housing for discharging air. Air that has been in contact with the hydrophobic filter membrane can be discharged to the outside through said aperture.
One characteristic feature of the present invention is that the hydrophilic filter membrane provided inside the infusion filter is a polysulfone membrane or a Posidyne membrane.
A Posidyne filter membrane is a charge-modified nylon 6,6 filter membrane, and usually it exhibits a positively-charged Zeta potential in solution. Posidyne is a registered trademark of Pall Corporation.
The polysulfone material used for the polysulfone membrane is a synthetic polymer compound having a sulfonyl group-containing repeat structure, and is a hydrophobic material. A hydrophilic polysulfone membrane can be produced by treating it with a hydrophilizing agent (e.g. polyvinylpyrrolidone) to increase the hydrophilicity of the polysulfone material.
There are no particular limitations regarding the pore size of the Posidyne filter membrane or polysulfone membrane, and it is preferably 0.2-1.2 μm. In order to substantially completely remove the risk of contamination by fungi and Gram-negative bacteria, the pore size is preferably 0.2 μm. It should be noted that here, the pore size refers not to a numerical value measured physically, but to the numerical value obtainable by judging whether or not the target microbes can be removed. For example, a 0.2 μm filter membrane is decided upon by evaluating the ability to remove the target bacteria Brevundimonas diminuta. Such evaluation can be easily performed by a person skilled in the art.
Also, it is preferable that the Posidyne filter membrane/polysulfone membrane has as uniform a pore size as possible and that it is integrated so that membrane separation is unlikely.
3. Infusion agent, bottle needle, drip tube, clamp, infusion tube
Here, the infusion agent denotes an infusion loaded in the vessel for housing the infusion to be drip-injected; there are no particular limitations, and it can be an infusion loaded in a plastic bottle, plastic bag or the like.
Here, the bottle needle is the connecting part for the infusion agent and infusion tube, and it can be used to pass the infusion into the infusion tube; it is usually needle-shaped, and using it to pierce a specified position of the infusion agent (e.g. the rubber bung) allows the infusion to pass through the infusion tube. The bottle needle is also called the introduction needle. There are no particular limitations on the type of bottle needle; it may be a side-hole needle, tsubomi needle, shibori needle or the like, and it may be a metal needle or a plastic needle. For coring, the bottle needle is preferably a plastic needle.
Here, the drip tube (also called the drip chamber) may be understood as a reservoir for fluid in an infusion line. The main role of the drip tube is to make it easier to check that the infusion is flowing, to estimate the drip rate, and to bleed air.
Here, the clamp is usually placed midway on the infusion line, and is used to adjust the amount of fluid, and so forth. The clamp can also be referred to as the klemme. There are no particular limitations relating to the type of clamp, and it may be a roller clamp, V-clamp, screw clamp or the like.
Here, the infusion tube is the conduit for the infusion; it is, for example, a flexible transparent tube made from a material such as polyvinyl chloride (PVC). There are no particular limitations regarding the type of infusion tube; however, because polyvinyl chloride (PVC) can harden slightly when used for infusion tubes, it is preferable to use a plasticiser to lessen the hardening.
3. Preparation and acquisition of the inventive infusion agent
One characteristic feature of the inventive intravenous drip infusion set is that the amount of active ingredient per administration is 200 mg, calculated as isavuconazole. When isavuconazonium sulfate is used as the active ingredient, 200 mg calculated as isavuconazole is equivalent to 372.6 mg isavuconazonium sulfate. This can be stated simply as equivalent to 372 mg isavuconazonium sulfate. For example, the amount of isavuconazole or prodrug thereof contained in the infusion agent provided in the inventive intravenous drip infusion set can be 200 mg, calculated as isavuconazole. An infusion agent containing 200 mg isavuconazonium sulfate calculated as isavuconazole (372.6 mg as isavuconazonium sulfate), and an intravenous drip infusion set provided with the same infusion agent, are examples.
