EP4580680A1 - Transporteurs d'oxygène à l'échelle nanométrique modifiés par la lécithine (lenox) - Google Patents

Transporteurs d'oxygène à l'échelle nanométrique modifiés par la lécithine (lenox)

Info

Publication number
EP4580680A1
EP4580680A1 EP23762414.3A EP23762414A EP4580680A1 EP 4580680 A1 EP4580680 A1 EP 4580680A1 EP 23762414 A EP23762414 A EP 23762414A EP 4580680 A1 EP4580680 A1 EP 4580680A1
Authority
EP
European Patent Office
Prior art keywords
albumin
solution
artificial oxygen
lecithin
oxygen carrier
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.)
Pending
Application number
EP23762414.3A
Other languages
German (de)
English (en)
Inventor
Andrea STEINBICKER
Katja FERENZ
Fabian Nocke
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.)
Universitaet Duisburg Essen
Original Assignee
Universitaet Duisburg Essen
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 Universitaet Duisburg Essen filed Critical Universitaet Duisburg Essen
Publication of EP4580680A1 publication Critical patent/EP4580680A1/fr
Pending legal-status Critical Current

Links

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
    • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
    • 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
    • A61K9/0026—Blood substitute; Oxygen transporting formulations; Plasma extender
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/08—Plasma substitutes; Perfusion solutions; Dialytics or haemodialytics; Drugs for electrolytic or acid-base disorders, e.g. hypovolemic shock

