Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
  • G01N23/00—Investigating or analysing materials by the use of wave or particle radiation, e.g. X-rays or neutrons, not covered by groups G01N3/00 – G01N17/00, G01N21/00 or G01N22/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
  • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
  • A61K35/14—Blood; Artificial blood
  • A61K35/16—Blood plasma; Blood serum
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
  • A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
  • A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
  • A61K41/0071—PDT with porphyrins having exactly 20 ring atoms, i.e. based on the non-expanded tetrapyrrolic ring system, e.g. bacteriochlorin, chlorin-e6, or phthalocyanines
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
  • A61K41/10—Inactivation or decontamination of a medicinal preparation prior to administration to an animal or a person
  • A61K41/17—Inactivation or decontamination of a medicinal preparation prior to administration to an animal or a person by ultraviolet [UV] or infrared [IR] light, X-rays or gamma rays
• • 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—Disinfection or sterilisation of materials or objects, in general; Accessories therefor
  • A61L2/02—Disinfection or sterilisation of materials or objects, in general; Accessories therefor using physical processes
• • 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—Disinfection or sterilisation of materials or objects, in general; Accessories therefor
  • A61L2/02—Disinfection or sterilisation of materials or objects, in general; Accessories therefor using physical processes
  • A61L2/08—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
  • A61L2/00—Disinfection or sterilisation of materials or objects, in general; Accessories therefor
  • A61L2/02—Disinfection or sterilisation of materials or objects, in general; Accessories therefor using physical processes
  • A61L2/08—Radiation
  • A61L2/10—Ultraviolet [UV] radiation
• • 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
• • 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
• • 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
  • A61L2103/00—Materials or objects being the target of disinfection or sterilisation
  • A61L2103/05—Living organisms or biological materials