When the amount of isavuconazole or prodrug thereof in the inventive infusion agent is 200 mg per administration, if for example a freeze-dried preparation containing 200 mg of isavuconazole or prodrug thereof per administration has been prepared in advance, said freeze-dried preparation can be dissolved in physiological saline, injection water, or the like when the inventive intravenous drip infusion set is to be used; the redissolved solution can also be incorporated into a commercially available infusion agent or the like. More specifically, for example, freeze-dried isavuconazonium sulfate preparation (CRESEMBA (registered trademark); Non-patent Document 6), which is used in clinical practice outside Japan, can be dissolved in injection water or the like at the time of use; the redissolved solution can also be incorporated into a commercially available infusion agent or the like.
“Japanese Pharmacopoeia Physiological Saline (Terumo Corporation)” (Non-patent Document 13, Terumo TP-A03NS) and “Japanese Pharmacopoeia Glucose Injection Solution (5 w/v%) (Terumo Corporation)” (Non-patent Document 14, Terumo TP-A03G05V) are preferred as the commercially available infusion agent.
Excipient, stabilizer, pH regulator, antiseptic, solubility enhancer, antioxidant, buffer, preservative, antifreeze agent and the like can be added, as appropriate, when preparing a preparation (e.g. freeze-dried preparation, prefilled syringe solution) containing 200 mg isavuconazole or prodrug thereof per administration. For example, a freeze-dried preparation containing 200 mg isavuconazole or prodrug thereof per administration can be produced by preparing a solution containing isavuconazonium sulfate (372.6 mg), sugar alcohol such as mannitol (10-200 mg) and pH regulator (sulfuric acid or the like), loading the resulting solution into a vial, and freeze-drying it by a common method.
The inventive infusion agent can also contain sodium chloride and glucose, as appropriate. There are no particular limitations relating to the osmotic pressure of the inventive infusion agent, and the ratio (osmotic pressure ratio) to the osmotic pressure of blood or physiological saline is preferably around 1-3. There are also no particular limitations relating to the pH of the inventive infusion agent, and on considering stimulation of blood vessels and blood cells or the like, it is generally preferably around 6-8.
4. Production and acquisition of the inventive air-vented infusion filter
The inventive air-vented infusion filter can easily be obtained or produced by a method known per se (Patent Document 3, Non-patent Documents 7-11). The “Infusion filter (ELD)” provided in “JMS Infusion Set (JMS JR-PF06)” (Non-patent Document 8) manufactured and distributed by JMS Co., Ltd. is preferred as the air-vented infusion filter provided with a hydrophilic filter membrane where the hydrophilic filter membrane is a Posidyne membrane. The “Air-vented filter” provided in “Terufusion Infusion Set” (Non-patent Document 7, “TI-J352P”) manufactured and distributed by Terumo Corporation is preferred as the air-vented infusion filter provided with a hydrophilic filter membrane where the hydrophilic filter membrane is a polysulfone membrane.
5. Production, acquisition, use etc. of the inventive intravenous drip infusion set
The inventive intravenous drip infusion set can easily be obtained or produced by a method known per se (Patent Document 3, Non-patent Documents 7-11). The inventive intravenous drip infusion set is provided with at least: an infusion agent comprising isavuconazole or prodrug thereof, a bottle needle, a drip tube, a clamp, an air-vented infusion filter and an infusion tube; as described above, the infusion agent and infusion filter can easily be produced or obtained by a person skilled in the art, and for the other parts, a commercially available infusion set provided with at least a bottle needle, a drip tube, a clamp and an infusion tube can be purchased and used.
“Terufusion Infusion Set” (Non-patent Document 7, “TI-J352P”) manufactured and distributed by Terumo Corporation and “JMS Infusion Set” (Non-patent Document 9, “JMS JY-PB343L”) manufactured and distributed by JMS Co., Ltd. are examples of these commercially available infusion sets. When using “JMS Infusion Set” (Non-patent Document 9, “JMS JY-PB343L”), it is necessary to replace the infusion filter with an inventive infusion filter, and the “Infusion filter (ELD)” provided in “JMS Infusion Set” (Non-patent Document 8, “JMS JR-PF06”) is a preferred example of a replacement filter.
As described above, an inventive intravenous drip infusion set product can be produced by obtaining or producing an inventive infusion agent and then puncturing said infusion agent using the bottle needle provided in a “Terufusion Infusion Set”.
As described above, an inventive intravenous drip infusion set product can be produced by obtaining or producing an inventive infusion agent and then puncturing said infusion agent using the bottle needle provided in a “JMS Infusion Set”.
