WO2024046999A1 - 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) Download PDF

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WO2024046999A1
WO2024046999A1 PCT/EP2023/073579 EP2023073579W WO2024046999A1 WO 2024046999 A1 WO2024046999 A1 WO 2024046999A1 EP 2023073579 W EP2023073579 W EP 2023073579W WO 2024046999 A1 WO2024046999 A1 WO 2024046999A1
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albumin
solution
artificial oxygen
lecithin
oxygen carrier
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PCT/EP2023/073579
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German (de)
English (en)
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Andrea STEINBICKER
Katja FERENZ
Fabian Nocke
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Johann Wolfgang Goethe-Universität Frankfurt am Main
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    • 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—Liposomes
    • 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.
  • Jacoby C, et al. (in: Probing different perfluorocarbons for in vivo inflammation imaging by 19F MRI: image reconstruction, biological half-lives and sensitivity. NMR Biomed. 2014 Mar;27(3):261-71. doi: 10.1002/nbm.3059. Epub 2013 Dec 19. PMID: 24353148) describe PFCE emulsions that were generated by high pressure homogenization and further 10% w/w crown ether and 4% w/w purified egg lecithin E 80 S (Lipoid GmbH, Ludwigshafen, Germany) in isotonic buffer contained.
  • US 4,866,096 A describes a stable aqueous emulsion which contains 10-59% of an oxygen-transferring, saturated perfluorodecalin, triglycerides of fatty acids and 0.5-7% of a surface-active phospholipid and optionally albumin.
  • the emulsion is produced with cooling in a microfluidizer. It is also described that the emulsion is used as a synthetic blood substitute.
  • 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 an artificial oxygen carrier produced by a method according to the present invention.
  • the artificial oxygen carrier according to the invention has a higher stability compared to non-lecithin-containing artificial oxygen carriers based on perfluorocarbons (PFOCs) and can be produced directly in the typical crystalloid and colloidal volume replacement solutions, such as Sterofundin® ISO.
  • PFOCs perfluorocarbons
  • the above object is achieved by using the artificial oxygen carrier according to the present invention as a perfusion or transfusion solution or as a synthetic blood substitute.
  • the present inventors have already developed artificial oxygen carriers based on perfluorocarbons, which were emulsified with 5% albumin (albumin-derived perfluorocarbon-based artificial oxygen carrier, A-AOC) and which have already shown promising results (see, among others, Wrobeln A , et al. Albumin-derived perfluorocarbon-based artificial oxygen carriers: A physico-chemical characterization and first in vivo evaluation of biocompatibility. Eur J Pharm Biopharm. 2017 Jun; 115:52-64. https://doi.Org/10.1016 /j.ejpb.2017.02.015. Epub 2017 Feb 20. PMID: 28232105).
  • Perfluorocarbon-based oxygen carriers from physics to physiology. Pfluegers Arch. 2021 Feb;473(2):139-150. Doi: 10.1007/s00424-020-02482-2. Epub 2020 Nov 3. PMID: 33141239; PMCID: PMC7607370).
  • DE102008045152A1 and EP 2 296 635 B1 relate to artificial oxygen carriers and their use.
  • the oxygen carriers are not yet stable in every carrier solution that is clinically desirable.
  • no stable emulsions could be generated in the typical crystalloid and colloidal volume replacement solutions such as Sterofundin® ISO, so the oxygen carriers cannot be used universally.
  • 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.
  • aqueous carriers suitable for use as artificial oxygen carriers based on perfluorocarbons can be used.
  • the albumin is in a suitable aqueous buffer, water, a balanced full electrolyte solution for infusion therapy, such as Sterofundin® ISO, Ringerfundin®, Ringer solution, STEEN solution, OCS solution and/or in hydroxyethyl starch solved.
  • a balanced full electrolyte solution for infusion therapy such as Sterofundin® ISO, Ringerfundin®, Ringer solution, STEEN solution, OCS solution and/or in hydroxyethyl starch solved.
  • the typical crystalloid and colloidal volume replacement solutions, such as Sterofundin® ISO are particularly suitable.
  • the albumin used is not limited to one species.
