WO1994006289A1 - Procede d'inactivation de microbes dans le sang au moyen de l'iode - Google Patents

Procede d'inactivation de microbes dans le sang au moyen de l'iode Download PDF

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Publication number
WO1994006289A1
WO1994006289A1 PCT/US1993/004279 US9304279W WO9406289A1 WO 1994006289 A1 WO1994006289 A1 WO 1994006289A1 US 9304279 W US9304279 W US 9304279W WO 9406289 A1 WO9406289 A1 WO 9406289A1
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Prior art keywords
iodine
plasma
serum
blood
solvent
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PCT/US1993/004279
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English (en)
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Edward Shanbrom
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Edward Shanbrom
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Publication date
Application filed by Edward Shanbrom filed Critical Edward Shanbrom
Priority to JP6500934A priority Critical patent/JPH06511016A/ja
Priority to EP93913807A priority patent/EP0622989A1/fr
Publication of WO1994006289A1 publication Critical patent/WO1994006289A1/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
    • A61L2/0082—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 chemical substances

Definitions

  • This invention relates to the treatment of biological fluids generally, including such human transfusion blood, serum and plasma and fractions and products thereof, an biological fluids used for diagnostic testing or the production of biologicals for diagnostic tests.
  • Iodine was officially recognized by the Pharmacopeia of the United States in 1930, also as tincture iodine (tincture of iodine) and linimentum iodi (liniment of iodine). Clinicians and microbiologists described a great number of experimental data and clinical applications. Despite the successes that have been achieved with iodine, it was ascertained early that it also possesses properties unsuitable for practical application.
  • iodine reacts with basic N-H functions that are parts of some amino acids (e.g., lysine, histidine, arginine) and the bases of nucleotides (adenine, cytosine, and guanine) forming the corresponding N-iododerivatives.
  • basic N-H functions that are parts of some amino acids (e.g., lysine, histidine, arginine) and the bases of nucleotides (adenine, cytosine, and guanine) forming the corresponding N-iododerivatives.
  • Iodine oxidizes the S-H group of the amino acid cysteine, through which the connections of protein chains by disulfide (-S-S-) bridges, as an important factor in the synthesis of proteins, are lost.
  • Iodine reacts with the phenolic group of the amino acid tyrosine, forming mono- or diiodo-derivatives.
  • Iodine - polymer complexes e.g., with poly(vinylpyrrolidone) (PVP), and complexes of iodine with nonionic surfactants, eg, polyethylene glycol mono(nonylphenyl) ether have been used with considerable success.
  • PVP poly(vinylpyrrolidone)
  • nonionic surfactants eg, polyethylene glycol mono(nonylphenyl) ether
  • use in direct contact with labile biological materials has been limited because either the killing power of iodine is dissipated in the biological material or damages the biological material.
  • Povidone iodine is capable, in certain circumstances, of killing all classes of pathogens encountered in nosocomial infections: gram-positive and gram-negative bacteria, mycobacteria, fungi, yeasts, viruses and protozoa. Most bacteria are killed within 15 to 30 seconds of contact.
  • Iodine is consumed by proteinaceous substrates and its efficacy as a disinfectant is reduced at certain antiseptic applications. This is due to a reducing effect of the material to be disinfected which leads to the conversion of iodine into non-bactericidal iodide. Thus, not only the reservoir of available iodine is diminished but also the equilibrium of triiodide is influenced as well. Both of these effects cause a decrease in the proportion of free molecular iodine, the actual anti-microbial agent.
  • povidone-iodine preparations are contaminated with liquid substrata, e.g.
  • Iodine is used widely in human medicine is the disinfection of skin,
  • Iodine preparations are also used for therapeutic purposes, e.g., the treatment of infected and burned skin but is a strong irritant. Iodophors largely overcome the irritation. Iodine has also been used for the disinfection of medical equipment, such as catgut, catheters, knife blades, ampules, plastic items, rubber goods, brushes, multiple-dose vials, and thermometers.
  • iodine as an aerial disinfectant has been advocated since 1926, and experiments on the disinfection of air have been carried out, mainly during World War II.
  • Aerial disinfection of air-raid shelters with iodine vapors as a prophylactic measure against influenza has been recommended and a "relatively tolerable" concentration of 0.1 mg/ft 3 (3.5 mg/m 3 ) was found to be sufficient for a rapid kill of freshly sprayed salivary organisms.
  • a "relatively tolerable" concentration of 0.1 mg/ft 3 (3.5 mg/m 3 ) was found to be sufficient for a rapid kill of freshly sprayed salivary organisms.
  • iodine vapors pose to the respiratory organs, documented by the fact that the maximum allowed concentration of iodine comes to 1.0 mg/m 3 '