An infusion set obtained by puncturing and thereby connecting an inventive infusion agent using 1) or 2) is a preferred inventive intravenous drip infusion set product.
1) “Terufusion Infusion Set” (Non-patent Document 7, “TI-J352P”)
2) “JMS Infusion Set” (Non-patent Document 9, “JMS JY-PB343L”)
(Note that the infusion filter provided in the infusion set is replaced by a “JMS Infusion Set (Non-patent Document 8, “JMS JR-PF06”)” or the like.)
Priming and drip infusion can be performed using an inventive intravenous drip infusion set by obtaining or producing a venous needle, as described later, and appropriately fitting the venous needle into the connector provided at the end opposite the bottle needle, provided in the inventive intravenous drip infusion set. Broadly, there are two types of infusion supply for intravenous drip infusion; one is infusion supply by gravity (natural fall), and the other is infusion supply using an infusion pump or device. The type of infusion supply can easily be selected by a person skilled in the art.
The venous needle is a needle for insertion into a vein in the arm or the like, and there are no particular limitations; it can be an infusion needle, butterfly needle or peripheral intravenous indwelling needle. Usually, if the intravenous drip infusion is to proceed for about several hours, it is preferable to use an infusion needle or butterfly needle as the venous needle, and in longer cases it is preferable to use a peripheral intravenous indwelling needle. A peripheral intravenous indwelling needle is a plastic catheter that is inserted into a vein in the arm or the like, and usually, after puncturing the patient using the peripheral intravenous indwelling needle, the metal needle housed in the peripheral intravenous indwelling needle is pulled out and the catheter is left in place.
6. Evaluation of the performance of the inventive intravenous drip infusion set
As described above, the infusion filter refers to a filtration device, the main purpose of which is to remove or decrease the amount of microparticles contained in the infusion such as foreign substances that have become incorporated in the infusion or microorganisms that have become incorporated in the infusion. Infusion filter performance can easily be evaluated by a person skilled in the art.
The inventive intravenous drip infusion set can be evaluated by comparing 1) analysis results for the inventive infusion agent with 2) analysis results for the inventive infusion agent after it has been filtered using the inventive intravenous drip infusion set.
Gross examination, removal or decrease in the amount of microparticles, and removal or decrease in the amount of analogs of isavuconazole or prodrug thereof are preferred evaluation items. Clarity and coloration are examples of evaluation items in the gross examination. The removal rate of ≧10 μm microparticles and the removal rate of ≧25 μm microparticles can be used as items for evaluating the removal or decrease in the amount of microparticles. Isavuconazole can be used as the item for evaluating the removal or decrease in the amount of analogs of isavuconazole or prodrug thereof. A person skilled in the art can easily perform these evaluations by methods known per se.
On evaluation, an inventive freeze-dried preparation containing isavuconazole or prodrug thereof (e.g. CRESEMBA (registered trademark); Non-patent Document 6) is dissolved in physiological saline or injection water at the time of use, and the resulting redissolved solution is mixed with a commercially available infusion agent to produce the inventive infusion agent; the commercially available infusion agent is preferably physiological saline or glucose injection solution.
7. Administration method, therapeutic drug and intravenous drip infusion method
One mode of the present invention is an intravenous drip administration method of isavuconazole or prodrug thereof into a patient, characterized by the use of the inventive intravenous drip infusion set. The administration route, administration site, administration frequency, etc., can be decided by the medical staff, as appropriate. The dose per administration is 200 mg calculated as isavuconazole (if using isavuconazonium sulfate, this is equivalent to 372.6 mg isavuconazonium sulfate).
Another mode of the present invention is a preparation for the treatment of mycosis comprising the inventive intravenous drip infusion set. Deep-seated mycosis such as invasive aspergillosis (IA) is a preferred example of mycosis.
Another mode of the present invention is a method for the treatment of mycosis, characterized by the use of the inventive intravenous drip infusion set. The administration route, administration site, administration frequency, etc., can be decided by the medical staff, as appropriate. The dose per administration is 200 mg calculated as isavuconazole.
Embodiments
The present invention is described below in more detail with reference to embodiments. It should be noted that the present invention is not limited to the following embodiments, and any embodiment can be implemented provided that the scope of the present invention is not exceeded.