  • a method according to the present invention is preferred, wherein the albumin is selected from Group consisting of mammalian albumin, human serum albumin (HSA) and bovine serum albumin (BSA), or suitable derivatives thereof, such as pegylated albumins.
  • HSA human serum albumin
  • BSA bovine serum albumin
  • the albumin solution is then mixed with at least one suitable artificial oxygen carrier based on perfluorocarbons.
  • All artificial oxygen carriers based on perfluorocarbons can be used.
  • Lecithin is then added in a suitable manner.
  • Fat-free vegetable lecithin for example from soy with a purity of >97%, is preferred.
  • These new, stable oxygen carriers which the inventors call “Lecithin modified nanoscale oxygen carrier” (LENOX)
  • LNOX the precursors, called albumin-derived artificial oxygen carriers (A-AOCs) and organ-life fluid (OLF) in that lecithin is now added during the synthesis.
  • A-AOCs albumin-derived artificial oxygen carriers
  • OLF organ-life fluid
  • the phospholipid lecithin was also incorporated into the albumin shell.
  • the present emulsion has the advantage of not requiring any other stabilizers in addition to the two emulsifiers albumin and lecithin.
  • a method according to the present invention is therefore preferred, wherein the artificial oxygen carrier is produced or consists exclusively of the specified materials.
  • Both albumin and lecithin are already clinically approved for intravenous use.
  • the components used to produce an emulsion are first premixed to form a coarsely disperse preemulsion, which can also be referred to as a raw or preemulsion or premix. Homogenization then takes place, with the disperse phase being crushed into droplets (fine emulsification). The droplet size spectrum of the raw or preemulsion shifts significantly towards smaller drops.
  • O/W emulsions for parenteral use are usually produced by first premixing an oil phase and water phase using a rotor-stator stirrer to form a preemulsion.
  • the subsequent pre-emulsification of the mixture prepared above takes place by rapid stirring with suitable cooling.
  • the preemulsion is emulsified as above under (high) pressure via a high-pressure homogenizer, e.g. a counter-jet disperser (see e.g. DE 102018205 493 Al) with suitable cooling and subsequent storage for at least 30 minutes, also under suitable cooling.
  • a process according to the present invention is preferred, wherein the emulsification of the preemulsion takes place at a pressure between 10,000 PSI (approx. 689 bar) and 40,000 PSI (approx. 2758 bar), preferably at 30,000 PSI (2068 bar) and is optionally repeated several times , preferably between 1 and 12 times (more preferably between 5 and 10, ideally repeat 8 times)
  • the steps of the process relating in particular to homogenization and emulsification are carried out with suitable cooling at ⁇ 10 ° C or less, preferably at 4 ° C. Of course, freezing should be avoided.
  • PFOCs perfluorocarbons
  • albumin in a concentration between 2-20%, preferably 5-10%, more preferably about 5%
  • perfluorodecalin (PFD) in a concentration between about 10-50% being preferred of about 17%
  • lecithin can be emulsified in water in a concentration between about 1-16%, preferably about 2%.
  • albumin used leads, as an important advantage, to a physiological colloid osmotic pressure, with an optimum being surprisingly found at around 5%.
  • the combination PFOC + albumin + lecithin therefore leads to a stable formulation and a ready-to-use product in full electrolyte/volume replacement solution.
  • artificial oxygen carriers (AOC) with other albumin proportions are also advantageous (between 2 - 20%, 4 - 10%, 4 - 6%).
  • the emulsion is prepared at 20,000 PSI with BSA in water and the particle diameter in the emulsion is between 50 nm and 400 nm, more preferably between 60 nm and 300 nm, optimally between 70 nm and 250 nm is. See in particular Synthesis 5, below.
  • the average particle diameter in the emulsion prepared with BSA is 92.5 nm ⁇ 8.5 nm and the oxygen release is 3.99 pmol/mL ⁇ 0.20 pmol/mL.
  • a process according to the present invention is particularly preferred, in which the artificial oxygen carrier is produced exclusively from the specified materials, or albumin and lecithin are present as the only carriers and/or emulsifiers.