Definitions

  • the present invention relates to new, stable artificial oxygen carriers based on perfluorocarbons, their production and their use as synthetic blood substitutes.
  • Perfluorocarbons are synthetically produced, perfluorinated carbon compounds (hydrocarbons whose hydrogen atoms are completely replaced by halogens, usually fluorine atoms). Due to the cavities between the individual molecules, they have a high solubility for respiratory gases such as oxygen and carbon dioxide compared to water, depending on the partial pressure, and can therefore take over or support the transport of oxygen in the blood instead of or together with erythrocytes. Oxygen uptake and release occurs two times faster than in erythrocytes and is directly proportional to the oxygen partial pressure. More than 90% of the dissolved oxygen is delivered to the tissue, achieving three times the oxygen extraction rate (oxygen delivery to the tissue) of an RBC.
  • perfluorocarbons Due to the very high carbon-fluorine binding energy, perfluorocarbons are chemically and metabolically inert, so that they do not react even with highly reactive compounds and do not form toxic degradation products. In terms of degradation, the perfluorodecalin (PFD) we use will be excreted in the air we breathe due to its high vapor pressure. High vapor pressure means that a liquid evaporates under mild conditions. Here this means that PFD comes to the lungs as a liquid and is then vaporized and exhaled.
  • PFD perfluorodecalin
  • EP0282948B1 and EP0282949B1 describe aqueous emulsions made from perfluorocarbons in which, among other things, phospholipids are used as emulsifiers. Additional emulsifier additives can also be present, such as: B. Albumin, especially bovine serum albumin (BSA). This can be present in the emulsion in an amount of 0.2-2% by weight as an “oncontic agent”.
  • CN111214459A (“Perfluorocarbon and albumin nanoparticles and application in production of tumor treating medicine thereof”) describes nanoparticles made of perfluorocarbon and albumin as a drug delivery system for “phosphonic acid drugs”.
  • a manufacturing process is described in which the “phosphonic acid drug” is in an emulsion in which, among other things: Lecithin and cholesterol may be included, to which perfluorocarbon/albumin nanoparticles are added to produce biologically active double membrane particles.
  • Lecithin and cholesterol may be included, to which perfluorocarbon/albumin nanoparticles are added to produce biologically active double membrane particles.
  • This publication therefore concerns liposomes. Nanoparticles with a shell made of albumin and lecithin are not described. The registration is not related to artificial oxygen carriers or blood substitute solutions, but to tumor therapy.
  • CN109908085A describes similar emulsions made from BSA, lecithin and perfluorocarbons.
  • the BSA does not serve as an emulsifier, but rather as an example protein for the drug carrier system.
  • nanoparticles with a shell made of albumin and lecithin are not explicitly described in the application.
  • the registration is not related to artificial oxygen carriers or blood replacement solutions, but rather to the therapy of heart failure.
  • EP0033402A1 describes a perfusate fluid which consists of a previously used crystalloid volume replacement solution (Ringer's solution) in which albumin is dissolved and which additionally contains, among other things, may contain a perfluorocarbon and an emulsifying agent.
  • the emulsifying agent can, among other things, be a phospholipid.
  • the albumin is not used as an emulsifier, but rather forms an additive in the carrier solution.
  • US 4,186,253 A describes the non-cooled production of a perfluorocarbon emulsion using nozzle-like emulsifiers, the emulsion being intended to be used in organ transplantation.
  • the emulsion also contains a modified Ringer's solution in which albumin is dissolved.
  • WO 94/18954 A1 describes microemulsions for use as blood substitutes which contain albumin, lecithin and perfluorodecalin.
  • perfluorocarbons are only used as artificial oxygen carriers in the form of emulsions, although the instability of the emulsions or the short half-life still cause difficulties (Lambert, E., Janjic, J.M. Quality by design approach identifies critical parameters Driving oxygen delivery performance in vitro for perfluorocarbon based artificial oxygen carriers. Sci Rep 11, 5569 (2021). https://doi.org/10.1038/s41598-021-84076-l).
  • Newer preparations e.g. Oxygent® (a 60% PFC emulsion with 58% perfluorooctyl bromide, 2% perfluorodecyl bromide and egg yolk phospholipids), work with a combination of the slightly less stabilizing (but better tolerated) phospholipids, e.g. from egg yolk and high molecular weight PFCs such as perfluorodecyl bromide (CF3(CF2)10Br), perfluorotributylamine (N(CF2CF2CF2CF3)3) or perfluoromethylcyclohexylpiperidine (C12F22N) (Ferenz KB, 2015. Artificial oxygen carriers - how long do we have to wait? Hemotherapy 25, 27-36).
  • PFCs such as perfluorodecyl bromide (CF3(CF2)10Br), perfluorotributylamine (N(CF2CF2CF2CF3)3) or perfluoromethylcyclohexy
  • the above object is achieved by a process for producing artificial oxygen carriers based on perfluorocarbons (PFOCs).
  • the method comprises the steps of a) providing a suitable aqueous albumin solution and mixing with at least one suitable artificial oxygen carrier based on perfluorocarbons, b) appropriate addition of lecithin, c) pre-emulsification by rapid stirring under suitable cooling, d) emulsification of the pre-emulsion from step c) under pressure via a high-pressure homogenizer with suitable cooling and subsequent storage for at least 30 minutes, also under suitable cooling.
  • PFOCs perfluorocarbons