  • oxidizing iodine including "compounds incorporating molecules of oxidizing iodine” e.g. absorbed or grafted on a purified vegetable carbon, as blood-contacting reagents having bactericidal and bacteriostatic action are mentioned in passing in connection with an autotransfuser device in U.S. Patent 4,898,572, Surugue nee Lasnier, et al but without any explanation or elucidation.
  • Iodine is, thus, an excellent, prompt, effective microbicide with a broad range of action that includes almost all of the important health-related microorganisms, such as enteric bacteria, enteric viruses, bacterial viruses, and protozoan cysts, if the sometimes severe limitations inherent in its use are overcome.
  • Mycobacteria and the spores of bacilli and clostridia can also be killed by iodine.
  • iodine also exhibits a fungicidal and trichomonacidal activity. As to be expected, varying amounts of iodine are necessary to achieve complete disinfection of the different classes or organisms.
  • iodine is the cysticide of choice because it does not produce side reactions that interfere with its disinfecting properties. Iodine would require the smallest mg/L dosage compared to chlorine or bromine to "break any water” to provide a free residual. I 2 is 2 to
  • Polyvinylpyrrolidone (PVP, Povidone) is manufactured by BASF Aktiengesellschaft, Unternehemens Buffalo Feincheme, D-6700 Ludwigshaven, Germany and sold under the trademark KOLIDON®. Povidone-iodine products and the preparation of such products are described in U.S. Patents 2,707,701, 2,826,532, and 2,900,305 to Hosmer and Siggia, assigned to GAF Corporation and in a number of GAF Corporation publications; see, e.g. Tableting with Povidone USP (1981) and PVP Polyvinylpyrrolidone (1982).
  • Patent No. 3,468,831 Barabas, et.al., 1969 - graft co-polymers of N-vinyl pyrrolidone; U.S. Patent No. 3,468,832, Barabas, et.al., 1969 - graft co- polymers of N-vinyl pyrrolidone; U.S. Patent No. 3,488,312, Barabas, et. al, 1970 - water-insoluble graft polymer-iodine complexes; U.S. Patent No. 3,689,438, Field, et. al., 1972 - cross-linked polymer-iodine manufacture; U.S. Patent No. 3,907,720, Field, et. al., 1975 - cross-linked polymer-iodine manufacture; U.S. Patent No. 4,017,407, Cantor, et. al., 1977 - solid N-vinyl-
  • 2-pyrrolidone polymer carriers for iodine U.S. Patent No. 4,128,633, Lorenz et al, 1978 - preparation of PVP-I complex; U.S. Patent No. 4,139,688, Dixon, 1979 - cross-linked vinylpyrrolidone; U.S. Patent No. 4,180,633, Dixon, 1979 - cross-linked vinylpyrrolidone; U.S. Patent No. 4,190,718, Lorenz, et.al., 1980 -increasing molecular weight of polyvinylpyrrolidone.
  • PVP polyvinyl urethane
  • the single most attractive property of PVP is its binding capability. This property has permitted utilization in numerous commercial applications. Small quantities of PVP stabilize aqueous emulsions and suspensions, apparently by its absorption as a thin layer on the surface of individual colloidal particles.
  • the single most widely studied and best characterized PVP complex is that of PVP-iodine. For example, hydrogen triiodide forms a complex with PVP that is so stable that there is no appreciable vapor pressure. It is superior to tincture of iodine as a germicide.
  • poloxamers i.e., polyether alcohols
  • iodine i.e., Prepodyne, Septodyne
  • the iodophors are available in a variety of forms, such as a 10% applicator solution, 2% cleansing solution (scrub), aerosol spray, aerosol foam, vaginal gel (for trichonomal and candidal infections) ointment powder, mouthwash, perineal wash, and whirlpool concentrate (all 2%).
  • iodophors may be used in this invention in some of its various uses and applications and, to the extent that the iodophor is effective and does not injure the material undergoing treatment, are considered generally as equivalents or potential equivalents of povidone iodine.
  • povidone-I 2 the growth of bacteria in blood and blood products at various stages of production and processing introduces pyrogens into the blood component or product which must be removed before the product can be used in therapy.
  • Introduction of molecular iodine, e.g. povidone-I 2 at an early stage in processing of blood products greatly reduces or eliminates the pyrogen-load of the ultimate product or fraction.
  • this invention is applicable to the treatment of donated blood, products produced from blood, and biological liquids for therapeutic use or the preparation of diagnostic materials, for inactivating virus, bacteria, chlamydia, rickettsia, mycoplasma and other potentially pathogenic microorganisms.
  • Iodine is added to the liquid biological sample to be freed of pathogenic microorganisms, a period of time, from a minute or two up to 24 hours or more, is permitted to elapse to permit the iodine and then the iodine is removed by separation from the biological fluid by solvent extraction or precipitation and filtration or centrifugation.
  • Safe transfusion blood, or blood substitute is manufactured by removing a substantial portion of blood plasma or serum from whole blood. In the case of plasma removal, a blood cell concentrate remains. If serum is separated directly from blood, cells from another unit of blood may be used.
  • the plasma or serum is passed into contact with a solid source of available oxidizing iodine for inactivating pathogenic microbes in the blood and for transferring an effective amount of oxidizing iodine, from about 0.01% by weight to five percent by weight, into the plasma or serum to inactivate pathogenic microbes in both the plasma or serum and in the blood cell concentrate.
