WO2023130850A1 - Procédé de traitement d'inactivation de pathogènes du plasma fondé sur un procédé photochimique de riboflavine - Google Patents

Procédé de traitement d'inactivation de pathogènes du plasma fondé sur un procédé photochimique de riboflavine Download PDF

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Publication number
WO2023130850A1
WO2023130850A1 PCT/CN2022/133877 CN2022133877W WO2023130850A1 WO 2023130850 A1 WO2023130850 A1 WO 2023130850A1 CN 2022133877 W CN2022133877 W CN 2022133877W WO 2023130850 A1 WO2023130850 A1 WO 2023130850A1
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WO
WIPO (PCT)
Prior art keywords
bag
riboflavin
plasma
light
pathogen inactivation
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PCT/CN2022/133877
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English (en)
Chinese (zh)
Inventor
潘维超
王艺玮
何琴玲
肖国锋
周军
李郑
胡政芳
潘庆
赵婷
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南京双威生物医学科技有限公司
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Publication of WO2023130850A1 publication Critical patent/WO2023130850A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2/00—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor
    • A61L2/0005—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor for pharmaceuticals, biologicals or living parts
    • A61L2/0011—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor for pharmaceuticals, biologicals or living parts using physical methods
    • A61L2/0029—Radiation
    • A61L2/0047—Ultraviolet radiation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2202/00—Aspects relating to methods or apparatus for disinfecting or sterilising materials or objects
    • A61L2202/20—Targets to be treated
    • A61L2202/22—Blood or products thereof