Definitions

• the invention relates to a method for inactivating pathogens such as bacteria and viruses in donor blood (blood), blood plasma (plasma) and / or packed red blood cells (EKs) by photodynamic treatment and / or irradiation with ultraviolet light.
• pathogens such as bacteria and viruses in donor blood (blood), blood plasma (plasma) and / or packed red blood cells (EKs)
• the principle is based on exposing the product in question in the presence of a photoactive substance (a photosensitizer).
• a photosensitizer a photoactive substance
• the incident light must contain a wavelength range which can be absorbed by the photosensitizer and activated by it.
• the absorbed energy is transferred either directly to the target structure in question (e.g., the nucleic acid or surface proteins of a virus), which is thereby destroyed, or to dissolved oxygen molecules which are thereby activated. It produces singlet oxygen, which has a pronounced virucidal and bactericidal activity.
• the photosensitizer used has a high affinity for essential components of viruses and other pathogens, eg for their nucleic acids and little or no for the components of the preparation to be decontaminated.
• the pathogens are inactivated while maintaining product activity.
• the photosensitizer for the treatment of plasma for example, the phenothiazine dye methylene blue is described; Riboflavin (vitamin B2) is used for the decontamination of platelet concentrates and phthalocyanines have been tested for the decontamination of EKs.
• methods for photodynamic pathogen inactivation in EKs have not been beyond the laboratory scale. This is even more true for blood itself.
• UV light i. in the wavelength range between about 200 and 320 nm, in particular 200 to less than 300 nm (UVB and UVC) can also inactivate pathogens. Above 320 nm, the energy of the radiation is too low to inactivate microorganisms and viruses.
• UVB and UVC short-wave ultraviolet
• the mere irradiation with UV light basically has the advantage of being effective on its own and does not require the addition of reactive chemicals or photoactive substances.
• UVC ultraviolet C
• protein-containing solutions such as plasma or turbid suspensions (for example blood and EKs)
• turbid suspensions for example blood and EKs
• UVC was used during and shortly after World War II to sterilize plasma and albumin solutions, especially to inactivate hepatitis viruses.
• the solution was passed in a flow-through apparatus as a thin film past a UVC light source.
• the method proved to be insufficiently safe and was abandoned (Kallenbach NR, Cornelius PA, Negus D, et al., Inactivation of Virus by Ultraviolet Light, Curr., Stud Hematol., Blood Transfus, 1989, 56, 70-82).
• UVB is also microbicidal and virucidal, although not to the same extent as UVC. It penetrates proteinaceous solutions and turbid suspensions slightly better than UVC, but its penetration depth, e.g. in plasma, even in the range of a few millimeters.
• Plasma and ECs are usually isolated from individual blood donations, or obtained by mechanical apheresis of individual donors.
• the volume of the preparations is generally between approximately 200 and 350 ml.
• the volume of blood donations is usually ml between 450 and 500.
• the preparations are in flat plastic bags generally either deep frozen (plasma) or at about 4 0 C (blood donations EKs) stored.
• the preparations ie donor blood (blood), blood plasma (plasma) and / or packed red blood cells (EKs) are suitably moved in their exposure bags so that a constant circulation of the samples takes place in the container.
• the movement takes place so violently that, within the liquid or suspension, regions form layers which are so thin that they can be penetrated by the light used.
• the movement must simultaneously be such that the liquid or suspension in the bag is effectively mixed. Both are realized if the following conditions are met: 1.
• the captioning references are highly flexible, and they are not fixed during the exposure, eg not trapped between glass or quartz plates. They thus adapt to the change in shape of the plasma or the suspension (blood, EK), which results when the bags are moved.
• the exposure bags are filled to a maximum of 30%, in particular to a maximum of 15%, of the maximum filling volume.
• the exposure bag is in the lying filled state only a few mm thick, for example, less than 10 mm, preferably less than 5 mm and is determined sample volumes of eg Take 200 to 500 ml.
• the maximum capacity (volume) of the exposure bag is at least a factor of 3, usually at least 6.66 times greater, preferably at least 10 or even at least 20 times greater than the actual sample volume contained in it.
• the experiments described illustrate the effectiveness of the method and are not limited to the inactivation of said viruses. There is also no restriction on the plasmas or ECs used in the experiments described, which originated from blood donations; the method according to the invention is also applicable to preparations which are prepared in another way. All experiments described were carried out three to six times. The results given in each case represent the average values from these experiments.
• the plasma units used and the EKs were produced from individual blood donations by means of conventional methods. They had a volume of about 250 to 300 or up to 350 ml and were stored in conventional plastic bags for blood preparations. Residual leukocytes or platelets were removed by filtration. The EKs were suspended in the stabilizer medium SAG-M. The plasmas were stored at temperatures below -30 ° C and thawed for the experiments in a water bath. The EKs were stored at 4 to 8 ° C in the cold room.
• VSV vesicular stomatitis virus
• ATCC VR-68 Sinbis virus
• SHV-I suicide herpesvirus
• TCID 50 Tissue Culture Infective Dose
• Vero cells served as indicator cells. The initial virus concentration in the experiments carried out was about 10 5 to 10 7 TCID 50 .
• One of the exposure systems used was equipped with tubes emitting UVC light (wavelength: 254 nm). Irradiation was from both sides of the applied bag, i. from above and below.
• a second exposure equipment was equipped with tubes emitting UVB light (280-320 nm). The irradiation also took place from both sides.
• a third exposure system was equipped with LEDs (light-emitting diodes) emitting intense red light in the wavelength range around 635 nm. All three systems were placed in operation on an orbital shaker (manufacturer company Bühler, Tübingen, type SM 25) which performed up to 100 revolutions per minute.
• the exposure bags used were made of thin UV-permeable and highly flexible plastic film.
• Plasma units in exposure bags were felt with VSV and exposed to UVC for 2 min.
• a sample was shaken at 100 rpm and was firmly clamped between two quartz plates during the irradiation.
• the other samples were only on a quartz plate so that they could move within the bag during pouring.
• the speed of the shaker was varied between 30 and 100 rpm.
• the results are summarized in Tab. 1. In the tightly clamped sample, the virus titer was only reduced by a factor of about 0.3 log 10 .
• the speed had a direct influence on the extent of virus inactivation: while at 30 and 50 rpm, respectively, the inactivation factors were only about 1.1 and 2.4 log 10 , respectively, compared to the untreated control samples 75 rpm to about 5.1 and at 100 rpm to about 6.6 log 10 at.
• the results of this experiment demonstrate that plasma must be shaken vigorously during treatment in order for the UV light to be effective. However, in order for the shaking effect to have an effect, the samples must be placed loosely so that thin layers are formed during shaking, which can be irradiated.
• Plasma units were spiked with VSV, Sindbis virus or SHV-I and irradiated for 1-5 min.
• the loosely placed samples on the orbital shaker were moved at 100 rpm.
• Control samples were irradiated for 5 minutes but not shaken.
• the results of the experiments are summarized in Tab. In the shaken samples, the titer of VSV was depleted by a factor of more than 6.5 logio within 3 min, while the inactivation factor in the unshaken control did not exceed 1.5 log.
• Sindbis viruses were found to be more stable than VSV; but the great difference between shaken and unshaken samples was also evident here: After a radiation time of 5 min, the virus titer in the shaken sample had decreased by about 5.1 logio, in the unshaken sample only by 0.30 logio.
• Inactivation of VSV in plasma by irradiation with UVB inactivation kinetics Plasma units were spiked with VSV and irradiated for 1 to 5 min. The loosely placed samples on the orbital shaker were moved at 100 rpm. A control sample was irradiated for 5 minutes but not shaken. As is clear from the Tab. 3 indicates the virus titer was depleted min by a factor of 6.36 logio within 5 in the shaken samples in the unshaken control sample by only about 1.5 logi 0th The results show that the phenomenon discovered - the increase in pathogen inactivation in loosely placed samples by vigorous shaking - is not limited to UVC.
• Plasma units were spiked with VSV, added with 0.25 ⁇ M / L of the photosensitizer methylene blue (MB) and irradiated on the orbital shaker at a speed of 100 rpm for up to 30 min with red LED light. Control samples were exposed in the presence of the same concentration of MB for 20 minutes, but did not move while. As Table 4 shows, the level of viral inactivation was much greater in the shaken than in the unshaken samples. In the latter, the virus titer had decreased by a factor of about 4.4 logio after 20 min; After 30 minutes, about 5.8 10g 10 . In the still samples, the reduction factor after 20 minutes was not higher than about 2.7 log 10 .
• MB photosensitizer methylene blue

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