<Embodiment 1> Production of the intravenous drip infusion set
(1) Production of the inventive infusion agent
Four types of infusion agent were produced.
(A) An intravenous drip infusion set provided with an air-vented infusion filter, where an inventive infusion agent obtained by adding a redissolved freeze-dried isavuconazonium sulfate preparation to physiological saline is connected by puncture, and the hydrophilic filter membrane provided inside the air-vented infusion filter is a polysulfone membrane (hereinafter also referred to as a physiological saline-polysulfone type infusion set)
(B) An intravenous drip infusion set provided with an air-vented infusion filter, where an inventive infusion agent obtained by adding a redissolved freeze-dried isavuconazonium sulfate preparation to physiological saline is connected by puncture, and the hydrophilic filter membrane provided inside the air-vented infusion filter is a Posidyne membrane (hereinafter also referred to as a physiological saline-Posidyne type infusion set)
(C) An intravenous drip infusion set provided with an air-vented infusion filter, where an inventive infusion agent obtained by adding a redissolved freeze-dried isavuconazonium sulfate preparation to a glucose injection solution is connected by puncture, and the hydrophilic filter membrane provided inside the air-vented infusion filter is a polysulfone membrane (hereinafter also referred to as a glucose injection solution-polysulfone type infusion set)
(D) An intravenous drip infusion set provided with an air-vented infusion filter, where an inventive infusion agent obtained by adding a redissolved freeze-dried isavuconazonium sulfate preparation to a glucose injection solution is connected by puncture, and the hydrophilic filter membrane provided inside the air-vented infusion filter is a Posidyne membrane (hereinafter also referred to as a glucose injection solution-Posidyne type infusion set)
“Japanese Pharmacopoeia Physiological Saline (Terumo Corporation)” (Non-patent Document 13, Terumo TP-A03NS) was used as the physiological saline. The amount of physiological saline used was 250 mL, and the salt concentration was 0.9%. It was physiological saline for intravenous injection or intravenous drip infusion.
“Japanese Pharmacopoeia Glucose Injection Solution (5 w/v%) (Terumo Corporation)” (Non-patent Document 14, Terumo TP-A03G05V) was used as the glucose injection solution. The amount of glucose injection solution used was 250 mL, and the glucose concentration was 5%. It was a glucose injection solution for intravenous injection or intravenous drip infusion.
“CRESEMBA (registered trademark)” (Non-patent Document 6), which is used in clinical practice outside Japan, was the freeze-dried isavuconazonium sulfate preparation used in the redissolved freeze-dried isavuconazonium sulfate preparation that was added to the physiological saline or glucose injection solution. The redissolved solution was prepared by adding 5.0 mL injection water to the freeze-dried preparation “CRESEMBA (registered trademark)” (Non-patent Document 6), and shaking the vial containing the freeze-dried preparation.
5 mL physiological saline or glucose injection solution was removed to obtain 245 mL physiological saline or glucose injection solution, to which 5 mL redissolved freeze-dried isavuconazonium sulfate preparation was added, and the resulting system was shaken 20 times in 40 seconds; thus two types of inventive infusion agent (hereinafter also referred to as a physiological saline-based infusion agent and a glucose injection solution-based infusion agent) were produced.
A physiological saline-polysulfone type infusion set (A) and a glucose injection solution-polysulfone type infusion set (C) were produced by connecting an inventive infusion agent to “Terufusion Infusion Set” (Non-patent Document 7, “TI-J352P”) by puncture.
A physiological saline-Posidyne type infusion set (B) and a glucose injection solution-Posidyne type infusion set (D) were produced by connecting an inventive infusion agent to “JMS Infusion Set” (Non-patent Document 9, “JMS JY-PB343L”) by puncture. The infusion filter provided in the infusion set was replaced by “JMS Infusion Filter Set (Non-patent Document 8, “JMS JR-PF06”)”.
<Embodiment 2> Intravenous drip infusion set evaluation tests
(1) Test methods
As described above, the inventive intravenous drip infusion sets were evaluated by comparing the analysis results for the inventive infusion agent (hereinafter also referred to as a pre-filtration infusion agent) with the analysis results for the inventive infusion agent after it had been filtered using the inventive intravenous drip infusion set (hereinafter also referred to as a post-filtration infusion agent).