  • Another aspect of the present invention relates to an artificial oxygen carrier produced by a method according to the present invention.
  • an artificial oxygen carrier consisting of about 5% albumin, perfluorodecalin (PFD) at a concentration of about 17% and lecithin at a concentration of about 2% in a medium selected from water, Sterofundin® ISO, Ringerfundin® , STEEN solution, OCS solution, Ringer's solution and hydroxy-ethyl starch.
  • PFD perfluorodecalin
  • the artificial oxygen carrier according to the present invention is characterized in that it has a higher stability compared to non-lecithin-containing artificial oxygen carriers based on perfluorocarbons (PFOCs). This can be determined in particular by measuring the viscosity, particle size and distribution of the artificial oxygen carrier (see examples).
  • PFOCs perfluorocarbons
  • Another aspect of the present invention relates to a synthetic blood substitute comprising the artificial oxygen carrier according to the present invention.
  • a further aspect of the present invention relates to the use of the artificial oxygen carrier according to the present invention as a perfusion or transfusion solution or as a synthetic blood substitute.
  • Another aspect of the present invention relates to the artificial oxygen carrier according to the present invention for use in the treatment and prevention of oxygen deficiency and/or blood deficiency in an organ or patient, particularly in a human.
  • a further aspect of the present invention relates to a method for treating and/or preventing oxygen deficiency and/or blood deficiency in an organ or patient, comprising the use of the artificial oxygen carrier according to the present invention as a perfusion or transfusion solution or as a synthetic blood substitute, in particular a person.
  • the composition of the oxygen carrier according to the invention preferably consists of albumin, perfluorodecalin (PFD) and lecithin in water, the concentration of albumin being between 2-20%, preferably 5-10%, more preferably about 5%, the PFD Concentration between 10-50% (preferably 17%) and the lecithin concentration between 1-16% (preferably 2%).
  • the mean particle diameter with BSA is 92.5 nm ⁇ 8.5 nm and the oxygen release is 3.99 pmol/mL ⁇ 0.20 pmol/mL.
  • the addition of lecithin also surprisingly leads to significantly improved physicochemical properties of the nanoparticles obtained in this way compared to the previous OLF particles based only on albumin.
  • the oxygen carriers according to the invention (LENOX) are significantly smaller, less polydisperse and less cloudy than the previous OLF oxygen carriers (Fig. 1). They can be synthesized in particular with HSA as well as BSA and are stable in a larger temperature range (-20 to +100 °C).
  • the oxygen carriers according to the invention are long-term compatible with Ringer's solution, Sterofundin® ISO ( Figure 3), Ringerfundin®, STEEN solution, OCS solution and 6% HES (130/0.4) and can be used directly in these solutions synthesize stably.
  • Ringer's solution Sterofundin® ISO ( Figure 3)
  • Ringerfundin® Ringerfundin®
  • STEEN solution OCS solution
  • 6% HES 6% HES
  • the oxygen carriers according to the invention have very good properties in terms of stability, viscosity, particle size and oxygen release.
  • Figure 1 Viscosity curve of the OLF particles in comparison to the LENOX (example synthesis I, HSA).
  • Figure 2 Diameter (A) and polydispersion index (B) of the OLF particles compared to the LENOX (example synthesis I, HSA).
  • Figure 4 Diameter and polydispersion index of the OLF particles and the LENOX, synthesized in Sterofundin® ISO (example synthesis II).
  • FIG. 5 Microscopy images of OLF particles (state of the art) synthesized in Ringer solution (A), HES 6% (B) and Sterofundin® ISO (C).
  • the noisy background in images B and C suggests that these emulsions are destroyed.
  • the emulsion in image A is still intact, but shows particles > 1 pm.
  • the LENOX (example synthesis I, BSA) are not visible in the microscope because they are below the resolution limit (D).
  • the artifacts in image D are caused by residues on the Neubauer chamber and do not come from the emulsion drops.
  • Figure 7 Viscosity of the OLF particles and the LENOX (example synthesis II) before and after storage for 4 h at 37 °C.