Definitions

  • the invention relates to the technical field of pathogen inactivation of blood components, in particular to a plasma pathogen inactivation treatment method based on riboflavin photochemical method.
  • S/D method organic solvent/detergent mixture method
  • methylene blue photochemical method methylene blue photochemical method
  • psoralen photochemical method riboflavin photochemical method.
  • studies have confirmed that: the S/D method is ineffective against non-lipid enveloped viruses; the inactivation effect of methylene blue photochemical method on non-lipid enveloped viruses is inconsistent, and may cause long-term side effects clinically; psoralen has potential toxicity.
  • riboflavin photochemical method is: the riboflavin structure of riboflavin can make it bind to the DNA or RNA nucleic acid chain, under the irradiation of ultraviolet light, absorb the energy of photons, and pass through the 1,10 positions on the isoalloxazine
  • the reversible redox reaction of nitrogen atoms transfers electrons, which breaks the guanine residues on the nucleic acid chain, resulting in changes in the structure of the nucleic acid chain of the pathogen, causing the pathogen to lose its replication activity, destroying the nucleic acid or preventing the replication and transcription of the nucleic acid.
  • Non-enveloped viruses, intracellular viruses, bacteria and protozoa can be effectively inactivated, and the virus inactivation spectrum is quite wide.
  • the riboflavin product after light irradiation is the same as its normal metabolite in the human body, and what is produced is only the protein derivative produced by the combination of photochromant and protein with riboflavin, without distortion and mutagenesis.
  • the results of clinical toxicity test prove that riboflavin and its light products have not found any toxic reaction in in vivo and in vitro models.
  • riboflavin photochemically inactivates pathogens in a wide range is safe and non-toxic, and the protein in plasma after treatment is stable, it has been widely studied and applied, especially in the field of biomedicine. Therefore, it is very necessary to design and develop a treatment method and a corresponding treatment system for riboflavin photochemical inactivation of plasma pathogens to meet the market demand for such products.
  • the present invention provides a plasma pathogen inactivation treatment method based on the riboflavin photochemical method.
  • the technical scheme adopted in the present invention is as follows: a plasma pathogen inactivation treatment method based on riboflavin photochemical method, the plasma added with riboflavin medicinal liquid is irradiated under narrow-band ultraviolet light within the wavelength range of 300-308nm, The light energy is calculated as 0.55 ⁇ 0.65J/mL, and the overall thickness of the light bag containing plasma is not greater than 9.5mm during the light.
  • Step S1. Prepare riboflavin medicinal solution
  • Step S2 The plasma is mixed with the riboflavin solution, and transferred to the light bag;
  • Step S3. Irradiating the light bag under narrow-band ultraviolet light
  • Step S4 Transfer the plasma in the light bag to the blood storage bag.
  • step S1 is specifically as follows: sieve the riboflavin raw material drug under the condition of avoiding light, add it into physiological saline, heat it in a water bath until it is completely dissolved, and prepare a riboflavin drug solution with a concentration of 450-550 ⁇ mol/L.
  • step S2 is specifically:
  • Step S2.1 Add the riboflavin medicinal solution to the medicinal solution bag for shading treatment;
  • Step S2.2 Connect the original blood bag, drug solution bag and light bag in sequence
  • Step S2.3 Turn on the switch on the catheter, so that the plasma in the original blood bag enters the drug solution bag under the action of gravity, mixes with the riboflavin drug solution in the drug solution bag, and further enters the light bag.
  • step S2 the leukocyte filtration operation is performed before the blood plasma is mixed with the riboflavin liquid.
  • step S3 is specifically:
  • Step S3.1 Heat sealing to remove the liquid medicine bag and the corresponding catheter, if there is a white blood cell filter component on the catheter, heat sealing and removal;
  • Step S3.2 Place the light bag under narrow and wide ultraviolet light with a wavelength range of 300-308nm for 10-40 minutes, and the power of the ultraviolet lamp is 40W.
  • the riboflavin drug solution is stored in a drug solution bag, and the drug solution bag is made of a calendered film or a three-layer co-extruded film.
  • the drug solution bag stores 30-40 mL of riboflavin drug solution with a concentration of 450-550 ⁇ mol/L, and the light-emitting bag can hold 1-2 units of plasma.
  • a light-shielding bag is arranged outside the medicine solution bag, and the medicine solution bag, the light-emitting bag and the blood storage bag are sequentially connected to form a joint bag.
  • a white blood cell filter assembly is provided on the catheter of the medical solution bag used to connect to the original blood bag.
  • the overall thickness of the light bag is controlled within 9.5mm, which can improve the light performance and ensure the inactivation effect of pathogens, further reduce the light energy demand and reduce the damage to blood components;
  • the bag can also be equipped with a white blood cell filter to remove white blood cells and protein precipitates in the plasma, so that it can be applied to cryoprecipitated plasma.
  • Fig. 1 is a flow chart of the plasma pathogen inactivation treatment method according to the embodiment of the present invention.
  • Fig. 2 is a schematic diagram of a joint bag in an embodiment of the present invention.
  • Fig. 3 is a schematic diagram of another joint bag in the embodiment of the present invention.
  • Liquid medicine bag 1 shading bag 101; light bag 2; blood storage bag 3; leukocyte filter assembly 4, filter 401, bypass 402, stop clamp 3; catheter 5; catheter 2; catheter 3 7; Puncture needle 8; Blind-end catheter 9; No. 1 frangible part 10; No. 2 frangible part 11;
  • FIG. 1 it is a flowchart of a plasma pathogen inactivation treatment method based on riboflavin photochemical method, and the specific steps are as follows.
  • Step S1. Prepare riboflavin medicinal solution.
  • riboflavin raw material drug was sieved under the condition of avoiding light, added into physiological saline, heated in a water bath until completely dissolved, and prepared into a riboflavin drug solution with a concentration of 500 ⁇ mol/L.
  • riboflavin physiological saline solution has the advantages of isotonicity with human body, good uniformity, strong stability, and convenient mixing with blood plasma.
  • Step S2 The plasma is mixed with the riboflavin drug solution, and transferred to the light-emitting bag 2 .
  • Step S2.1 Add the riboflavin drug solution to the drug solution bag 1 for light-shielding treatment.
  • Step S2.2 Connect the original blood bag, the drug solution bag 1 and the light bag 2 in sequence.
  • Step S2.3 Open the switch on the catheter (such as a frangible piece), the plasma in the original blood bag enters the drug solution bag 1 under the action of gravity, mixes with the riboflavin drug solution in the drug solution bag 1, and further Enter the light bag 2.
  • the switch on the catheter such as a frangible piece
  • the liquid medicine bag 1 and the illumination bag 2 use calendered films with good biocompatibility, and the medicine liquid bag 1 can also use a three-layer co-extruded film.
  • the liquid medicine bag 1 has a volume of 35mL and requires good airtightness. It is packaged with a light-shielding bag 101 outside to avoid light exposure.
  • the light-shielding bag 101 can be made of aluminum foil, tin foil or metal-plastic composite material; the volume of the light-shielding bag 2 can accommodate 1 ⁇ 2 units of plasma is appropriate, and good light transmittance and airtightness are required.
  • the thickness of the material of the light bag 2 is 0.38mm. During the light treatment, the overall thickness of the light bag 2 after being spread out (ie, the light thickness) is required to be no more than 9.5mm, so as to facilitate the penetration of ultraviolet rays and improve the inactivation effect.
  • the plasma pathogen inactivation treatment method of the present embodiment adopts a combined bag, specifically as shown in Figure 2, the combined bag is composed of No. 1 catheter 5, medicinal solution bag 1, No. 7 and the blood storage bag 3 are sequentially connected to form.
  • the pre-prepared riboflavin drug solution is stored in the drug solution bag 1, and the end of the first catheter 5 away from the drug solution bag 1 is provided with a puncture needle 8 (or blind-end catheter 9), and the inlet and outlet of the drug solution bag 1 are respectively
  • a No. 1 easy-break piece 10 and a No. 2 easy-break piece 11 are provided, and a No. 1 flow-stop clip 12 and a No. 2 flow-stop clip 13 are respectively arranged on the No. 2 conduit 6 and the No. 3 conduit 7 .
  • step 2 The specific operation of step 2 is as follows: connect the puncture needle 8 (or blind-end catheter 9) to the original blood bag (not shown in Figure 2), open the No. Enter the drug solution bag 1 through the puncture needle 4 (or the blind end 5 after aseptic connection) and the No. 1 catheter 5, and at the same time open the No. 2 frangible part 11 at the outlet of the drug solution bag 1 to mix the plasma of the riboflavin drug solution That is, it enters the light bag 2 by gravity. It can be seen that the addition of riboflavin liquid medicine can be completed automatically by using this kind of joint bag, which saves the link of aseptic connection, which not only saves cost, but also reduces the risk of contamination.
  • the white blood cell filter assembly 4 is arranged on the No. 1 catheter 5 and before the medical solution bag 1, and is composed of a filter 401 and a bypass 402, and a No. 3 stop clamp 403 is arranged on the bypass 402.
  • the leukocyte filter assembly 4 can not only remove leukocytes in plasma, but also be suitable for cryoprecipitating plasma to remove protein precipitation and ensure plasma quality.
  • Step 3 Put the light bag 2 under narrow-band ultraviolet light for irradiation.
  • Step 3.1 Heat sealing to remove the drug solution bag 1 and the second catheter 6, if there is a white blood cell filter assembly 4, also remove it.
  • Step 3.2 Flatten the light bag 2, place it under a narrow and wide ultraviolet light with a wavelength range of 300-308nm and a peak of 308nm, and irradiate for 25 minutes, with the power of the ultraviolet lamp tube at 40W.
  • the peaks of ultraviolet light with the best inactivation effect on plasma pathogens are 254nm, 313nm, and 365nm.
  • the ultraviolet light used to inactivate plasma pathogens is mostly broad-spectrum ultraviolet light, and the light energy used is 6.57J/ml, where the light energy is defined by the irradiation energy and the blood volume.
  • Table 1 shows the inactivation effects of different spectra and light energy on Escherichia coli
  • Table 2 shows the inactivation effects of 308nm narrow-band ultraviolet light on different viruses.
  • Virus 308nm Regular broad-spectrum UV light E. coli 4.9 4.3 Phage 2.1 2.35 Hepatitis C virus (HCV) >2.0 3.15 Encephalomyocarditis virus (EMCV) >5.0 3.15 Hepatitis B virus (HBV) >3.15 2.35 Vesicular stomatitis virus (VSV) >4.9 the
  • narrow-band ultraviolet light with a wavelength of 300-308nm, especially a wavelength of 308nm has a good effect on the inactivation of plasma pathogens, can reduce the demand for light energy, increase the inactivation effect, and reduce the loss of plasma components. less.
  • Step 4 Transfer the plasma in the light exposure bag 2 to the blood storage bag 3 .