  • albumin is in a concentration between 2-20%, preferably 5-10%, more preferably 5%, perfluorocarbon perfluorodecalin (PFD) in a concentration between 10-50%, preferably from 17%, lecithin in a concentration between 1-16%, preferably from 2%, in a medium selected from water and electrolytes in a plasma-like composition, preferably Sterofundin® ISO, Ringerfundin®, Ringer's solution and hydroxy-ethyl -Starch, STEEN Solution, OCS solution and other crystalloid and colloidal volume replacement solutions.
  • PFD perfluorocarbon perfluorodecalin
  • the above object is achieved by a process for producing artificial oxygen carriers based on perfluorocarbons (PFOCs).
  • the method first includes the step of providing a suitable aqueous albumin solution.
  • Lecithin (97%, Roth, Düsseldorf, DE) was also used for the newly developed oxygen carrier (LENOX).
  • Sterofundin® ISO B.Braun, Melsungen, DE
  • HES 6% Fresenius Kabi, Bad Homburg, DE
  • Ringer's solution Fresenius Kabi, Bad Homburg, DE
  • the particle size and the polydispersion index were determined using dynamic light scattering (Stabino Nano-flex, Particle Metrix, Inning am Ammersee, DE).
  • the oxygen capacity was measured with a respirometer (O2k, Oroboros Instruments, Innsbruck, AUT) and the turbidity with a photometer (Specord S600, Analytik) ena, Jena, DE).
  • the viscosity was determined using a rheometer (MCR 92, Anton Paar, Ostfildern, DE). The viscosity was determined at two different shear rates because some emulsions exhibited non-Newtonian behavior. A very low shear rate (50/s) and a physiological shear rate (645/s) were chosen.
  • Organ Life Fluid particles The synthesis of the pure Organ Life Fluid particles (OLF particles) corresponded to that in patent application DE102021211272.2.
  • 20 mL albumin (BSA or HSA) and 4 mL PFD were introduced and pre-emulsified with an Ultra-Turrax (T25 Basic, IKA-Werke, Staufen, DE) at 9,500 revolutions/min.
  • the preemulsion was then placed in the microfluidizer and the entire volume was processed once at a pressure of 20,000 PSI (approx. 1379 bar).
  • the outlet coil of the device and therefore the product must be cooled with ice. After homogenization, the product was stored in a vessel filled with ice for at least 30 min.
  • Synthesis I-IV is carried out with a pressure of 30,000 PSI and a cycle rate of eight times, from Synthesis V onwards the pressure changes to 20,000 PSI and the cycle number changes to seven times.
  • LENOX For the synthesis of LENOX, 20 mL of a 5% albumin solution (bovine serum albumin (BSA) or human serum albumin (HSA)) and 4 mL of PFD were presented. 0.4 g of lecithin was added to the 2-phase mixture and pre-emulsified with an Ultra-Turrax (9,500 revolutions/min). The pre-emulsion was then placed in the microfluidizer and the entire thing was processed eight times at a pressure of 30,000 PSI (approx. 2068 bar). During the process, the outlet coil of the device and therefore the product must be cooled with ice. After homogenization, the product was stored in a vessel filled with ice for at least 30 min.
  • BSA bovine serum albumin
  • HSA human serum albumin
  • BSA bovine serum albumin
  • bovine serum albumin (BSA) was dissolved in 20 mL of HES (6%).
  • BSA bovine serum albumin
  • 4 mL of PFD and then 0.4 g of lecithin were added to this solution.
  • the mixture was pre-emulsified with an Ultra-Turrax at 9,500 revolutions/min.
  • the preemulsion was then placed in the microfluidizer and the entire volume was processed eight times at a pressure of 30,000 PSI (approx. 2068 bar).
  • the dispenser coil of the device and therefore the product must be cooled with ice. After homogenization, the product was stored in a vessel filled with ice for at least 30 min.
  • the OriginPro® software (version 2020) was used for the statistical evaluation of the analysis data.
  • the experimental data presented below are the mean values of the groups ⁇ standard deviation. The standard deviation is shown in the form of error bars.
  • the LENOX have an average particle diameter of 92.5 ⁇ 8.5 nm (Synthesis I, BSA) or 123.5 ⁇ 2.2 nm (Synthesis I, HSA) and release 3.99 ⁇ 0.2 pmol of oxygen per mL Sample free (at 17 vol.%).
  • the emulsion has properties of a Newtonian fluid, with the viscosity only changing minimally as the shear rate increases. Compared to the LENOXs, the OLF particles form a non-Newtonian fluid, and the viscosity changes significantly as the shear rate changes (see Figure 1).
  • the mean particle diameter and the polydispersion index are significantly different between the OLF particles (HSA) and the LENOXs.
  • HSA OLF particles
  • a visually visible difference between the OLF emulsion and the LENOX emulsion is the turbidity.
  • the LENOX emulsion (Synthesis I, HSA) is significantly (*p ⁇ 0.001) more transparent to light with a wavelength of 860 nm than the OLF emulsion.
  • the OLF emulsion appears very cloudy, whereas the LENOXs emulsion appears clear.
  • bovine serum albumin (BSA) was dissolved in 20 mL of Sterofundin ISO.
  • PFD bovine serum albumin
  • lecithin 4 mL of lecithin were added to this solution.
  • the mixture was pre-emulsified with an Ultra-Turrax (9,500 revolutions/min).
  • the pre-emulsion was then placed into the microfluidizer and at a pressure of 20,000 PSI (approx. 1379 bar) the entire volume was cycled through the microfluidizer seven times.
  • PSI approximately 1379 bar
  • d stands for the hydrodynamic diameter of the particles and S for the range of the particle size distribution.
  • dlO means that 10% of the measured particles are exactly the same size or smaller than the specified particle diameter, d50 corresponds to 50% and d90 corresponds to 90%.
  • dlO 75 nm means that 10% of the measured particles were 75 nm or smaller.
  • Viscosity (at 200 s' 1 ):