  • perfluorodecalin HP F2 Chemicals, Lancashire, UK
  • Millipore water Q-Pod, Merck, Darmstadt, DE
  • albumin fraction V bovine serum albumin, Roth, Düsseldorf, DE
  • Albunorm human serum albumin, Octapharma, Langenfeld, DE
  • 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.
  • both the OLF particles and the LENOX were synthesized in different perfusion media (Ringer's solution, Sterofundin® ISO and HAES 6%).
  • Ringer's solution an intact emulsion was created with both the OLF particles and the LENOX.
  • the OLF particles were visible under a light microscope, whereas the LENOX particles were too small to be seen under a light microscope.
  • the OLF particles When synthesized in Ringer's solution, the OLF particles are significantly larger than the LENOX particles in the same medium. Strong background noise can be seen in the light microscope images of the OLF particles in HES 6% and in Sterofundin® ISO. This is a sign of a destroyed emulsion. This means that no stable OLF emulsions are formed in HES 6% and in Sterofundin® ISO.
  • LENOX are significantly smaller, less polydisperse and less cloudy than the OLF particles.
  • LENOX can be synthesized with both HSA and BSA.
  • LENOX are more stable at different temperatures (-20 to +100 °C).
  • LENOX are compatible with Ringer solution, Sterofundin® ISO, STEEN solution, OCS solution and HAES 6%, OLF particles show incompatible behavior (viscosity, stability, etc.) in many of these solutions.
  • the particle size distribution was determined by dynamic light scattering (DLS) with Nano-flex (Microtrac). The refractive indices were adopted from previous work. The high and low temperature viscosity was determined individually for each batch and each test. After a zero measurement for 300 s with water, 1 ml of the sample was filled into a 2 mL reaction vessel and measured three times for 300 s.
  • DLS dynamic light scattering
  • Nano-flex Microtrac
  • a rheometer (MCR 92, Anton Paar) was used to measure the shear rate-dependent viscosity.
  • the software internal calibration process was used to set up and calibrate the device. For the measurement, 1 mL of the sample was placed on the measuring table and the system was put into measuring mode. The system was heated to 20 °C and the viscosity was measured at different shear rates. Immediately after the first measurement, the system was heated to 37 °C and the measurement was repeated to determine the high-temperature viscosity.
  • Oxygen release was measured using an SDR SensorDish Reader (PreSens) under hypoxic conditions.
  • PreSens SDR SensorDish Reader
  • 0.5 ml of water or saline solution was prepared per well in a special 24-well plate equipped with oxygen sensors (OxoDish OD 24, PreSens). This plate was stored under a hypoxic workstation (Whitley H35) (1% O2, 5% CO2, 94% N2) until the oxygen level no longer changed.
  • 2.5 mL of the sample was transferred to a gas-tight flask and oxygenated with 100% O2 at a gas flow of 0.5 mL/min for 15 minutes.
  • 0.5 ml of the previously oxygenated sample was added to each well and the oxygen release was measured until the value returned to baseline.
  • Zeta potential The zeta potential was determined by stream potential measurement (Stabino Zeta, Microtrac). For the zeta potential measurements, 1 ml of the sample was filled into the specific volumetric flask and the flask was connected to the measuring system (Stabino, Microtrac). The sample was measured ten times for 10 s each and the results were averaged.
  • 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 preemulsion was then placed in the microfluidizer and the entire volume was processed seven times at a pressure of 20,000 PSI (approx. 1379 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
  • 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 (9,500 revolutions/min).
  • the preemulsion was then placed in the microfluidizer and the entire volume was processed seven times at a pressure of 20,000 PSI (approx. 1379 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
  • 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 ):
  • LENOX was stored upright in completely filled 2 mL reaction vessels at 4 °C. The emulsion was analyzed every 7 days for a period of 42 days. Each batch of LENOX was divided into six reaction vessels so that one closed vessel was used each day and the already opened vessels were discarded.
  • Viscosity (at 200 s' 1 )

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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.
PCT/EP2023/073579 2022-08-31 2023-08-29 Transporteurs d'oxygène à l'échelle nanométrique modifiés par la lécithine (lenox) WO2024046999A1 (fr)

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