  • the next step comprises reconstituting the whole blood by mixing the iodized plasma with the blood cell concentrate or reconstituting a blood substitute by mixing the iodized serum with the blood cell concentrate, the available oxidizing iodine in the plasma or serum being from about 0.01% to about five percent by weight of the serum and sufficient to inactivate substantially all pathogenic microbes in the blood cell concentrate.
  • viricidal and/or biocidal compounds may be added to the serum or to the reconstituted blood to enhance the viral inactivation and interfere with the virus replication in the cells.
  • the reconstituted blood is contacted with a solvent for iodine that has no effect or minimal effect on blood cells and the hydrophilic components of the blood.
  • a solvent for iodine that has no effect or minimal effect on blood cells and the hydrophilic components of the blood.
  • Normal alkane e.g. n-heptane
  • iodine that has been reduced to iodide will remain, largely, in the aqueous blood phase.
  • extraction solvents include analogous homolog of heptane and vegetable oils such as soy bean oil, cotton seed oil, corn oil, etc.
  • Any hydrophobic solvent for iodine that is essentially inert biologically and has sufficient density difference from water and respecting which water has a high enough interfacial tension to form a clean separation from the aqueous phase may be used as the solvent.
  • Iodine may also be removed by adding starch solution and removing the starch-iodine precipitate that forms, or by contacting the plasma with cross-linked povidone.
  • Safe transfusion plasma is manufactured by passing the plasma into contact with a solid source of available oxidizing iodine, or otherwise introducing oxidizing iodine into the plasma, for inactivating pathogenic microbes in the plasma and for transferring an effective amount of oxidizing iodine, from about 0.01% by weight to five percent by weight, into the plasma to activate pathogenic microbes in the plasma.
  • a solvent for iodine that has no effect or minimal effect on plasma and the hydrophilic components.
  • Normal alkane e.g. n-heptane, is a suitable extraction solvent for removing oxidizing iodine from the blood.
  • iodine that has been reduced to iodide will remain, largely, in the aqueous phase.
  • Other extraction solvents include analogous homolog of heptane and vegetable oils such as soy bean oil, cotton seed oil, corn oil, etc. Any hydrophobic solvent for iodine that is essentially inert biologically and has sufficient density difference from water and respecting which water has a high enough interfacial tension to form a clean separation from the aqueous phase may be used as the solvent.
  • Safe transfusion serum is manufactured by passing the serum into contact with a solid source of available oxidizing iodine, or otherwise introducing oxidizing iodine into the serum, for inactivating pathogenic microbes in the serum and for transferring an effective amount of oxidizing iodine, from about 0.01% by weight to five percent by weight, into the serum to activate pathogenic microbes in the serum.
  • a solvent for iodine that has no effect or minimal effect on serum and the hydrophilic components.
  • Normal alkane e.g. n-heptane, is a suitable extraction solvent for removing oxidizing iodine from the blood.
  • iodine that has been reduced to iodide will remain, largely, in the aqueous phase.
  • Other extraction solvents include analogous homolog of heptane and vegetable oils such as soy bean oil, cotton seed oil, corn oil, etc. Any hydrophobic solvent for iodine that is essentially inert biologically and has sufficient density difference from water and respecting which water has a high enough interfacial tension to form a clean separation from the aqueous phase may be used as the solvent.
  • plasma or other biological liquid can be freed of iodine by addition of starch solution containing dissolved starch in an amount sufficient to bind all of the added iodine or by contacting the plasma, serum or other liquid with solid, cross-linked polyvinyl povidone which adsorbs the iodine forming a PVP-iodine complex, then removing the solid cross-linked polyvinyl pyrrolidone, including the iodine complexed therewith.
  • the plasma is then contacted with a solid source of oxidizing iodine that holds the iodine loosely enough to permit some of the iodine to enter into the plasma.
  • a solid source of oxidizing iodine that holds the iodine loosely enough to permit some of the iodine to enter into the plasma.
  • One convenient way of carrying out the invention is to express plasma through a bed (filter) of polymer-iodine particles. This provides contact with a solid source of oxidizing iodine and helps effect a separation of the plasma from the cell concentrate. Any of several forms of solid povidone- iodine or other polymer-iodine complex is a suitable form of such iodine.
  • a unit of transfusion quality blood is separated into plasma and blood cell concentrate and the plasma is coagulated to produce serum.
  • This separation may be accomplished by compressing the blood through a filter to express a substantial amount of the plasma from the container leaving a blood cell concentrate, by centrifuging the blood lightly and decanting the plasma, or in any other way.