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Hematology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Diabetes (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Organic Chemistry (AREA)
  • Dispersion Chemistry (AREA)
  • Inorganic Chemistry (AREA)
  • Dermatology (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Medicinal Preparation (AREA)

Abstract

La présente invention concerne un nouveau type de composition pour le développement de transporteurs d'oxygène synthétiques stables à base d'hydrocarbures perfluorés, leur fabrication, et leur utilisation en tant que transporteurs d'oxygène et de substituts sanguins synthétiques et en tant que substituts de volume.
EP23762414.3A 2022-08-31 2023-08-29 Transporteurs d'oxygène à l'échelle nanométrique modifiés par la lécithine (lenox) Pending EP4580680A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP22193221 2022-08-31
PCT/EP2023/073579 WO2024046999A1 (fr) 2022-08-31 2023-08-29 Transporteurs d'oxygène à l'échelle nanométrique modifiés par la lécithine (lenox)

Publications (1)

Publication Number Publication Date
EP4580680A1 true EP4580680A1 (fr) 2025-07-09

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ID=83151549

Family Applications (1)

Application Number Title Priority Date Filing Date
EP23762414.3A Pending EP4580680A1 (fr) 2022-08-31 2023-08-29 Transporteurs d'oxygène à l'échelle nanométrique modifiés par la lécithine (lenox)

Country Status (2)

Country Link
EP (1) EP4580680A1 (fr)
WO (1) WO2024046999A1 (fr)

Family Cites Families (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5331209B2 (fr) * 1973-10-05 1978-09-01
JPS5835485B2 (ja) * 1976-02-03 1983-08-03 株式会社ミドリ十字 酸素運搬輸液
US4186253A (en) 1978-10-10 1980-01-29 The Green Cross Corporation Perfusate for preserving organ to be transplanted and preserving method
US4423077A (en) * 1982-07-27 1983-12-27 The University Of Pennsylvania Perfluorochemical emulsion artificial blood
US4927623A (en) * 1986-01-14 1990-05-22 Alliance Pharmaceutical Corp. Dissolution of gas in a fluorocarbon liquid
US4895876A (en) 1987-03-20 1990-01-23 Air Products And Chemicals, Inc. Concentrated stable fluorochemical aqueous emulsions containing triglycerides
US4866096A (en) 1987-03-20 1989-09-12 Air Products And Chemicals, Inc. Stable fluorochemical aqueous emulsions
US5171755A (en) * 1988-04-29 1992-12-15 Hemagen/Pfc Emulsions of highly fluorinated organic compounds
NZ262679A (en) 1993-02-22 1997-08-22 Vivorx Pharmaceuticals Inc Compositions for in vivo delivery of pharmaceutical agents where the agents are contained in a polymeric shell
US5439686A (en) * 1993-02-22 1995-08-08 Vivorx Pharmaceuticals, Inc. Methods for in vivo delivery of substantially water insoluble pharmacologically active agents and compositions useful therefor
US20070026024A1 (en) * 2005-07-27 2007-02-01 Drees Thomas C Compositions and methods for emulsifying a pefluorocarbon with an oxygen-carrying surfactant
DE102008045152A1 (de) 2008-07-09 2010-01-14 Universität Duisburg-Essen Künstliche Sauerstoffträger und ihre Verwendung
EP2470282A4 (fr) * 2009-08-25 2015-07-29 Agnes Ostafin Procédé et appareil permettant une élimination en continu des particules submicroniques présentes dans un système d'écoulement de liquide en circuit fermé
DE102018205493A1 (de) 2018-04-11 2019-10-17 B. Braun Melsungen Ag Verfahren zur Herstellung einer O/W-Emulsion, O/W-Emulsion und Anlage zur Herstellung einer O/W-Emulsion
CN109908085B (zh) 2019-04-23 2021-12-03 董红燕 一种呼吸道给药的药物载体、其制备方法及其在制备治疗心脏病药物中的应用
CN111214459B (zh) 2020-03-13 2022-09-23 南京大学 全氟化碳白蛋白纳米粒及其在制备肿瘤治疗药物中的应用

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