Abstract

Est divulgué dans la présente invention, un procédé de traitement d'inactivation de pathogènes du plasma fondé sur un procédé photochimique de riboflavine, comprenant : le placement du plasma additionné de riboflavine sous une lumière ultraviolette à spectre étroit dans la plage de longueurs d'onde de 300 à 308 nm pour une irradiation, l'énergie d'éclairage étant comprise entre 0,55 et 0,65 J/ml, et l'épaisseur totale d'une poche d'éclairage pendant l'éclairage n'étant pas supérieure à 9,5 mm. Selon la présente invention, des rayons ultraviolets à spectre étroit ayant une longueur d'onde spécifique et une condition d'énergie d'éclairage spécifique étant sélectionnés pour effectuer un traitement sur le plasma auquel est ajouté un médicament liquide à base de riboflavine, et toute l'épaisseur de la poche d'éclairage pendant l'éclairage étant régulée pour être à moins de 9,5 mm, et ainsi, la présente invention a un bon effet d'inactivation de pathogènes, et présente peu de dommages sur les constituants du sang ; la poudre de riboflavine est dissoute à l'aide d'une solution saline normale, de telle sorte que le médicament liquide est isotonique pour le corps humain, et le médicament liquide présente une bonne uniformité, une stabilité élevée et est pratique à préparer ; une poche combinée, formée par combinaison d'une poche de médicament liquide, de la poche d'éclairage et d'une poche de stockage de sang est utilisée, de telle sorte qu'une connexion stérile dans un procédé existant est omise, le coût est réduit, et le risque de pollution est réduit ; et la poche combinée est en outre pourvue d'un filtre de leucocytes servant à éliminer les leucocytes et les précipités de protéines dans le plasma, de telle sorte que le procédé peut être approprié pour la cryoprécipitation du plasma.
PCT/CN2022/133877 2022-01-10 2022-11-24 Procédé de traitement d'inactivation de pathogènes du plasma fondé sur un procédé photochimique de riboflavine WO2023130850A1 (fr)

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CN202210020012.5A CN114366831A (zh) 2022-01-10 2022-01-10 一种基于核黄素光化学法的血浆病原体灭活处理方法
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