  • This step, separating a substantial amount of the plasma from the blood cell concentrate can be carried out using any convenient manipulation(s). It is not necessary that all of the plasma be separated; however, best results are achieved when substantially all of the plasma not interstitially trapped between the cells of the cell concentrate is removed. If two units of blood are available, one unit may be coagulated and the serum used to reconstitute blood substitute.
  • the serum is then contacted with a solid source of oxidizing iodine that holds the iodine loosely enough to permit some of the iodine to enter into the serum.
  • a solid source of oxidizing iodine Any of several forms of solid povidone-iodine or other polymer-iodine complex are suitable forms of such iodine.
  • Cross-linked povidone iodine and polymer- iodine complexes have been known for many years.
  • Solid polyvinylpyrrolidone-iodine complexes are described, inter alia, by: Barabas, et.al., 1969 - graft co-polymers of N-vinyl pyrrolidone; U.S. Patent No. 3,468,832; Barabas, et.al., 1969 - graft co-polymers of N-vinyl pyrrolidone; Barabas, et al., 1970, U.S. Patent No. 3,488,312 - water-insoluble graft polymer-iodine complexes; Field et al, 1972, U.S. Patent No. 3,689,438 - cross-linked polymer-iodine manufacture; Field, et. al., 1975 - U.S. Patent No.
  • the plasma and the blood cell concentrate are reconstituted to form whole blood or the serum and blood cell concentrate are reconstituted to form a blood substitute.
  • Residual iodine in the plasma, or serum is present in a sufficient amount, from 0.001 to five percent, typically from 0.1 to 1 percent, by weight, in the plasma, or serum, to kill or inactivate all extracellular virus in the blood cell concentrate and substantially all or all intracellular virus by penetration into the cell.
  • a brief reaction period is required after the reconstitution of the whole blood. A minimum of about two minutes is necessary, and at least about 15 minutes is desirable, before extracting iodine from the blood to permit the iodine to inactivate the pathogenic microbes in the blood.
  • the blood is then gently mixed with a solvent for iodine that is substantially inert to blood.
  • N-heptane is a good solvent for iodine and has minimal effect, on short exposure, to blood and blood cells. Close n-alkane analogs and vegetable oils may also be used.
  • Soy bean oil, cotton seed oil, corn oil, etc. are generally biologically inert as to blood and blood cells and are also suitable solvents for iodine.
  • the solvent extraction may be carried out in any suitable vessel that will permit intimate mixing of the blood and solvent and decantation of the hydrophobic phase from the top or withdrawal of the blood from the bottom.
  • the blood substitute may be contacted with solid particles of cross-linked povidone which complexes with the iodine.
  • the particles are removed by a suitable filter, settling or mild centrifugation. The process results in transfusion quality whole blood that is safe, being free of pathogenic microbes, and which is also free of any added chemicals except for iodide (resulting from reduction of the iodine).
  • reducing substances e.g. reducing sugars, ascorbic acid or ascorbate, sodium sulfite, etc.
  • biologically compatible reducing substances e.g. reducing sugars, ascorbic acid or ascorbate, sodium sulfite, etc.
  • reducing sugars e.g. reducing sugars, ascorbic acid or ascorbate, sodium sulfite, etc.
  • the present invention therefore, obviates objections to the introduction of povidone or other polymeric substances into the blood stream of the patient. Blood Plasma.
  • Serum and Other Biological Liquids Plasma, serum, or other biological liquid is, preferably, passed through a filter or column that constitutes a solid source of oxidizing iodine that holds the iodine loosely enough to permit some of the iodine to enter into the liquid. Any other means of introducing oxidizing iodine into the liquid with introduction of undesirable carriers or other liquids may be used as well. Any of several forms of solid povidone-iodine or other polymer-iodine complex is a suitable form of such iodine. Cross-linked povidone iodine and polymer-iodine complexes as described above are quite suitable.
  • plasma, serum or other biological liquid can be freed of iodine by addition of starch solution containing dissolved starch in an amount sufficient to bind all of the added iodine.
  • Iodine that has not been reduced, I 3 binds very firmly to starch, forming a blue precipitate that can be separated by filtration or centrifugation from the liquid.
  • the starch- iodine complex retains iodine's biocidal properties.
  • the same procedure can be used, somewhat less satisfactorily, with reconstituted blood; however, the blood must be reconstituted using the cell-containing fractions after centrifugation.
  • the blood substitute may be contacted with solid particles of cross-linked povidone which complexes with the iodine. The particles are removed by a suitable filter, settling or mild centrifugation.
  • the process results in plasma, serum, or other biological fluid, that is safe, being free of pathogenic microbes, and which is also free of any added chemicals except for iodide (resulting from reduction of the iodine).
  • reducing substances e.g. reducing sugars, ascorbic acid or ascorbate, sodium sulfite, etc.
  • Pathogenic microbes include virus, bacteria, chlamydia, rickettsia, mycoplasma and other potentially pathogenic microorganisms.
  • This invention is useful in the preparation of safe transfusion blood and biological liquids.