A physiological saline-based infusion agent or glucose injection solution-based infusion agent was passed through the inventive intravenous drip infusion set and filtered; the first 20 mL filtrate were discarded, and a post-filtration infusion agent sample was taken from the filtrate obtained thereafter. Again, a pre-filtration infusion agent was shaken 20 times in 40 seconds, and a pre-filtration infusion agent sample was taken from the resulting pre-filtration infusion agent.
Gross examination, rate of removal of microparticles, and rate of removal of analogs of isavuconazole or prodrug thereof were used as the main evaluation items. The gross examination comprised 3 items: clarity, coloration and visible microparticles. The rate of removal of microparticles comprised 2 items: ≧10 μm microparticles removal rate (%) and ≧25 μm microparticles removal rate (%). The rate of removal of analogs of isavuconazole or prodrug thereof was the isavuconazole removal rate (%). Analog removal was evaluated by repeating 3 times and adopting the arithmetic mean (n = 3).
(2) Test results
The evaluation results for the physiological saline-polysulfone type infusion set are shown in Table 1.
Figure JPOXMLDOC01-appb-T000003
It is obvious that the physiological saline-polysulfone type infusion set can not only markedly decrease the amount of microparticles, but also, contrary to expectation, markedly decrease the amount of isavuconazole.
The evaluation results for the physiological saline-Posidyne type infusion set are shown in Table 2.
Figure JPOXMLDOC01-appb-T000004
It is obvious that the physiological saline-Posidyne type infusion set can markedly decrease the amount of ≧10 μm microparticles.
The evaluation results for the glucose injection solution-polysulfone type infusion set are shown in Table 3.
Figure JPOXMLDOC01-appb-T000005
It is obvious that the glucose injection solution-polysulfone type infusion set not only markedly decreased the amount of microparticles, but also, contrary to expectation, markedly decreased the amount of analogs of isavuconazole. The physiological saline-polysulfone type infusion set also exhibited the same excellent characteristics, which suggests that an infusion set provided with an air-vented infusion filter wherein the hydrophilic filter membrane provided inside the air-vented infusion filter is a polysulfone membrane can markedly decrease the amount of isavuconazole regardless of the type of infusion.
The evaluation results for the glucose injection solution-Posidyne type infusion set are shown in Table 4.
Figure JPOXMLDOC01-appb-T000006
It is obvious that the glucose injection solution-Posidyne type infusion set affords an excellent ≧10 μm microparticles removal rate.
<Comparative example>
The results obtained when operations were performed as in Embodiment 1 but using a polyethersulfone (PES) membrane are shown in the table below. The numbers in the table denote isavuconazole (%).
Figure JPOXMLDOC01-appb-T000007
The present invention provides an air-vented infusion filter having excellent filtration performance, and an intravenous drip infusion set provided with the same filter. The present invention is extremely useful in the pharmaceutical industry.

Claims (4)

  1. An intravenous drip infusion set containing as an active ingredient 200 mg isavuconazole or prodrug thereof, calculated as isavuconazole, per administered dose, wherein
    said intravenous drip infusion set is provided with at least: an infusion agent comprising isavuconazole or prodrug thereof, a bottle needle, a drip tube, a clamp, an air-vented infusion filter and an infusion tube;
    and said infusion tube is a tube that connects said bottle needle, said drip tube and said air-vented infusion filter,
    and a hydrophilic filter membrane provided inside said air-vented infusion filter is a polysulfone membrane or a Posidyne membrane.
  2. An air-vented infusion filter, for use in an intravenous drip infusion set containing as an active ingredient 200 mg isavuconazole or prodrug thereof, calculated as isavuconazole, per administered dose,
    wherein a hydrophilic filter membrane provided in said infusion filter is a polysulfone membrane or a Posidyne membrane.
  3. An intravenous drip infusion set according to Claim 1,
    wherein the material of said hydrophilic filter membrane is polysulfone, and
    it is possible to decrease the amount of analogs of isavuconazole or prodrug thereof that may be contained in said infusion agent.
  4. An intravenous drip infusion set according to Claim 1,
    wherein said infusion agent comprising isavuconazole or prodrug thereof contains a glucose injection solution.
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