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Abstract

Procédé de préparation de fluides biologiques sûrs, consistant à ajouter de l'iode oxydant au fluide biologique, à maintenir le fluide suffisamment longtemps pour permettre l'inactivation des microbes pathogènes, et à extraire ou précipiter l'iode oxydant restant à partir du fluide.
PCT/US1993/004279 1992-05-04 1993-05-04 Procede d'inactivation de microbes dans le sang au moyen de l'iode WO1994006289A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
JP6500934A JPH06511016A (ja) 1992-05-04 1993-05-04 安全な生物流体
EP93913807A EP0622989A1 (fr) 1992-05-04 1993-05-04 Procede d'inactivation de microbes dans le sang au moyen de l'iode

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US87819492A 1992-05-04 1992-05-04
US07/878,194 1992-05-04

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WO1994006289A1 true WO1994006289A1 (fr) 1994-03-31

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5591350A (en) * 1994-04-15 1997-01-07 Pall Corporation Iodine disinfection method using a gaseous iodine treated porous medium
US6096216A (en) * 1994-06-09 2000-08-01 American National Red Cross Iodinated matrices for disinfecting biological fluids
US6106773A (en) * 1998-09-24 2000-08-22 American National Red Cross Pathogen inactivating compositions for disinfecting biological fluids
WO2024023572A1 (fr) * 2022-07-29 2024-02-01 Romano Laboratory Srls Sang enrichi en iode moléculaire, son procédé de préparation et ses utilisations

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4909940A (en) * 1987-12-30 1990-03-20 New York Blood Center, Inc. Extraction of process chemicals from labile biological mixtures with organic alcohols or with halogenated hydrocarbons

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4909940A (en) * 1987-12-30 1990-03-20 New York Blood Center, Inc. Extraction of process chemicals from labile biological mixtures with organic alcohols or with halogenated hydrocarbons

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
F.A. COTTON and G.W. WILKINSON, "Advanced Inorganic Chemistry", published 1966 by Interscience Publishers (NY), pages 555-556, see entire document. *
Journal of Applied Bacteriology, Volume 46, issued 1979, R.W. LACEY, "Antibacterial Activity of Povidone Iodine Towards Non-Sporing Bacteria", pages 443-446, especially pages 447 and 448. *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5591350A (en) * 1994-04-15 1997-01-07 Pall Corporation Iodine disinfection method using a gaseous iodine treated porous medium
US6096216A (en) * 1994-06-09 2000-08-01 American National Red Cross Iodinated matrices for disinfecting biological fluids
US6106773A (en) * 1998-09-24 2000-08-22 American National Red Cross Pathogen inactivating compositions for disinfecting biological fluids
WO2024023572A1 (fr) * 2022-07-29 2024-02-01 Romano Laboratory Srls Sang enrichi en iode moléculaire, son procédé de préparation et ses utilisations

Also Published As

Publication number Publication date
EP0622989A1 (fr) 1994-11-09
JPH06511016A (ja) 1994-12-08

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